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Introduction The congenital Long QT Syndrome (cLQTS) is associated with an increased risk of sudden cardiac death (SCD). Thus, cLQTS patients are susceptible to develop depression or anxiety, both of which have been associated with poor outcomes including risk of mortality. Aim We examined if a cLQTS diagnosis and the severity of cLQTS disease onset was associated with an increased risk of depression, anxiety, and all-cause mortality compared with a matched control population. Methods Using Danish nationwide registries and inherited cardiac disease clinics, we identified all patients with known cLQTS (1994–2016) who were ≥18 years at the time of diagnosis. The disease onset for cLQTS was identified as asymptomatic, ventricular tachycardia [VT]/ syncope, aborted SCD [aSCD], or unknown (i.e. no available information). After cLQTS diagnosis, we determined the risk of depression (i.e. depression diagnosis or prescription of antidepressants), anxiety (i.e. anxiety diagnosis or prescription of anxiolytics), and mortality using multivariable Cox proportional hazards regression. Patients were followed for three years. An age and gender matched control population was identified (matching 1:4). Competing risk analysis with death as competing risk was used to generate cumulative incidence plots. Results Overall, 428 cLQTS patients were identified of which 107/428 (25%) developed depression or anxiety after being diagnosed with cLQTS compared with 285/1712 (16.6%) from the control population (p Conclusion The prevalence of depression and anxiety was high among cLQTS patients after diagnosis. Moreover, a graded relationship between severity of disease onset and risk of depression or anxiety was identified. These findings highlight a need for increased awareness following a cLQTS diagnosis in order to reduce the risk of adverse outcomes. Cumulative incidence curve Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Fund of Rigshospitalet

Background. Perioperative red blood cell transfusion is associated with adverse outcomes after cardiac operations. Although restrictive transfusion protocols have been developed, their safety and efficacy are not well demonstrated, and considerable variation in transfusion practice persists. We report our experience with a restrictive transfusion protocol. Methods. We analyzed the outcomes in 409 patients undergoing cardiac operations enrolled in a trial conducted at 30 centers worldwide. Blood products were administered on the basis of a transfusion algorithm applied across all centers, with a restrictive transfusion trigger of hemoglobin less than or equal to 6 g/dL. Transfusion was acceptable but not mandatory for hemoglobin 6 to 8 g/dL. For hemoglobin 8 to 10 g/dL, transfusion was acceptable only with evidence for endorgan ischemia. Results. The patient population was moderately complex, with 20.5% having combined procedures and 29.6% having nonelective operations. The mean EuroSCORE for the population was 4.3, which predicted a substantial incidence of morbidity and mortality. Actual outcomes were excellent, with observed mortality of 0.49% and rates of cerebrovascular accident, myocardial infarction, and acute renal failure 1.2%, 6.1%, and 0.98%, respectively. The frequency of red blood cell transfusion was 33.7%, which varied significantly by center. Most transfusions (71.9%) were administered for hemoglobin 6 to 8 g/dL; 21.4% were administered for hemoglobin 8 to 10 g/dL with evidence for end-organ ischemia; 65.0% of patients avoided allogeneic transfusion altogether. Conclusions. A restrictive transfusion protocol can be safely applied in the care of moderate-risk patients undergoing cardiac operations. This strategy has significant potential to reduce transfusion and resource utilization in these patients, standardize transfusion practices across institutions, and increase the safety of cardiac operations.

ObjectivesCardiac surgery with cardiopulmonary bypass frequently leads to excessive bleeding, obligating blood product transfusions. Because low factor XIII (FXIII) levels have been associated with bleeding after cardiac surgery, we investigated whether administering recombinant FXIII after cardiopulmonary bypass would reduce transfusions.MethodsIn this double-blinded, placebo-controlled, multicenter trial, 409 cardiac surgical patients at moderate risk for transfusion were randomized to receive an intravenous dose of recombinant FXIII, 17.5 IU/kg (n = 143), 35 IU/kg (n = 138), or placebo (n = 128) after cardiopulmonary bypass. Transfusion guidelines were standardized. The primary efficacy outcome was avoidance of allogeneic blood products for 7 days postsurgery. Secondary outcomes included amount of blood products transfused and reoperation rate. Serious adverse events were measured for 7 weeks.ResultsStudy groups had comparable baseline characteristics and an approximately 40% decrease in FXIII levels after cardiopulmonary bypass. Thirty minutes postdose, FXIII levels were restored to higher than the lower 2.5th percentile of preoperative activity in 49% of the placebo group, and 85% and 95% of the 17.5- and 35-IU/kg recombinant FXIII groups, respectively (P

