A comparative analysis of heterogeneity in commercially available recombinant factor VIII products.

INTRODUCTION: Advances in analytical technologies enable investigation of possible correlations between molecular structure, aggregation and subvisible particle content. Regulatory agencies place increasing attention on potential risks associated with protein aggregates in the micron range in biological therapeutics. AIM: Assess the heterogeneity, high-molecular-weight protein (HMWP) species, subvisible particle content and posttranslational modifications in six commercially available recombinant FVIII (rFVIII) products. METHODS: Three B-domain-deleted (BDD) or B-domain truncated rFVIII products (turoctocog alfa, simoctocog alfa and moroctocog alfa) and three full-length rFVIII products (octocog alfa FS and two octocog alfa) were analysed. HMWP content, amount of micron range subvisible particles, tyrosine-1680 sulphation and N-glycan analysis were investigated. RESULTS: The B-domain-modified products had more protein size homogeneity vs the full-length products. Size exclusion-high-performance liquid chromatography data indicated no association between B-domain structure and aggregate content or size of the products tested. The rFVIII products showed large variation in subvisible particle concentration, with turoctocog alfa and simoctocog alfa having the lowest numbers (1000-1600 and 1800-2400 particles/100 IU, respectively). Turoctocog alfa and simoctocog alfa displayed the most complete tyrosine sulphation (>99.5%). CONCLUSION: Overall, there was no association between molecular structure (full-length B-domain, BDD or truncated) and subvisible particle or HMWP content. Dissimilarities may be related to production and product handling differences. In this study, turoctocog alfa, such as simoctocog alfa, had one of the lowest levels of subvisible particles and HMWP content, and high protein size homogeneity.

Efficacy of dofetilide in the treatment of atrial fibrillation-flutter in patients with reduced left ventricular function: a Danish investigations of arrhythmia and mortality on dofetilide (diamond) substudy.

BACKGROUND: In patients with left ventricular dysfunction, atrial fibrillation and flutter (AF and AFl, respectively) are common arrhythmias associated with increased morbidity and mortality. The present study investigated the potential of dofetilide in AF-AFl patients with left ventricular dysfunction to restore and maintain sinus rhythm, which might reduce mortality and hospitalizations. METHODS AND RESULTS: In the Danish Investigations of Arrhythmia and Mortality ON Dofetilide (DIAMOND) studies, 506 patients were in AF-AFl at baseline. Over the course of study, cardioversion occurred in 148 (59%) dofetilide- and 86 (34%) placebo-treated patients. In these patients, the probability of maintaining sinus rhythm for 1 year was 79% with dofetilide versus 42% with placebo (P<0.001). Dofetilide had no effect on all-cause mortality, but restoration and maintenance of sinus rhythm was associated with significant reduction in mortality (risk ratio [RR], 0.44; 95% CI, 0.30 to 0.64; P<0.0001). In addition, dofetilide therapy was associated with a significantly lower risk ratio versus placebo for either all-cause (RR, 0.70; 95% CI, 0.56 to 0.89; P

Trandolapril reduces the incidence of atrial fibrillation after acute myocardial infarction in patients with left ventricular dysfunction.

BACKGROUND: Studies have suggested that ACE inhibitors have an antiarrhythmic effect on ventricular arrhythmias. Whether they have an effect on atrial fibrillation is unknown. METHODS AND RESULTS: We investigated the effect of ACE inhibition with trandolapril on the incidence of atrial fibrillation in patients with reduced left ventricular function secondary to acute myocardial infarction. The patients in this study were those who qualified for inclusion into the TRAndolapril Cardiac Evaluation (TRACE) study, a randomized double-blind placebo-controlled study and who had sinus rhythm on the ECG obtained at randomization. Patients who fulfilled the criteria for inclusion were randomized to treatment with the ACE inhibitor trandolapril or placebo and were followed up for 2 to 4 years. Development and time to occurrence of atrial fibrillation in one 12-lead ECG recorded at the outpatient visits was the primary end point of this investigation. Of the 1749 patients included in the TRACE study, 1577 had sinus rhythm on the ECG recorded at randomization. Of these patients, 790 were randomized to trandolapril treatment and 787 to placebo treatment. The groups differed only slightly with respect to baseline characteristics. A total of 64 patients developed atrial fibrillation during the 2- to 4-year follow-up period. Significantly more patients developed atrial fibrillation in the placebo group than in the trandolapril group, 5.3% (n=42) versus 2.8% (n=22), respectively, P<0.05. Cox multivariable regression analysis, adjusting for important baseline characteristics, revealed that trandolapril treatment significantly reduced the risk of developing atrial fibrillation (RR, 0.45; 95% CI, 0.26 to 0.76; P<0.01). CONCLUSIONS: The results from the present study demonstrate that trandolapril treatment reduces the incidence of atrial fibrillation in patients with left ventricular dysfunction after acute myocardial infarction.

