Jan Kyst Madsen

Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data.

BACKGROUNDnCombinations of aspirin, clopidogrel, and vitamin K antagonists are widely used in patients after myocardial infarction. However, data for the safety of combinations are sparse. We examined the risk of hospital admission for bleeding associated with different antithrombotic regimens.nnnMETHODSnBy use of nationwide registers from Denmark, we identified 40 812 patients aged 30 years or older who had been admitted to hospital with first-time myocardial infarction between 2000 and 2005. Claimed prescriptions starting at hospital discharge were used to determine the regimen prescribed according to the following groups: monotherapy with aspirin, clopidogrel, or vitamin K antagonist; dual therapy with aspirin plus clopidogrel, aspirin plus vitamin K antagonist, or clopidogrel plus vitamin K antagonist; or triple therapy including all three drugs. Risk of hospital admission for bleeding, recurrent myocardial infarction, and death were assessed by Cox proportional hazards models with the drug exposure groups as time-varying covariates.nnnFINDINGSnDuring a mean follow-up of 476.5 days (SD 142.0), 1891 (4.6%) patients were admitted to hospital with bleeding. The yearly incidence of bleeding was 2.6% for the aspirin group, 4.6% for clopidogrel, 4.3% for vitamin K antagonist, 3.7% for aspirin plus clopidogrel, 5.1% for aspirin plus vitamin K antagonist, 12.3% for clopidogrel plus vitamin K antagonist, and 12.0% for triple therapy. With aspirin as reference, adjusted hazard ratios for bleeding were 1.33 (95% CI 1.11-1.59) for clopidogrel, 1.23 (0.94-1.61) for vitamin K antagonist, 1.47 (1.28-1.69) for aspirin plus clopidogrel, 1.84 (1.51-2.23) for aspirin plus vitamin K antagonist, 3.52 (2.42-5.11) for clopidogrel plus vitamin K antagonist, and 4.05 (3.08-5.33) for triple therapy. Numbers needed to harm were 81.2 for aspirin plus clopidogrel, 45.4 for aspirin plus vitamin K antagonist, 15.2 for clopidogrel plus vitamin K antagonist, and 12.5 for triple therapy. 702 (37.9%) of 1852 patients with non-fatal bleeding had recurrent myocardial infarction or died during the study period compared with 7178 (18.4%) of 38 960 patients without non-fatal bleeding (HR 3.00, 2.75-3.27, p<0.0001).nnnINTERPRETATIONnIn patients with myocardial infarction, risk of hospital admission for bleeding increased with the number of antithrombotic drugs used. Treatment with triple therapy or dual therapy with clopidogrel plus vitamin K antagonist should be prescribed only after thorough individual risk assessment.nnnFUNDINGnDanish Heart Foundation and the Danish Medical Research Council.

Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: nationwide propensity score matched study

Objective To examine the effect of proton pump inhibitors on adverse cardiovascular events in aspirin treated patients with first time myocardial infarction. Design Retrospective nationwide propensity score matched study based on administrative data. Setting All hospitals in Denmark. Participants All aspirin treated patients surviving 30 days after a first myocardial infarction from 1997 to 2006, with follow-up for one year. Patients treated with clopidogrel were excluded. Main outcome measures The risk of the combined end point of cardiovascular death, myocardial infarction, or stroke associated with use of proton pump inhibitors was analysed using Kaplan-Meier analysis, Cox proportional hazard models, and propensity score matched Cox proportional hazard models. Results 3366 of 19u2009925 (16.9%) aspirin treated patients experienced recurrent myocardial infarction, stroke, or cardiovascular death. The hazard ratio for the combined end point in patients receiving proton pump inhibitors based on the time dependent Cox proportional hazard model was 1.46 (1.33 to 1.61; P<0.001) and for the propensity score matched model based on 8318 patients it was 1.61 (1.45 to 1.79; P<0.001). A sensitivity analysis showed no increase in risk related to use of H2 receptor blockers (1.04, 0.79 to 1.38; P=0.78). Conclusion In aspirin treated patients with first time myocardial infarction, treatment with proton pump inhibitors was associated with an increased risk of adverse cardiovascular events.