Background: There is a growing body of evidence linking Chlamydia pneumoniae to the progression of coronary heart disease. Smaller studies have indicated that intervention with macrolide antibiotics might reduce coronary events in patients with cardiovascular diseases. Objective: To describe the design of a large-scale intervention study on the effects of a macrolide antibiotic on coronary events in patients with stable coronary heart disease (documented myocardial infarction and/or angina pectoris). Methods: This study is a double-blind, randomised, placebo-controlled, multicentre study with parallel groups. Patients are randomised to 14 days of treatment with clarithromycin (500 mg, once daily) or matching placebo. The follow-up period is 2 years, and the primary end point is a composite end point of death, non-fatal myocardial infarction or unstable angina pectoris, whichever occurs first. Recruitment began in October 1999 and will be completed in 2000. In total, 4,600 patients will be randomised. Prospectives: The study is powered to detect a reduction in coronary events of 20%. Also, the study will examine the question of whether the presence of a C. pneumoniae antibody titre is associated with a significantly increased risk of future coronary events. Finally, in the case of a significant outcome, it will be possible to test whether the effect is restricted to patients with C. pneumoniae antibodies only, or to a universal effect without any coherence to C. pneumoniae antibodies.

Verapamil is well tolerated in patients with stable and unstable angina pectoris, as well as in patients with threatened infarction. No data exist documenting verapamil to be inferior to beta-blockers in these stages of coronary heart diseases. In the prethrombolytic era i.v. intervention with verapamil did not add any benefit in the early phase of AMI. However, a retrospective analysis suggests the hypothesis that i.v. verapamil given in combination with thrombolysis may improve the prognosis, and an ongoing study (VAMI trial) examines this hypothesis. When given in the late in-hospital phase of AMI to patients without heart failure verapamil significantly reduces mortality and morbidity. When given in the late in-hospital phase to patients with heart failure verapamil did not cause the course or prognosis to deteriorate and might even improve it in patients with residual ischaemia, especially when given in combination with an ACE-inhibitors. A planned study (DAVIT III study) has to confirm these preliminary data.

Background: Angina pectoris accompanied by transient ST-segment changes during the in-hospital phase of acute myocardial infarction (AMI) is a well established marker of subsequent cardiac death and reinfarction. Hypothesis: This study was undertaken to record the prognostic significance of angina pectoris experienced during the first month following discharge from AMI. Methods: In all, 803 patients included in the placebo arm of the Danish Verapamil Infarction Trial II were followed up for 18 months in 20 coronary care units in Denmark. The patients were randomized to placebo and were still on study treatment 1 month after discharge. Of these patients, 311 (39%) reported chest pain during the first month following discharge. Results: Patients with angina pectoris had a significantly increased risk of reinfarction [hazard 1.71; 95%-confidence limit (CL): 1.09, 2.69] and increased mortality risk which, however, only reached borderline statistical significance (hazard 1.52; 95%-CL: 0.96, 2.40). When patients were subdivided according to both angina pectoris and heart failure, those with one or both of these risk markers had significantly increased mortality (p 0.03) and reinfarction (p 0.02) rates compared with patients free of both angina pectoris and heart failure. Conclusion: Patients with postinfarction angina pectoris have a significantly increased morbidity risk.