The occurrence and prognostic significance of atrial fibrillation/-flutter following acute myocardial infarction. TRACE Study group. TRAndolapril Cardiac Evalution.

AIMS: To investigate the occurrence and prognostic significance of atrial fibrillation/-flutter following acute myocardial infarction. METHODS AND RESULTS: The occurrence and prognostic significance of atrial fibrillation/-flutter were studied in 6676 consecutive patients with acute myocardial infarction screened in 27 centres in Denmark for inclusion into the TRAndolapril Cardiac Evaluation (TRACE) study. Information about occurrence of atrial fibrillation/-flutter during hospitalization was prospectively collected for the following three periods: day 1-2, day 3-4 and from day 5 until discharge. A total of 1395 patients (21%) suffered from atrial fibrillation/-flutter in one or more of the specified periods during hospitalization. Patients with atrial fibrillation/-flutter were significantly older, a significantly greater proportion were women, left ventricular systolic dysfunction was more extensive, thrombolytic therapy was received less frequently, and anterior Q wave myocardial infarction was experienced more frequently than patients without atrial fibrillation/-flutter. History of acute myocardial infarction and/or angina pectoris was similar in patients with and without atrial fibrillation/-flutter, whereas significantly more patients with atrial fibrillation/-flutter had a history of hypertension, congestive heart failure, diabetes mellitus, pulmonary disease and stroke. The unadjusted in-hospital mortality rate was significantly higher in patients with atrial fibrillation/-flutter in one or more of the specified periods during hospitalization (18%) than in patients without atrial fibrillation/-flutter (9%), P<0.001. After adjustment for baseline characteristics, the presence of atrial fibrillation/-flutter was still associated with increased in-hospital mortality; odds ratio=1.5 (95% Cl: 1.2-1.8), P<0.001. In patients surviving hospitalization, the unadjusted 5-year mortality rate was also significantly higher in patients suffering from atrial fibrillation/-flutter (56%) than in patients without atrial fibrillation/-flutter (34%), P<0.001. After adjustment for important prognostic baseline characteristics, the presence of atrial fibrillation/-flutter was still associated with an increased mortality, relative risk=1.3 (95% Cl: 1.2-1.4). Subgroup analysis revealed that sustained atrial fibrillation/-flutter during hospitalization was associated with the highest risk of dying, relative risk=1.4 (95% Cl: 1.2-1.7). CONCLUSION: Atrial fibrillation/-flutter often occurs after acute myocardial infarction and our analysis demonstrated that it was an independent predictor of an increased short and long-term mortality.

[The significance of trandelapril for mortality after AMI in patients with reduced left ventricular function. TRACE Study Group]. / Trandolaprils betydning for overlevelse efter AMI hos patienter med nedsat funktion af venstre ventrikel. TRACE Study Group.

