Jan Erik Nordrehaug

Coronary artery bypass surgery versus percutaneous coronary intervention with stent implantation in patients with multivessel coronary artery disease (the Stent or Surgery trial): a randomised controlled trial

BACKGROUND: Results of trials, comparing percutaneous transluminal coronary angioplasty (PTCA) with coronary artery bypass grafting (CABG), indicate that rates of death or myocardial infarction are similar with either treatment strategy. Management with PTCA is, however, associated with an increased requirement for subsequent, additional revascularisation. Coronary stents, used as an adjunct to PTCA, reduce restenosis and the need for repeat revascularisation. The aim of the Stent or Surgery (SoS) trial was to assess the effect of stent-assisted percutaneous coronary intervention (PCI) versus CABG in the management of patients with multivessel disease. METHODS: In 53 centres in Europe and Canada, symptomatic patients with multivessel coronary artery disease were randomised to CABG (n=500) or stent-assisted PCI (n=488). The primary outcome measure was a comparison of the rates of repeat revascularisation. Secondary outcomes included death or Q-wave myocardial infarction and all-cause mortality. Analysis was by intention to treat. FINDINGS: All patients were followed-up for a minimum of 1 year and the results are expressed for the median follow-up of 2 years. 21% (n=101) of patients in the PCI group required additional revascularisation procedures compared with 6% (n=30) in the CABG group (hazard ratio 3.85, 95% CI 2.56-5.79, p<0.0001). The incidence of death or Q-wave myocardial infarction was similar in both groups (PCI 9% [n=46], CABG 10% [n=49]; hazard ratio 0.95, 95% CI 0.63-1.42, p=0.80). There were fewer deaths in the CABG group than in the PCI group (PCI 5% [n=22], CABG 2% [n=8]; hazard ratio 2.91, 95% CI 1.29-6.53, p=0.01). INTERPRETATION: The use of coronary stents has reduced the need for repeat revascularisation when compared with previous studies that used balloon angioplasty, though the rate remains significantly higher than in patients managed with CABG. The apparent reduction in mortality with CABG requires further investigation.BACKGROUND Results of trials, comparing percutaneous transluminal coronary angioplasty (PTCA) with coronary artery bypass grafting (CABG), indicate that rates of death or myocardial infarction are similar with either treatment strategy. Management with PTCA is, however, associated with an increased requirement for subsequent, additional revascularisation. Coronary stents, used as an adjunct to PTCA, reduce restenosis and the need for repeat revascularisation. The aim of the Stent or Surgery (SoS) trial was to assess the effect of stent-assisted percutaneous coronary intervention (PCI) versus CABG in the management of patients with multivessel disease. METHODS In 53 centres in Europe and Canada, symptomatic patients with multivessel coronary artery disease were randomised to CABG (n=500) or stent-assisted PCI (n=488). The primary outcome measure was a comparison of the rates of repeat revascularisation. Secondary outcomes included death or Q-wave myocardial infarction and all-cause mortality. Analysis was by intention to treat. FINDINGS All patients were followed-up for a minimum of 1 year and the results are expressed for the median follow-up of 2 years. 21% (n=101) of patients in the PCI group required additional revascularisation procedures compared with 6% (n=30) in the CABG group (hazard ratio 3.85, 95% CI 2.56-5.79, p<0.0001). The incidence of death or Q-wave myocardial infarction was similar in both groups (PCI 9% [n=46], CABG 10% [n=49]; hazard ratio 0.95, 95% CI 0.63-1.42, p=0.80). There were fewer deaths in the CABG group than in the PCI group (PCI 5% [n=22], CABG 2% [n=8]; hazard ratio 2.91, 95% CI 1.29-6.53, p=0.01). INTERPRETATION The use of coronary stents has reduced the need for repeat revascularisation when compared with previous studies that used balloon angioplasty, though the rate remains significantly higher than in patients managed with CABG. The apparent reduction in mortality with CABG requires further investigation.

Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography: a randomized controlled trial.