UNLABELLED: The objective of this study is to describe the agreement between randomized trial outcome assessment by committee and outcomes entirely identified through public registers.METHODS: In the CLARICOR trial, 4,372 patients with stable coronary heart disease received a short course of clarithromycin versus placebo and were followed up for 2.6 years. The pertinent hospital records and death certificates had originally been evaluated by the adjudication committee using common definitions of outcomes mapped into a 6-category list. We now mechanically converted the International Classification of Diseases-coded diagnoses of the public registries into the same categories. After cross-tabulation of the committee diagnoses with National Patient Register diagnoses and Register of Causes of Death, we calculate agreement and compare the estimated intervention effects of the 2 data sets.RESULTS: With public register data, the protocol-specified categories were slightly more frequent. Overall agreement was 74% for hospital discharges and 60% for cause of death, but the intervention effect, expressed as a hazard ratio, stayed within 4% of the value originally obtained with the adjudication committee (P≥ .35).CONCLUSIONS: Our results show a modest agreement between formal adjudication and outcomes deducible from public registers. However, the estimated intervention effect did not differ noticeably between the 2 data sources. If studies on a wide range of public registers confirm these findings, register outcomes may be considered as a replacement for adjudication committees.

The prognostic sign of angina pectoris and the effect of intervention with verapamil on the incidence of angina pectoris were studied in patients recovering from myocardial infarction and included in the Danish Verapamil Infarction Trial II. During the second week after admission patients were double-blindly randomized to treatment with verapamil 360 mg. day−1 or placebo. Treatment was continued for up to 18 months. At discharge angina pectoris was reported in 11% of 869 patients randomized to verapamil and in 12% of 888 randomized to placebo (ns). One month after discharge a significantly increase in the prevalance of angina pectoris was reported in both the verapamil (33%) ( P

Objective In clinical trials, agreement on outcomes is of utmost importance for valid estimation of intervention effects. As there is limited knowledge about adjudicator agreement in cardiology, we examined the level of agreement among three cardiology specialists adjudicating all possible events in a randomized controlled clinical trial of patients with stable coronary heart disease. Study Design and Setting All information (hospital records, death certificates, etc.) was forwarded to two randomly selected blinded adjudicators. If they disagreed, the third arbiter had to choose the more likely of the two alternatives. Files of 5,475 nonfatal and 362 fatal events were evaluated. Results For nonfatal outcomes, pairwise kappa values ranged from 0.75 to 0.80. The three adjudicators had 4.3%, 9.5%, and 6.1% of their nonfatal outcome classifications overruled by their arbiter. If stable angina pectoris, unstable angina pectoris, and acute myocardial infarction were treated as one, agreement increased minimally. For fatal outcomes, the pairwise kappa values ranged from 0.65 to 0.90. The three adjudicators had 12%, 9%, and 10% of their death classifications overruled. Conclusion Specialists in cardiology can attain a reasonably high agreement on outcomes in patients with stable coronary heart disease.

Objectives: To elucidate potential mechanisms for the clarithromycin-induced excess mortality observed in the CLARICOR trial during 2.6 year follow-up of patients with stable coronary artery disease. Methods: Cox analyses using out-of-hospital death as a proxy for sudden death compared to in-hospital (nonsudden) death. Result: In 100 of 189 (53%) cardiovascular (CV) deaths in which it was possible to examine the question, there was a strong association between place of death and the classification of CV death as sudden or not-sudden. The excess mortality in the clarithromycin group was confined to sudden CV death in patients not on statins at trial entry (HR: 2.61, 95% CI: 1.69–4.05, p < 0.0005). Other categories of deaths showed no marked drug-placebo difference. Conclusions: Short-term clarithromycin administration was significantly associated with increased risk of sudden CV death in stable coronary heart disease patients not using statins.

The relationship between myocardial ischemia revealed by exercise testing and ventricular arrhythmias on Holter monitoring, and the effect of anti-ischemic intervention on the incidence of ventricular arrhythmias in patients with residual ischemia were studied in 125 patients recovering from myocardial infarction. Prior to discharge exercise testing and 24-h Holter monitoring were carried out In patients with ST-segment depression (n = 34), ventricular arrhythmias on Holter monitoring were seen in 7 (21%) compared with 20 (22%) patients without ST-segment depression (NS). Patients were hereafter double-blindly randomized to intervention with verapamil (n = 63) or placebo (n = 62). One month after discharge, 24-h Holter monitoring was repeated. In the verapamil group ventricular arrhythmias increased from 25 to 33% (NS). In the placebo group the figures were 18 and 27%, respectively (NS). In patients with ST-segment depression and verapamil treatment, the prevalence increased from 25 to 38% (NS). In the placebo group the figures were 17 and 22%, respectively (NS). The differences between the groups were not significant. A significantly increased prevalence of ventricular arrhythmias was found in patients with either heart failure or non-Q-wave infarct. In these patients myocardial ischemia during exercise did not correlate with ventricular arrhythmias either. ST-segment depression during predischarge exercise testing correlated with neither the prevalence nor the incidence of ventricular arrhythmias, and anti-ischemic intervention with verapamil did not influence the incidence of ventricular arrhythmias in both patients with and without myocardial ischemia.