Angiotensin converting-enzyme (ACE) inhibition reduces mortality among patients surviving an acute myocardial infarction, but whether to give ACE-inhibitors to all patients or target their use to selected patients is unclear. Seven thousand and one consecutive enzyme-confirmed myocardial infarctions were screened. One thousand seven hundred and forty-nine patients with echocardiographic signs of left ventricular dysfunction were randomized to oral trandolapril (876 patients) or placebo (873 patients) starting from days three to seven following the infarction. Average follow-up was 27 months. There were 304 deaths (34.7 percent) among patients on trandolapril vs. 369 deaths (42.3 percent) among patients on placebo (p = 0.0013). Relative risk (RR) of death in the trandolapril group was 0.78 (95% confidence interval (CD 0.67-0.91). Trandolapril reduced cardiovascular death (RR 0.75, CI 0.63-0.89) and sudden death (RR 0.76, CI 0.59-0.98). Progression to severe/resistant heart failure was reduced (RR 0.71, CI 0.56-0.90). Recurrent myocardial infarction (fatal or non-fatal) was not significantly reduced (RR 0.86, CI 0.66-1.13). It is concluded that long-term treatment with trandolapril in patients with reduced left ventricular function shortly after myocardial infarction significantly reduced total mortality. The substantial mortality risk reduction was obtained in 25% of consecutive patients screened for entry encouraging a selective use of ACE inhibition following myocardial infarction.

A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group.

BACKGROUND: Treatment with angiotensin-converting-enzyme (ACE) inhibitors reduces mortality among survivors of acute myocardial infarction, but whether to use ACE inhibitors in all patients or only in selected patients is uncertain. METHODS: We screened 6676 consecutive patients with 7001 myocardial infarctions confirmed by enzyme studies. A total of 2606 patients had echocardiographic evidence of left ventricular systolic dysfunction (ejection fraction, < or = 35 percent). On days 3 to 7 after infarction, 1749 patients were randomly assigned to receive oral trandolapril (876 patients) or placebo (873 patients). The duration of follow-up was 24 to 50 months. RESULTS: During the study period, 304 patients (34.7 percent) in the trandolapril group died, as compared with 369 (42.3 percent) in the placebo group (P = 0.001). The relative risk of death in the trandolapril group, as compared with the placebo group, was 0.78 (95 percent confidence interval, 0.67 to 0.91). Trandolapril also reduced the risk of death from cardiovascular causes (relative risk, 0.75; 95 percent confidence interval, 0.63 to 0.89; P = 0.001) and sudden death (relative risk, 0.76; 95 percent confidence interval, 0.59 to 0.98; P = 0.03). Progression to severe heart failure was less frequent in the trandolapril group (relative risk, 0.71; 95 percent confidence interval, 0.56 to 0.89; P = 0.003). In contrast, the risk of recurrent myocardial infarction (fatal or nonfatal) was not significantly reduced (relative risk, 0.86; 95 percent confidence interval, 0.66 to 1.13; P = 0.29). CONCLUSIONS: Long-term treatment with trandolapril in patients with reduced left ventricular function soon after myocardial infarction significantly reduced the risk of overall mortality, mortality from cardiovascular causes, sudden death, and the development of severe heart failure. That mortality was reduced in a randomized study enrolling 25 percent of consecutive patients screened should encourage the selective use of ACE inhibition after myocardial infarction.

[Transesophageal atrial stimulation is useful in supraventricular arrhythmias]. / Transøsofageal atrial stimulation er brugbar ved supraventrikulaere arytmier.

The results of transoesophageal atrial stimulation (TAS) were retrospectively evaluated in 22 patients (13 women, nine men, mean age forty-five years), in whom the method was used in the process of diagnosing or specifying supraventricular arrhythmias. The patients were tested for corrected sinus node recovery time, the response to incremental stimulation and burst pacing. TAS resulted in a pathological outcome in 11 patients (50%). Among 14 patients suffering from unprovoked palpitations suspicious of tachyarrhythmias TAS was able to induce a pathological response in 10 patients (71%). In five of eight patients (63%) with inducible SVT, this arrhythmia had not previously been observed. TAS was able to induce atrial fibrillation in four of eight patients with an accessory pathway. Typical symptoms rather than a prior pathological electrocardiography (12-lead ECG, Holter-monitoring, exercise-ECG) was able to predict the outcome of TAS (p < 0.05). We conclude that TAS is a safe and suitable supplement in the evaluation of supraventricular arrhythmias; primarily among patients with characteristic symptoms.