Three-year follow-up in a subset of high-risk patients randomly assigned to off-pump versus on-pump coronary artery bypass surgery: the Best Bypass Surgery Trial

Objective To evaluate off-pump versus on-pump coronary artery bypass grafting (CABG) in patients with three-vessel disease and a high-risk operative profile. Design A randomised clinical trial. Setting Rigshospitalet, University Hospital, Copenhagen, Denmark. Participants 341 patients with three-vessel disease and a EuroSCORE of 5 or greater. Main exclusion criteria were previous heart surgery, poor left ventricular function (ejection fraction <30%), or unstable preoperative condition. Intervention CABG performed with versus without cardiopulmonary bypass. Main outcome measure The primary outcome was a composite of major adverse cardiac and cerebrovascular events (MACCE) including all-cause mortality, acute myocardial infarction, cardiac arrest with successful resuscitation, low cardiac output syndrome/cardiogenic shock, stroke and coronary reintervention. Results MACCE occurred in 69 (40%) patients allocated to off-pump versus 54 (33%) patients allocated to on-pump CABG during the median 3.7u2005years of follow-up (HR 1.22; 95% CI 0.86 to 1.75; p=0.26). All-cause mortality was significantly increased in the off-pump group (24% vs 15%; HR 1.66, 95% CI 1.02 to 2.73; p=0.04), but cardiac-related death was not significantly different (10% vs 7%; HR 1.30, 95% CI 0.64 to 2.66; p=0.47). An insignificant trend towards a reduction in myocardial infarction after off-pump CABG was observed (7% vs 14%; HR 0.53, 95% CI: 0.27 to 1.04; p=0.06). Conclusions No significant difference in the primary outcome of MACCE was found between off-pump and on-pump CABG. However, mortality seemed higher after off-pump CABG. Trial registration http://clinicaltrials.gov/ number, NCT00120991.

Efficacy of Post-Operative Clopidogrel Treatment in Patients Revascularized With Coronary Artery Bypass Grafting After Myocardial Infarction

OBJECTIVESnThe objective of this study was to examine the clinical efficacy of clopidogrel treatment on death and recurrent myocardial infarction (MI) among MI patients revascularized by coronary artery bypass graft surgery (CABG).nnnBACKGROUNDnThe benefit from post-operative clopidogrel in CABG-treated MI patients is largely unknown.nnnMETHODSnAll patients admitted with first-time MI between 2002 and 2006, treated with CABG within 180 days after admission, were identified by nationwide administrative registers. Clopidogrel treatment was determined by claimed prescriptions after discharge from surgery. Risk of death or recurrent MI, and of a combined end point of the 2, were assessed by cumulative incidence and Cox proportional hazards model. A propensity score-matched subgroup analysis was done.nnnRESULTSnWe included 3,545 patients, and of these, 957 (27.0%) were treated with clopidogrel after CABG. Mean follow-up was 466 ± 144 days. Among patients treated with clopidogrel, 39 (4.1%) died or experienced a recurrent MI, whereas that occurred in 203 (7.8%) patients without clopidogrel (log-rank p = 0.0003). Hazard ratio was 0.59 (95% confidence interval [CI]: 0.42 to 0.85) for patients treated with clopidogrel, with no-clopidogrel as reference. By propensity score, of 945 patients with or without clopidogrel treatment who were matched, death or recurrent MI occurred in 38 (4.0%) patients with clopidogrel and 57 (6.0%) without clopidogrel (log-rank p = 0.05). Corresponding hazard ratio was 0.67 (95% CI: 0.44 to 1.00) for clopidogrel users, with no-clopidogrel as reference.nnnCONCLUSIONSnAmong MI patients revascularized by CABG, only 27% received clopidogrel after discharge. Clopidogrel-treated patients had a lower risk of the combined end point of death or recurrent MI. Focus on discharge clopidogrel treatment of these patients should be made.

Global longitudinal strain is not impaired in type 1 diabetes patients without albuminuria: the Thousand & 1 study