Background. Patients with stable coronary artery disease (CAD) have a poor prognosis. The aim of the study was to evaluate the extent to which serum high-sensitivity C-reactive protein (hs-CRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurement alone or together could be prognostic biomarkers in patients with stable CAD. Materials and methods. During the 2.6-year follow-up period 270 patients among the 4264 patients with stable CAD in the CLARICOR trial suffered myocardial infarction (MI) and 377 died (187 cardiovascular deaths (CVD)). Results. Serum NT-proBNP was significantly associated with MI (hazard ratio (HR), 1. 65 (refers to a 2.72 fold increase in serum level, p = 0.0005), CVD (HR, 2.42, p

Udgivelsesdato: 2010-Apr The association observed between coronary heart disease (CHD) and Chlamydia (Chlamydophila) pneumoniae antibodies prompted, during the 1990s, several primary and secondary prevention trials with various antibiotics. In our CLARICOR trial, a randomized placebo-controlled trial in 4372 patients with stable CHD, a brief clarithromycin regimen was followed, unexpectedly, by increased long-term mortality. We now compare C. pneumoniae antibody levels at entry with population levels, with the patients' individual histories, and with their subsequent outcomes. IgG antibody levels were somewhat raised, but elevated IgA and IgG titers were unrelated to entry data (including prior acute myocardial infarction), except for an association with smoking and with not using statins. Hazards of mortality and of other outcomes tended to slightly increase with IgA and decrease with IgG titers, but the unfavorable clarithromycin effect was unrelated to antibody levels and remains unexplained. Smoking-related lung disease probably underlies the link between heart disease and increased IgG titers.

Twenty-four hour Holter monitoring and symptom-limited exercise testing were carried out prior to discharge in 157 patients recovering from acute myocardial infarction. Supraventricular arrhythmias (SVT) during Holter monitoring were recorded in 15%, and ST segment depression during exercise in 27%. No association between exercise-provoked ischaemia and SVT was found in the late hospital phase of myocardial infarction. After the tests, patients were double-blindly randomized to treatment with verapamil 120 mg t.i.d. or placebo. One month after randomization 24 h Holter monitoring was repeated in 125 patients (verapamil = 63, placebo = 62). At one month a significantly increased incidence of SVT was found in the placebo group (25%) compared to the verapamil-treated patients (9%) (P = 0.04). The increased prevalence in the placebo group was mainly due to an increased incidence of SVT in patients with exercise-induced ischaemia (P = 0.03). This increment was blurred in the verapamil group. In conclusion, the prevalence of SVT increases during the first month after myocardial infarction. The increase is most pronounced in patients with residual myocardial ischaemia and seemed to be prevented by treatment with verapamil.

To determine the best sites for ambulatory monitoring leads to detect myocardial ischaemia.50 consecutive patients recovering from myocardial infarction. Six patients were excluded because of unsatisfactory recordings or baseline electrocardiographic abnormalities that influenced the diagnostic accuracy of ST segment depression. In 38 patients important ST segment changes were seen before the study recordings.Reproducibility of detecting the electrocardiographic ST segment changes with 12 bipolar leads alone or in combination.The highest reproducibility rate was found in infarcts involving both the anterior and inferior left ventricular walls (80%). The reproducibility decreased as the extent of ventricular wall involvement decreased and was lowest in inferior infarcts (31%) (p0.001). For large infarcts the detection rate was almost equal for the 12 study leads, whereas disparity between leads increased as the infarct size decreased. The highest overall reproducibility was found in a transthoracic lead (V2, V9R) (76%). This lead was significantly better (p = 0.03) than lead CM5 (50%). When the transthoracic lead was combined with an inferior lead, the reproducibility increased (82%) and was significantly better than the combination of CM5 and an inferior lead (58%) (p = 0.02).Extensive ischaemic electrocardiographic changes are better detected than smaller ones and anterior infarcts better than inferior. A transthoracic lead (V2, V9R) was significantly better than CM5 both alone and when CM5 and the transthoracic lead were combined with an inferior lead.