Regulation of tissue-type plasminogen activator-mediated fibrinolysis by plasminogen activator inhibitor type-1 in patients with ischaemic heart disease: possible unfavourable effect of diuretics.

BACKGROUND: Impaired endogenous tissue-type plasminogen activator (t-PA)-mediated fibrinolysis may be involved in the evolution of myocardial infarction. t-PA-mediated fibrinolysis is believed to depend on the amount of active t-PA present in the circulation. Accordingly, we investigated the possible mechanisms responsible for impaired t-PA-mediated fibrinolysis in patients with ischaemic heart disease. METHODS: Forty-five survivors of acute myocardial infarction were examined 8 weeks after discharge from hospital. Intravenous infusion of 1-desamino-8-D-arginine vasopressin (DDAVP; 0.4 micrograms/kg bodyweight) was used to stimulate the endogenous fibrinolytic system, and blood samples were collected before and after infusion. We compared the response of the t-PA-plasminogen activator inhibitor type-1 (PAI-1) fibrinolytic system in patients with preinfusion levels of active t-PA below or at the detection limit of the assay with that in patients with higher preinfusion levels of active t-PA. RESULTS: All patients responded to DDAVP infusion with an increase in plasma concentration of t-PA antigen. This response did not differ between the two groups. In contrast, the preinfusion levels of PAI activity were significantly higher in patients with undetectable plasma levels of active t-PA compared with patients with higher levels of active t-PA (22.3 versus 12.8 IU/ml; P < 0.01). Subgroup analyses demonstrated that patients treated with diuretics had significantly higher plasma concentrations of PAI-1 antigen (28.5 versus 17.9 ng/ml; P < 0.03) and a trend towards higher PAI activity (24.0 versus 14.6 IU/ml; P = 0.07) compared with patients not receiving diuretics. CONCLUSION: Our study strongly suggests that a high plasma level of PAI-1, the main inhibitor of t-PA, is responsible for impaired t-PA-mediated fibrinolysis in patients with ischaemic heart disease, and that treatment with diuretics may be associated with an unfavourable effect on the fibrinolytic system.

[Adenosine in the diagnosis and treatment of tachycardia]. / Adenosin i diagnostik og behandling af takykardi.

The correct diagnosis of tachycardia is important for reasons of treatment and prognosis. Intravenous bolus injection of adenosine can be used to diagnose tachycardia as ventricular or supraventricular and to convert AV-nodal re-entry tachycardia as well as re-entry tachycardia due to an accessory pathway. The effect of adenosine on different types of tachycardia is demonstrated. A strategy is proposed for examination and treatment of patients with manifest tachycardia to improve diagnosis and remove bias to supraventricular tachycardia and underdiagnosis of ventricular tachycardia.

[Familial neurofibromatosis and hypertrophic obstructive cardiomyopathy]. / Familiaer neurofibromatose og hypertrofisk obstruktiv kardiomyopati.

Two brothers both with hypertrophic obstructive cardiomyopathy, one of them also with neurofibromatosis are described. Only a few cases with this combination of diseases have been reported. The possibility of a coincidence or a causal relationship is mentioned. The importance of echocardiography in persons with cardiac murmurs is emphasized even in cases where the electrocardiogram and thoracic x-ray are normal.

[Telemetric monitoring of esophageal ECG]. / Telemetrimonitorering af esophagus-ekg.

Recording of the esophageal ECG is important in differentiating between different types of tachycardia. A method is described by which the Arzco pill electrode can be re-used. The electrode is introduced through the nose and connected to a telemetric monitor. In this way the esophageal ECG can be monitored continuously in order to characterize transient, self-limiting tachycardias. Monitoring has been performed for up to four days without problems.

[ST elevation in a patient with a healthy heart and acute appendicitis]. / ST-elevation hos en hjerterask patient med appendicitis acuta.

A male aged 57 years with acute appendicitis was found to have ST elevations in the EGG (precordial V1-V3 leads) suggesting acute myocardial infarction. The ECG returned to normal postoperatively. The patient showed no signs of ischaemic heart disease and the exercise test and myocardial scintigraphy were found to be normal.