CONTEXT Observational studies have reported associations between circulating total homocysteine concentration and risk of cardiovascular disease. Oral administration of folic acid and vitamin B(12) can lower plasma total homocysteine levels. OBJECTIVE To assess the effect of treatment with folic acid and vitamin B(12) and the effect of treatment with vitamin B(6) as secondary prevention in patients with coronary artery disease or aortic valve stenosis. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind controlled trial conducted in the 2 university hospitals in western Norway in 1999-2006. A total of 3096 adult participants undergoing coronary angiography (20.5% female; mean age, 61.7 years) were randomized. At baseline, 59.3% had double- or triple-vessel disease, 83.7% had stable angina pectoris, and 14.9% had acute coronary syndromes. INTERVENTIONS Using a 2 x 2 factorial design, participants were randomly assigned to 1 of 4 groups receiving daily oral treatment with folic acid, 0.8 mg, plus vitamin B(12), 0.4 mg, plus vitamin B(6), 40 mg (n = 772); folic acid plus vitamin B(12) (n = 772); vitamin B(6) alone (n = 772); or placebo (n = 780). MAIN OUTCOME MEASURES The primary end point was a composite of all-cause death, nonfatal acute myocardial infarction, acute hospitalization for unstable angina pectoris, and nonfatal thromboembolic stroke. RESULTS Mean plasma total homocysteine concentration was reduced by 30% after 1 year of treatment in the groups receiving folic acid and vitamin B(12). The trial was terminated early because of concern among participants due to preliminary results from a contemporaneous Norwegian trial suggesting adverse effects from the intervention. During a median 38 months of follow-up, the primary end point was experienced by a total of 422 participants (13.7%): 219 participants (14.2%) receiving folic acid/vitamin B(12) vs 203 (13.1%) not receiving such treatment (hazard ratio, 1.09; 95% confidence interval, 0.90-1.32; P = .36) and 200 participants (13.0%) receiving vitamin B(6) vs 222 (14.3%) not receiving vitamin B(6) (hazard ratio, 0.90; 95% confidence interval, 0.74-1.09; P = .28). CONCLUSIONS This trial did not find an effect of treatment with folic acid/vitamin B(12) or vitamin B(6) on total mortality or cardiovascular events. Our findings do not support the use of B vitamins as secondary prevention in patients with coronary artery disease. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00354081.

Cancer Incidence and Mortality After Treatment With Folic Acid and Vitamin B12

CONTEXT Recently, concern has been raised about the safety of folic acid, particularly in relation to cancer risk. OBJECTIVE To evaluate effects of treatment with B vitamins on cancer outcomes and all-cause mortality in 2 randomized controlled trials. DESIGN, SETTING, AND PARTICIPANTS Combined analysis and extended follow-up of participants from 2 randomized, double-blind, placebo-controlled clinical trials (Norwegian Vitamin Trial and Western Norway B Vitamin Intervention Trial). A total of 6837 patients with ischemic heart disease were treated with B vitamins or placebo between 1998 and 2005, and were followed up through December 31, 2007. INTERVENTIONS Oral treatment with folic acid (0.8 mg/d) plus vitamin B(12) (0.4 mg/d) and vitamin B(6) (40 mg/d) (n = 1708); folic acid (0.8 mg/d) plus vitamin B(12) (0.4 mg/d) (n = 1703); vitamin B(6) alone (40 mg/d) (n = 1705); or placebo (n = 1721). MAIN OUTCOME MEASURES Cancer incidence, cancer mortality, and all-cause mortality. RESULTS During study treatment, median serum folate concentration increased more than 6-fold among participants given folic acid. After a median 39 months of treatment and an additional 38 months of posttrial observational follow-up, 341 participants (10.0%) who received folic acid plus vitamin B(12) vs 288 participants (8.4%) who did not receive such treatment were diagnosed with cancer (hazard ratio [HR], 1.21; 95% confidence interval [CI], 1.03-1.41; P = .02). A total of 136 (4.0%) who received folic acid plus vitamin B(12) vs 100 (2.9%) who did not receive such treatment died from cancer (HR, 1.38; 95% CI, 1.07-1.79; P = .01). A total of 548 patients (16.1%) who received folic acid plus vitamin B(12) vs 473 (13.8%) who did not receive such treatment died from any cause (HR, 1.18; 95% CI, 1.04-1.33; P = .01). Results were mainly driven by increased lung cancer incidence in participants who received folic acid plus vitamin B(12). Vitamin B(6) treatment was not associated with any significant effects. CONCLUSION Treatment with folic acid plus vitamin B(12) was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease in Norway, where there is no folic acid fortification of foods. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00671346.