Udgivelsesdato: 2010-Feb In the CLARICOR trial, significantly increased cardiovascular (CV) and all-cause mortality in stable patients with coronary heart disease were observed after a short course of clarithromycin. We report on the impact of statin treatment at entry on the CV and all-cause mortality. The multicenter CLARICOR trial randomized patients to oral clarithromycin (500 mg daily; n = 2172) versus matching placebo (daily; n = 2201) for 2 weeks. Patients were followed through public databases. In the 41% patients on statin treatment at entry, no significant effect of clarithromycin was observed on CV (hazard ratio [HR], 0.68, 95% confidence interval [CI], 0.38-1.22; P = 0.20) or all-cause mortality (HR, 1.08; 95% CI, 0.71-1.65; P = 0.72) at 2.6-year follow up. In the patients not on statin treatment at entry, clarithromycin was associated with a significant increase in CV (HR, 1.90; 95% CI, 1.34-2.67; P = 0.0003; statin-clarithromycin interaction P = 0.0029) and all-cause mortality (HR, 1.33; 95% CI, 1.05-1.67; P = 0.016; statin-clarithromycin interaction P = 0.41). Multivariate analysis and 6-year follow up confirmed these results. Concomitant statin treatment in stable patients with coronary heart disease abrogated the observed increased CV mortality associated with 2 weeks of clarithromycin.

SummaryBleeding following cardiac surgery involving cardiopulmonary bypass (CPB) remains a major concern. Coagulation factor XIII (FXIII) functions as a clot-stabilising factor by cross-linking fibrin. Low post-operative levels of FXIII correlate with increased post-operative blood loss. To evaluate preliminary safety and pharmacokinetics of recombinant FXIII (rFXIII-A2) in cardiac surgery, patients scheduled for coronary artery bypass grafting were randomised to receive a single dose of either rFXIII-A2 (11.9,25,35 or 50 IU/kg) or placebo in a 4:1 ratio.Study drug was given post-CPB within 10 to 20 minutes after first protamine dose. Patients were evaluated until day 7 or discharge, with a follow-up visit at weeks 5–7.The primary end-point was incidence and severity of adverse events.Thirty-five patients were randomised to rFXIII-A2 and eight to placebo. Eighteen serious adverse events were reported.These were all complications well recognised during cardiac surgery. Although one patient required an implantable defibrillator, all recovered without sequelae. One myocardial infarction in a patient receiving 35 IU/ kg rFXIII-A2 was identified by the Data Monitoring Committee after reviewing ECGs and cardiac enzymes. No other thromboembolic events were seen. Dosing with 25–50 IU/kg rFXIII-A2 restored levels of FXIII to pre-operative levels, with a tendency towards an overshoot in receiving 50 IU/kg. rFXIII-A2, in doses from 11.9 IU/kg up to 50 IU/kg, was well tolerated. For postoperative FXIII replenishment, 35 IU/kg of rFXIII-A2 may be the most appropriate dose.