[The patterns of admission for patients with suspected acute myocardial infarction]. / Indlaeggelsesmønstret for patienter mistaenkt for akut myokardieinfarkt.

The patterns of admission to hospital for 161 patients with suspected acute myocardial infarction during the period 1.2.1988-30.9.1988 were investigated. This revealed that 59% called their doctor, 20% called the ambulance directly, 11% arrived at the doctor's office or casualty department and 7% were admitted with cardiac arrest. The durations of delay were investigated. The median duration of delay by the doctor was 15 minutes but only 7% of the cases were escorted to hospital by the doctor. In 53% of the cases, the doctors waited for the ambulance without escorting the patient. In 40% of the cases, the doctors did not wait for the ambulance. 44% of the patients with acute myocardial infarction referred to hospital by doctors who did not accompany them were in poor condition on arrival (one patient died in the ambulance). 33% of these patients died in hospital. The ambulances were staffed by three persons with paramedical training in only 5% of the cases when the patient first called the doctor and in 41% of the cases when the ambulance was called as an emergency. The study reveals that prehospital treatment of cardiac patients should be improved.

[Body temperature measurement. Rectal--oral?]. / Måling af legemstemperatur. Rektalt--oralt?

The reliability of daily routine oral temperature measured by the nursing staff with an electronic thermometer was tested by comparing the measurements with rectal temperature measured with a mercury thermometer. In each patient, rectal temperature was measured by the author just after the oral temperature measurement. The nursing staff was not informed about the investigation. In a small group of 12 patients with clinical suspicion of fever, six patients had normal oral temperatures (less than or equal to 37 degrees C). Three of these had rectal temperatures greater than or equal to 38 degrees C. In another group of 11 patients selected because of a normal oral morning temperature (less than or equal to 36.5 degrees C) seven had slightly elevated rectal temperatures (37.1-37.3 degrees C). Thus, a significant number of patients in the two groups had false normal oral temperatures. In five of the 12 and four of the 11 patients, the rectal temperature was 1 degree C or more above the oral temperature. The reason for measuring too low oral temperatures seems to be difficulties in avoiding external influence. The use of different measuring points each with its own lower limit of fever might lead to misinterpretation of the patients' temperature curve. Abolition of the mercury thermometer represents environmental progress. Unfortunately the sensor of the electronic thermometer, which is discarded after use, contains considerable amounts of different metals, mainly copper but also heavy metals. The rectum should remain the site of measurement of body temperature and the digital reuse thermometer the measuring device.

Surgery of ventricular tachycardia and ventricular fibrillation in patients with coronary artery disease and LV-aneurysms.

In 26 patients with left ventricular aneurysm and ventricular tachycardia and/or ventricular fibrillation following myocardial infarction, coronary angiography, left ventriculography and electrophysiologic examination were performed preoperatively. Surgery in all cases consisted of aneurysmectomy and mapping-guided endocardial resection of the area found to be the arrhythmogenic center. Four patients died peroperatively or during the postoperative hospital stay. The 22 survivors were followed up for 3-48 (mean 22) months postoperatively. There were no late deaths. Repeated electrophysiologic studies were performed in 18 of the survivors. Freedom from ventricular tachycardia and fibrillation was achieved in 21 patients, 17 after surgery alone and four after combined surgical and medical treatment. The remaining patient still has ventricular tachycardia despite combined treatment.

Skin perfusion pressure measured by isotope washout in legs with arterial occlusive disease. Evaluation of different tracers, comparison to segmental systolic pressure, angiography and transcutaneous oxygen tension and variations during changes in systemic blood pressure.