Incomplete Stent Apposition After Implantation of Paclitaxel-Eluting Stents or Bare Metal Stents Insights From the Randomized TAXUS II Trial

Background—The clinical impact of late incomplete stent apposition (ISA) for drug-eluting stents is unknown. We sought to prospectively investigate the incidence and extent of ISA after the procedure and at 6-month follow-up of paclitaxel-eluting stents in comparison with bare metal stents (BMS) and survey the clinical significance of ISA over a period of 12 months. Methods and Results—TAXUS II was a randomized, double-blind study with 536 patients in 2 consecutive cohorts comparing slow-release (SR; 131 patients) and moderate-release (MR; 135 patients) paclitaxel-eluting stents with BMS (270 patients). This intravascular ultrasound (IVUS) substudy included patients who underwent serial IVUS examination after the procedure and at 6 months (BMS, 240 patients; SR, 113; MR, 116). The qualitative and quantitative analyses of ISA were performed by an independent, blinded core laboratory. More than half of the instances of ISA observed after the procedure resolved at 6 months in all groups. No difference in the incidence of late-acquired ISA was observed among the 3 groups (BMS, 5.4%; SR, 8.0%; MR, 9.5%; P=0.306), with a similar ISA volume (BMS, 11.4 mm3; SR, 21.7 mm3; MR, 8.5 mm3; P=0.18). Late-acquired ISA was the result of an increase of vessel area without change in plaque behind the stent. Predictive factors of late-acquired ISA were lesion length, unstable angina, and absence of diabetes. No stent thrombosis occurred in the patients diagnosed with ISA over a period of 12 months. Conclusions—The incidence and extent of late-acquired ISA are comparable in paclitaxel-eluting stents and BMS. ISA is a pure IVUS finding without clinical repercussions.

Serotonin Is Associated with Coronary Artery Disease and Cardiac Events

BACKGROUND Blood platelets are related to coronary atherogenesis. Platelets secrete serotonin (5-hydroxytryptamine) which has several effects on the vascular wall and promotes thrombogenesis, mitogenesis, and proliferation of smooth muscle cells. Serotonin may therefore be one of the factors involved in the development of coronary artery disease (CAD). We have assessed serotonin among conventional predictors for CAD in patients undergoing coronary angiography for chest pain or clinically suspected angina pectoris. METHODS AND RESULTS Of 121 consecutive male patients (mean age 65, range 41 to 90 years) undergoing angiography, 96 had coronary artery stenosis and 25 had normal angiograms. Serotonin, blood platelet count, and conventional biochemical risk factors for CAD were determined in the morning the day before the angiography. High serotonin (cut-point 1000 nmol/L) was significantly associated with CAD with an odds ratio (OR) of 3.4 (95% confidence interval 1.2 to 9. 8). The corresponding OR for smokers was 4.8 (1.9 to 12.2); hypercholesterolemia (>7 mmol/L), 2.9 (1.1 to 7.6); high platelet count (cut-point 325 10(9)/L), 3.0 (1.0 to 9.5); and family history of heart disease, 2.3 (1.0 to 5.2). After adjustment with conventional risk factors, the OR for CAD was 3.8 (1.1 to 13.1), comparing high and low values of serotonin. The relation between serotonin and CAD was strengthened only when patients <70 years (n=82) were included in the analysis. In this age group, the occurrence of cardiac events during a mean of 3.7 years of follow-up was significantly associated with high serotonin values. CONCLUSIONS The study suggests that serotonin is associated with coronary artery disease and occurrence of cardiac events, particularly in younger age groups. This association seems to persist after adjustment for conventional risk factors.