OBJECTIVESnThe purpose of this study was to investigate if systolic myocardial function is reduced in all patients with type 1 diabetes (T1DM) or only in patients with albuminuria.nnnBACKGROUNDnHeart failure is a common cause of mortality in T1DM, and a specific diabetic cardiomyopathy has been suggested. It is not known whether myocardial dysfunction is a feature of T1DM per se or primarily associated with diabetes with albuminuria.nnnMETHODSnThis cross-sectional study compared 1,065 T1DM patients without known heart disease from the outpatient clinic at the Steno Diabetes Center with 198 healthy control subjects. Conventional echocardiography and global longitudinal strain (GLS) by 2-dimensional speckle-tracking echocardiography was performed and analyzed in relation toxa0normoalbuminuria (nxa0= 739), microalbuminuria (nxa0= 223), and macroalbuminuria (nxa0= 103). Data were analyzed in univariable and multivariable linear regression models adjusted for confounding factors including conventional risk factors, medication, and systolic and diastolic dysfunction. Investigators were blinded to degree of albuminuria.nnnRESULTSnMean age was 49.5 years, 52% men, mean glycated hemoglobin 8.2% (66 mmol/mol), mean body mass index 25.5 kg/m(2), and mean diabetes duration 26.1 years. In unadjusted analyses, GLS differed significantly between T1DM patients and control subjects (pxa0= 0.02). When stratified by degrees of albuminuria, the difference in GLS compared with control subjects wasxa0-18.8 ± 2.5% versusxa0-18.5 ± 2.5% for normoalbuminuria (pxa0= 0.28), versusxa0-17.9 ± 2.7% for microalbuminuria (pxa0= 0.001), and versusxa0-17.4 ± 2.9% for macroalbuminuria (pxa0< 0.001). Multivariable analyses, including clinical characteristics, diastolic and systolic dysfunction, and use of medication, did not change this relationship.nnnCONCLUSIONSnSystolic function assessed by GLS was reduced in T1DM compared with control subjects. This difference, however, was driven solely by decreased GLS in T1DM patients with albuminuria. T1DM patients with normoalbuminuria have systolic myocardial function similar to healthy control subjects. These findings do not support the presence of specific diabetic cardiomyopathy without albuminuria.

Prognosis and treatment in patients admitted with acute myocardial infarction on weekends and weekdays from 1997 to 2009

BACKGROUNDnLess invasive treatment and poorer outcomes have been shown among patients admitted with acute myocardial infarction (AMI) on weekends compared to weekdays.nnnOBJECTIVESnTo investigate the weekend-effect on mortality in patients with AMI.nnnMETHODSnUsing nationwide registers we identified 92,164 patients aged 30-90 years who were admitted to a Danish hospital with a first AMI from 1997 to 2009. Patients were stratified according to weekday- or weekend admissions and four time-periods to investigate for temporal changes. All-cause mortality at 2, 7, 30, and 365 days was investigated using proportional hazards Cox regression.nnnRESULTSnMortality rates were higher on weekends within seven days of admission in 1997-99 (absolute difference ranging from 0.8 to 1.1%). Weekend-weekday hazard-ratios were 1.13 (1.03-1.23) at day 2 and 1.10 (1.01-1.18) at day 7. There were no significant differences in 2000-09 and estimates suggested an attenuation of the initial weekend-effect. Overall, the use of coronary angiography (34.9% vs. 72.3%) and percutaneous coronary intervention (6.6% vs. 51.0%) within 30 days increased, as did the use of statins (49.9% vs. 80.1%.) and clopidogrel (26.7% vs. 72.7%). The cumulative mortality decreased during the study period from 5.4% to 2.5% at day of admission, from 19.5% to 11.0% at day 30 and from 28.0% to 19.0% at day 365 (all tests for trend p<0.0001).nnnCONCLUSIONSnNo persistent weekend-effect on mortality was present in patients with AMI in 1997-2009. Overall, mortality rates have decreased concomitantly with an increased use of current guideline-recommended invasive and medical therapy.

Graft patency after off-pump versus on-pump coronary artery surgery in high-risk patients

Abstract Objective. To compare angiographic graft patency in high-risk patients randomly allocated to off-pump vs. on-pump coronary artery bypass grafting (CABG). Design. From a randomised, single-centre clinical trial including patients undergoing isolated first-time coronary bypass surgery a subgroup of patients were scheduled to 1-year coronary angiographic follow-up. Patients had 3-vessel disease and a EuroSCORE ≥5. We evaluated graft patency using a patency index (percentage of patent grafts out of the total number of grafts in each patient). Results. One-year angiography was performed in 34 patients undergoing off-pump surgery and 35 patients undergoing on-pump surgery. The mean number of distal anastomoses was 3.38±0.65 in the off-pump group versus 3.46±0.61 in the on-pump group (NS). The number of patients without graft failure was 22 in the off-pump group and 24 in the on-pump group (NS). The overall patency index was 85% in the off-pump group versus 87% in the on-pump group with a mean difference of –2.1%, 95% confidence interval –12.9 to 8.7 (NS). Conclusions. In patients with 3-vessel disease and a high-risk profile we found no statistically significant difference in graft patency between off-pump and on-pump CABG at 1-year coronary angiographic follow-up. Trial registration: ClinicalTrials.gov identifier: NCT00120991.