The skin perfusion pressure (SPP) measured as the isotope washout cessation external pressure is valuable in selection of major amputation level. Five methodological investigations important to clinical use were carried out: (1) In five normal legs and 10 legs with arterial occlusive disease (AOD), 131I- -antipyrine (131I- -a.p.) was compared to Na(131I-) and 99Tcm-pertechnetate (99Tcm). The average SPP by 131I- -a.p. and by 131I- were approximately equal, 57.0 mmHg (range 18-93) compared to 56.3 mmHg (range 13-88) (P greater than 0.1). The average SPP by 99Tcm was just slightly higher, 60.3 mmHg (range 18-98) (P less than 0.02). The average washout constant for the three different tracers were approximately equal and correlated statistically significant with the SPP; (2) In 59 legs with AOD, segmental SPP was compared to segmental systolic blood pressures on the thigh, calf, ankle and first digit (strain gauge technique). The two different methods correlated statistically significant at all four levels, but the systolic blood pressures were higher than the SPP in particular in diabetic legs; (3) Angiograms in 35 legs with AOD showed that the SPP on the ankle was only consistently decreased in legs with arterial occlusions at two levels or more; (4) In 47 legs with AOD, the SPP on the calf or on the thigh was compared with transcutaneously measured pO2. The two different methods correlated statistically significant, but the scatter was great; (5) During induced variations in systemic blood pressure in seven patients (12 legs with AOD), the segmental SPP and the segmental systolic blood pressure were found on average to vary in proportion with intra-arterial mean and systolic pressure respectively; however, this proportional relationship was not valid for the individual leg. It is concluded that 99Tcm is as suitable as the 131I- -labelled tracers in estimating the SPP. The SPP is significantly correlated to skin blood flow, to systolic blood pressure, to tc pO2 and to angiographic findings. Correction of SPP for systemic blood pressure changes can be made in proportion with the measured variations in systemic mean blood pressure, but only for groups of patients.

Distribution of maximum coronary blood flow in the left ventricular wall of anesthetized dogs.

Blood flow in the circumflex branch of the left coronary artery was recorded by electromagnetic flowmeter. In a group of dogs progressive hemodilution was performed until the diastolic reactive hyperemic response to 10 s occlusion of the circumflex branch disappeared ("optimum" hemodilution). At this degree of hemodilution the distribution of blood flow in the left ventricular free wall was evaluated by measuring tissue activity concentrations of Xe-133 and radioactive microspheres after bolus injection into the aortic root. "Optimum" hemodilution was accompanied by a sixfold increase in systolic coronary flow, a 3-fold increase in diastolic flow and a relative endocardial hypoperfusion. These results indicate that the endocardial blood flow reserve is lower than the epicardial. This conclusion is supported by the influence of spontaneous oscillations of arterial blood pressure (Traube-Hering waves) on systolic and diastolic coronary blood flows before and during "optimum" hemodilution. In another group of dogs maximum coronary vasodilatation was produced by occlusion of the left coronary artery for 10 s. In this group the distribuition of Xe-133 and radioactive microspheres were measured after bolus injection into the aortic root at peak diastolic reactive hyperemia. The epi- and endocardial distribution of both Xe-133 and microspheres was uniform in the left ventricular wall, indicating a uniform flow to these regions. This might be explained by an increased endocardial perfusion during systole due to loss of myocardial contractility or by a decline towards resting level in epicardial flow at the time of injection, corresponding to a shorter duration of the hyperemic period in the epi- than endocardial region.

Regional blood flow in the left ventricular wall of dogs with a graded coronary artery stenosis.

Blood flow in the circumflex branch of the left coronary artery was recorded by electromagnetic flowmeter. In the area supplied by this branch vasodilatation was produced by progressive constriction until the diastolic reactive hyperemic response to 10 s occlusion disappeared ("optimum" stenosis). This degree of stenosis was accompanied by a 20% decrease in diastolic circumflex flow, while systolic flow remained unchanged. This distribution of blood flow in the left ventricular free was was evaluated at "optimum" stenosis by counting activity in tissue blocks following bolus injection of Xe-133 into the aortic root. When Xe-133 was injected immediately after occlusion of the left anterior descending branch the Xe-133 concentration of toncentration in the epicardial part. The concentrations in the two parts did not, however, differ significantly when occlusion of the left anterior descending branch was omitted. This indicates that the endocardial blood flow reserve is lower than the epicardial, and that, yet, a preferential fall in blood flow in the endocardial part of a post-stenotic area can be rapidly eliminated when blood supply from a neighbouring artery is available.