Drug-Eluting or Bare-Metal Stents for Coronary Artery Disease

BACKGROUND Limited data are available on the long-term effects of contemporary drug-eluting stents versus contemporary bare-metal stents on rates of death, myocardial infarction, repeat revascularization, and stent thrombosis and on quality of life. METHODS We randomly assigned 9013 patients who had stable or unstable coronary artery disease to undergo percutaneous coronary intervention (PCI) with the implantation of either contemporary drug-eluting stents or bare-metal stents. In the group receiving drug-eluting stents, 96% of the patients received either everolimus- or zotarolimus-eluting stents. The primary outcome was a composite of death from any cause and nonfatal spontaneous myocardial infarction after a median of 5 years of follow-up. Secondary outcomes included repeat revascularization, stent thrombosis, and quality of life. RESULTS At 6 years, the rates of the primary outcome were 16.6% in the group receiving drug-eluting stents and 17.1% in the group receiving bare-metal stents (hazard ratio, 0.98; 95% confidence interval [CI], 0.88 to 1.09; P=0.66). There were no significant between-group differences in the components of the primary outcome. The 6-year rates of any repeat revascularization were 16.5% in the group receiving drug-eluting stents and 19.8% in the group receiving bare-metal stents (hazard ratio, 0.76; 95% CI, 0.69 to 0.85; P<0.001); the rates of definite stent thrombosis were 0.8% and 1.2%, respectively (P=0.0498). Quality-of-life measures did not differ significantly between the two groups. CONCLUSIONS In patients undergoing PCI, there were no significant differences between those receiving drug-eluting stents and those receiving bare-metal stents in the composite outcome of death from any cause and nonfatal spontaneous myocardial infarction. Rates of repeat revascularization were lower in the group receiving drug-eluting stents. (Funded by the Norwegian Research Council and others; NORSTENT ClinicalTrials.gov number, NCT00811772 .).

The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA.CER) trial: study design and rationale

BACKGROUND The protease-activated receptor 1 (PAR-1), the main platelet receptor for thrombin, represents a novel target for treatment of arterial thrombosis, and SCH 530348 is an orally active, selective, competitive PAR-1 antagonist. We designed TRA*CER to evaluate the efficacy and safety of SCH 530348 compared with placebo in addition to standard of care in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) and high-risk features. TRIAL DESIGN TRA*CER is a prospective, randomized, double-blind, multicenter, phase III trial with an original estimated sample size of 10,000 subjects. Our primary objective is to demonstrate that SCH 530348 in addition to standard of care will reduce the incidence of the composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization compared with standard of care alone. Our key secondary objective is to determine whether SCH 530348 will reduce the composite of cardiovascular death, MI, or stroke compared with standard of care alone. Secondary objectives related to safety are the composite of moderate and severe GUSTO bleeding and clinically significant TIMI bleeding. The trial will continue until a predetermined minimum number of centrally adjudicated primary and key secondary end point events have occurred and all subjects have participated in the study for at least 1 year. The TRA*CER trial is part of the large phase III SCH 530348 development program that includes a concomitant evaluation in secondary prevention. CONCLUSION TRA*CER will define efficacy and safety of the novel platelet PAR-1 inhibitor SCH 530348 in the treatment of high-risk patients with NSTE ACS in the setting of current treatment strategies.

Effect of intravenous TRO40303 as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: MITOCARE study results