Objectives: We have reported increased 2.6-year mortality in clarithromycin- versus placebo-exposed stable coronary heart disease patients, but meta-analysis of randomized trials in coronary heart disease patients showed no significant effect of antibiotics on mortality. Here we report the 6-year mortality of clarithromycin- versus placebo-exposed patients and updated meta-analyses. Methods: Centrally randomized, placebo controlled multicenter trial. All parties were blinded. Analyses were by intention to treat. Meta-analyses followed the Cochrane Collaboration methodology. Results: We randomized 4,372 patients with stable coronary heart disease to clarithromycin 500 mg (n = 2,172) or placebo (n = 2,200) once daily for 2 weeks. Mortality was followed through public register. Nine hundred and twenty-three patients (21.1%) died. Six-year mortality was significantly higher in the clarithromycin group (hazard ratio 1.21, 95% confidence interval 1.06–1.38). Adjustment for entry characteristics (sex, age, prior myocardial infarction, center, and smoking) did not change the results (1.18, 1.04–1.35). Addition of our data to that of other randomized trials on antibiotics for patients with coronary heart disease versus placebo/no intervention (17 trials, 25,271 patients, 1,877 deaths) showed a significantly increased relative risk of death from antibiotics of 1.10 (1.01–1.20) without heterogeneity. Conclusions: Our results stress the necessity to consider carefully the strength of the indication before administering antibiotics to patients with coronary heart disease.

Signs of myocardial involvement are common in patients with acute cerebrovascular events. ST segment deviations, abnormal left ventricular function, increased N-terminal pro-brain natriuretic peptide (NT-proBNP), prolonged QT interval, and/or raised troponins are observed in up to one third of the patients. The huge majority of these findings are fully reversible. The changes may mimic myocardial infarction, but are not necessarily identical to coronary thrombosis. Based on the literature these signs may represent an acute catecholamine release provoked by the cerebrovascular catastrophe itself and not coronary thrombosis. However, all patients with signs of cardiac involvement during acute cerebrovascular events should receive a cardiological follow-up in order to exclude concomitant ischemic heart disease.

Verapamil is effective as antianginal medication but contraindicated in patients with congestive heart failure. Angiotensin-converting enzyme (ACE) inhibitors improve survival in patients with congestive heart failure but have limited effect on patients with angina pectoris. No studies have been published on the combined treatment with verapamil and ACE inhibitors in patients with stable angina pectoris and left ventricular dysfunction. We performed an open study in 14 patients with angina pectoris and ejection fraction < 40%. The patients received verapamil 180 mg and trandolapril 2 mg twice daily for 3 months. We found a significant increase in ejection fraction from 28 +/- 6 to 35 +/- 11 (p < 0.03), wall motion index from 1.0 +/- 0.3 to 1.2 +/- 0.3 (p < 0.03), exercise duration from 6.9 +/- 2.5 to 7.7 +/- 2.9 minutes (p < 0.01), and ratio of exercise to rest rate-pressure product from 2.2 +/- 0.4 to 2.5 +/- 0.6 (p < 0.02). Use of nitroglycerin and number of angina pectoris attacks were both significantly reduced after 3 months of treatment. These findings support the hypothesis that the combination of verapamil and trandolapril is useful in patients with attenuated left ventricular function and angina pectoris.

The efficacy of a sustained-release preparation of verapamil (verapamil-SR) has been compared with that of a conventional instant-release formulation (verapamil-IR) in 10 patients with stable angina pectoris treated for 3 weeks with both preparations. The diurnal serum concentrations of verapamil and norverapamil did not differ significantly during treatment with verapamil-IR 120 mg t.i.d. and verapamil-SR 360 mg once daily, but verapamil-SR 240 mg produced significantly lower serum concentrations. The differences did not affect the exercise capacity or the occurrence of ST-segment depression during maximal exercise. Verapamil-SR was well tolerated. A multiple instant-release dosage regime can now be replaced by once daily administration of the sustained-release preparation.

Of 388 patients consecutively referred to echocardiography, 49 were suspected of having a cardiac source of systemic arterial embolism (SE). Mitral annulus calcification (MAC) was revealed in 27% of the patients with SE and in 8% of the remaining patients (p less than 0.05). The group of patients with SE were slightly older (median age 67 years) and included more female patients (47%) compared to the group without SE (62 years, p less than 0.05; 40% female patients, p greater than 0.05). However, the small differences in age and sex distribution did not explain satisfactorily the considerably increased prevalence of MAC in the group of patients with SE. Our preliminary data indicated that thromboembolism caused by left atrial dilatation and atrial fibrillation might be the most important cause of the condition in patients with MAC and SE. However, the significance of the possible mechanisms of embolism in patients with MAC and the incidence of the complication should be further clarified before therapy and prophylaxis can be suggested.