One-year results of total arterial revascularization vs. conventional coronary surgery: CARRPO trial

AIMSnTo investigate clinical and angiographic outcomes after coronary surgery using total arterial revascularization (TAR).nnnMETHODS AND RESULTSnWe randomized 331 patients with multivessel or isolated left main disease to TAR [internal thoracic (ITA) and radial arteries] vs. conventional revascularization (CR) using left ITA and vein grafts. The primary angiographic outcome was the patency index: number of patent grafts (<50% stenosed) divided by number of constructed grafts. One-year angiography was complete for 83% of patients. Mean patency index (+/-SD) was 87 +/- 22% in the TAR group and 88 +/- 18% in the conventional group (P = 0.52). In 72% of TAR patients and 67% of the conventional group, all grafts were patent (P = 0.45). Multiple imputation of missing angiographic data did not influence on results. Within 1 year, 37 (23%) TAR patients and 43 (25%) conventional group patients suffered cardiac events (HR 1.09, 95% CI 0.70-1.69, P = 0.70). One patient (0.6%) in the TAR group and two (1.2%) in the conventional group died (P = 1.00).nnnCONCLUSIONnWithin 1 year post-operatively, TAR seems at least as safe and effective as CR. Prolonged follow-up will reveal whether this is sustained or superior results of TAR can justify a more general use.

Clopidogrel discontinuation after myocardial infarction and risk of thrombosis: a nationwide cohort study

AIMSnThe benefit of extending clopidogrel treatment beyond the 12-month period recommended in current guidelines after myocardial infarction (MI) is debated. We analysed the risk of adverse cardiovascular outcomes after discontinuation of 12 months of clopidogrel treatment.nnnMETHODS AND RESULTSnThis Danish retrospective nationwide study included all patients treated with clopidogrel after discharge from a first-time MI during 2004-09. The risk of death or recurrent MI after the discontinuation of clopidogrel was studied by multivariable Poisson regression models. Patients treated with and without percutaneous coronary intervention (PCI) were analysed separately. The follow-up was 18 months. Of the 29,268 patients included, 3214 (11.0%) experienced death or recurrent MI. There were 9819 (33.6%) patients treated only medically and 19,449 (66.4%) patients treated with PCI. Twelve months after the index MI, for patients treated only medically, the risk of death or recurrent MI in the first 90-day period of clopidogrel discontinuation was 1.07 (0.65-1.76; P= 0.79) [adjusted incidence rate ratio (IRR) and 95% confidence interval] compared with the next 90-day period of discontinuation. For patients treated with PCI, the corresponding IRR was 1.59 (1.11-2.30; P= 0.013). The risk of recurrent MI yielded an IRR of 0.77 (0.36-1.67; P= 0.51) for patients treated only medically and 1.87 (1.11-3.15; P= 0.019) for PCI-treated patients.nnnCONCLUSIONnDiscontinuation of clopidogrel 12 months after MI is associated with an increased risk of death or recurrent MI in the first 90 days of discontinuation compared with the next 90-day period of discontinuation for patients treated with PCI, but not for patients not treated with PCI.

Influence of distance from home to invasive centre on invasive treatment after acute coronary syndrome: a nationwide study of 24 910 patients

Objective To investigate whether distance from a patients home to the nearest invasive centre influenced the invasive treatment strategy in acute coronary syndrome (ACS). Methods This was an observational cohort study using nationwide registries involving 24u2008910 patients admitted with ACS (median age 67, range 30–90u2005years). All persons were grouped in tertiles according to the distance from their residence to the invasive centre. Cox proportional hazard models were applied to estimate the differences in coronary angiography and revascularisation rate within 60u2005days of admission according to the distance to the centre. The end points were coronary angiography and subsequent revascularisation. Results Of 24u2008910 patients with a first ACS, 33% resided <21u2005km from one of the five invasive centres in Denmark, 33% lived between 21 and 64u2005km away and 34% lived >64u2005km away. The incidence of coronary angiography was 68% for long distance versus 77% for short distance (p<0.05), with an HR of 0.78 (95% CI 0.75 to 0.81, p<0.0001). Adjustment for patient characteristics such as age, sex, co-morbidity and socioeconomic status did not attenuate the difference (HR 0.74, 95% CI 0.71 to 0.77, p<0.0001). Furthermore, revascularisation in the subgroup examined with coronary angiography was less likely for those residing a long distance from the invasive centre compared with those living nearer (adjusted HR of 0.82 (95% CI 0.78 to 0.85, p<0.0001). Conclusions In patients hospitalised with ACS, invasive examination and treatment were less likely the further away from an invasive centre the patients resided, thus equal and uniform invasive examination and treatment was not found.