AIM The MITOCARE study evaluated the efficacy and safety of TRO40303 for the reduction of reperfusion injury in patients undergoing revascularization for ST-elevation myocardial infarction (STEMI). METHODS Patients presenting with STEMI within 6 h of the onset of pain randomly received TRO40303 (n = 83) or placebo (n = 80) via i.v. bolus injection prior to balloon inflation during primary percutaneous coronary intervention in a double-blind manner. The primary endpoint was infarct size expressed as area under the curve (AUC) for creatine kinase (CK) and for troponin I (TnI) over 3 days. Secondary endpoints included measures of infarct size using cardiac magnetic resonance (CMR) and safety outcomes. RESULTS The median pain-to-balloon time was 180 min for both groups, and the median (mean) door-to-balloon time was 60 (38) min for all sites. Infarct size, as measured by CK and TnI AUCs at 3 days, was not significantly different between treatment groups. There were no significant differences in the CMR-assessed myocardial salvage index (1-infarct size/myocardium at risk) (mean 52 vs. 58% with placebo, P = 0.1000), mean CMR-assessed infarct size (21.9 g vs. 20.0 g, or 17 vs. 15% of LV-mass) or left ventricular ejection fraction (LVEF) (46 vs. 48%), or in the mean 30-day echocardiographic LVEF (51.5 vs. 52.2%) between TRO40303 and placebo. A greater number of adjudicated safety events occurred in the TRO40303 group for unexplained reasons. CONCLUSION This study in STEMI patients treated with contemporary mechanical revascularization principles did not show any effect of TRO40303 in limiting reperfusion injury of the ischaemic myocardium.

Systemic Markers of Interferon-γ–Mediated Immune Activation and Long-Term Prognosis in Patients With Stable Coronary Artery Disease

Objective—Interferon &ggr; (IFN-&ggr;) is centrally involved in atherosclerosis-related inflammation, but its activity cannot be reliably assessed by systemic measurements. In activated macrophages, IFN-&ggr; stimulates production of neopterin and conversion of tryptophan to kynurenine. We evaluated the relationships of plasma neopterin and plasma kyunernine:tryptophan ratio (KTR) to long-term prognosis in patients with stable angina pectoris and angiographically verified significant coronary artery disease. Methods and Results—Samples were obtained from 2380 patients with a mean age of 63.7 years; 77.3% were men. During a median follow-up of 56 months, 10.8% of patients experienced a major coronary event (MCE), and 9.5% died. For MCE, each SD increment of neopterin and KTR (logarithmically transformed) was associated with multivariable adjusted hazard ratios and 95% CIs of 1.28 (1.10 to 1.48) and 1.28 (1.12 to 1.48), respectively. The corresponding hazard ratios (95% CIs) for all-cause mortality were 1.40 (1.21 to 1.62) (neopterin) and 1.23 (1.06 to 1.43) (KTR). Conclusion—In patients with stable angina pectoris, systemic markers of IFN-&ggr; activity, plasma neopterin, and plasma KTR provide similar risk estimates for MCE and mortality. Our results support experimental data linking IFN-&ggr; to acute atherosclerotic complications.

Improving outcomes after myocardial infarction: a randomized controlled trial evaluating effects of a telephone follow-up intervention

Background Providing information is an important part of standard care and treatment for acute myocardial infarction inpatients. Evidence exists indicating that acute myocardial infarction patients experience an information gap in the period immediately after discharge from the hospital. The aim of this study was to assess the short-term effects of a nurse-led telephone follow-up intervention to provide information and support to patients with acute myocardial infarction after their discharge from hospital. Design and method A prospective randomized, controlled trial with a 6-month follow-up was conducted. A total of 288 patients were allocated to either an intervention group (n = 156) or a control group (n = 132). The latter received routine post-discharge care. The primary endpoint measured at 3 and 6 months after discharge was the health-related quality of life using the 36-item Short Form Health Survey. Secondary endpoints included smoking and exercise habits. Results In both groups, health-related quality of life improved significantly over time on most subscales. A statistically significant difference in favour of the intervention group was found on the 36-item Short Form Health Survey Physical Health Component Summary Scale (P=0.034) after 6 months. No difference was found between the groups on the Mental Health Component Summary Scale. We found a significant difference with respect to frequency of physical activity in favour of the intervention group after 6 months (P=0.004). More participants in the intervention group than the control group had ceased smoking at the 6-month follow-up (P=0.055). Conclusion A nurse-led systematic telephone follow-up intervention significantly improved the physical dimension of health-related quality of life in patients in the intervention group compared with usual care patients. Participation in this intervention also seemed to promote health behaviour change in patients after acute myocardial infarction.