Prophylaxis therapy in haemophilia A: current situation in Spain

Summary. The Spanish Epidemiological Study in Haemophilia carried out in 2006 enrolled 2400 patients [2081–86.7% with haemophilia A (HA) and 319–13.3% with haemophilia B]; 465 of them (19.4%) were on prophylaxis. These rates were higher in patients with severe haemophilia (45.4%) and severe paediatric cases (72.5%). On the basis of information recorded in this study, we analysed the current situation of prophylaxis therapy administered to patients with HA in Spain, as well as their orthopaedic status. Prophylaxis was used in 399 (19.2%) patients with HA; such prophylaxis was primary (PP) in 20.3% and secondary (SP) in 75.9% of cases. Among severe HA patients, 313 (45.9%) were on prophylaxis (22.3% on PP and 74.7% on SP). Taking into account the patients’ age, 34.7% of severe HA adults were on prophylaxis (6% PP and 92.1% SP), whereas 71.5% of severe HA paediatric patients (40.5% PP and 55.4% SP) received this kind of treatment. Established haemophilic arthropathy (EHA) was detected in 142 from 313 severe HA patients (45.3%) on prophylaxis, but only in 2.9% of patients under PP vs. 59% of patients receiving SP. There was no EHA in adult severe HA patient on PP, whereas 70.4% on SP had joint damage (P < 0.00001). Among paediatric severe HA patients, EHA was detected in 3.3% under PP and 37.8% under SP (P < 0.00001). In conclusion, our data suggest that an early initiation of prophylaxis avoids EHA in the long‐term in patients with severe HA. We should emphasize the early onset of prophylaxis regimens.     

Prevalence of supraventricular arrhythmias from the automated analysis of data stored in the DDD pacemakers of 617 patients: the AIDA study

The confirmation of the occurrence of supraventricular arrhythmias (SVAs) is possible only if a surface electrocardiogram (ECG) is recorded during an episode, or if SVAs occur during 24 h ambulatory monitoring (Holter). The automatic interpretation of memory functions in DDD pacemakers may be useful in this diagnostic task over longer periods of follow up. This hypothesis was tested in 384 men and 233 women (mean age = 70 ± 11 years) who had received Chorus 6034/6035, 6234 or 7034 pacemakers (ELA Medical, Montrouge, France) with fall-back function in case of sustained SVAs. The Automatic Interpretation for Diagnostic Assistance (AIDA) algorithm included in these pacemakers was compared with 24 h Holters recorded simultaneously (DI) and with the clinical history of symptoms consistent with SVAs up to 28 days of follow up (D28). Indications for pacing were atrioventricular block (AVB) in 269 patients, sinus node dysfunction (SND) in 248, and AVB + SND in 100. SVAs were documented before implant in 199 patients (32%). Among the 617 patients included at D1. 76 (12.4%) developed at least one SVA episode, lasting between 1 min and 24 hours, simultaneously recorded on Holter and by AIDA with a 93.8% sensitivity and 94.2% specificity. Data from 354 patients were available for analysis at D28. AIDA diagnosed SVAs in 179 patients (50.6%), 104 of whom (65%) had remained asymptomatic and 117 of whom (65%) had had no SVA documented before implant. Among the 354 patients, AIDA diagnosed SVAs in 76 (21%) asymptomatic patients who had no known SVA before implant. The prevalence of SVA in our AVB population was higher than reported in previous studies: 89 patients (56.3%) with AVB had SVAs versus 90 patients (45.9%) with other diagnoses (p=0.55). Furthermore atrial pacing was associated with fewer SVAs. These first clinical results of the AIDA study demonstrate that the memory functions of Chorus pacemakers and the AIDA software are reliable to analyze the prevalence of SVA at 1 month of follow-up. From a clinical point of view, AIDA is a valuable tool to evaluate the efficacy of antiarrhythmic therapy, particularly as it pertains to the prevention of stroke due to atrial fibrillation.     

Peak Endocardial Acceleration-Based Clinical Testing of the "BEST" DDDR Pacemaker

The peak endocardial acceleration (PEA, unit g) shows a near correlation with myocardial contractility during the isometric systolic contraction of the heart (dP/dtmax), with sympathetic activity and, thus, with physiological heart rate modulation. The (Biomechanical Endocardial Sorin Transducer (BEST) sensor is incorporated in the tip of a pacing lead and measures PEA directly near the myocardium. In an international study, the lead was implanted with the dual chamber pacemaker Living-1 (Sorin) in 105 patients. The behavior of the PEA signal was tested under conditions of physical and mental stress and during daily life activities by 24-hour recordings of PEA (PEA Holter) at 1 to 2 months and approximately 1 year after implantation. Implantation of the BEST lead was performed without complications in all patients. The sensor functioned properly in the short- and long-term in 98% of patients. Although PEA values differed from patient to patient, the values closely reflected the variations in sympathetic activity due to physical and mental stress in each patient. During exercise and during daily life activities a close correlation between PEA and heart rate was observed among patients with normal sinus rhythm. Peak endocardial acceleration allows a nearly physiological control of the pacing rate.     

Is on‐demand treatment effective in patients with severe haemophilia?

Summary. On‐demand therapy enables stopping haemorrhages rapidly, reducing joint pain and restoring joint mobility, but does not prevent the beginning and subsequent development of haemophilic arthropathy. The main objective of this study was to identify the clinical and orthopaedic status of severe haemophilic patients with bleeding phenotype receiving on‐demand treatment in Spain. We conducted an epidemiological, observational, retrospective study, recruiting 167 patients from 36 centres (92% of them with haemophilia A), median age at enrolment of 35 years. Forty per cent of the patients received a combination of on‐demand and short‐term prophylaxis regimen; the rest was under on‐demand treatment. One hundred and forty‐five patients (87%) reported at least one bleeding episode and 22 (13%) of the biologically severe patients had no bleeding phenotype. Seventy‐one per cent of the studied population presented established haemophilic arthropathy, reaching 80% if we exclude patients without bleeding phenotype. Forty‐three per cent of these patients had one or two joints affected, 28% of them had three or four affected joints, 20% reported five or six affected joints and 9% more than six injured joints. An increase in established haemophilic arthropathy with age was observed. Forty‐six patients underwent orthopaedic surgery at least once. These data show that on‐demand therapy is not effective in preventing the development of haemophilic arthropathy in severe haemophilic population with bleeding phenotype. Therefore, we suggest that the optimal treatment in these patients should be based on prophylaxis. We recommend analysing the reasons for ending prophylaxis, in case its reinstatement should be necessary.     

ECAT angina pectoris study: baseline associations of haemostatic factors with extent of coronary arteriosclerosis and other coronary risk factors in 3000 patients with angina pectoris undergoing coronary angiography

The ECAT Angina Pecioris Study is a European multicentre studyinvestigating the pathogenetic and possibly predictive roleof the haemostatic system in the progress of coronary heartdisease. In this paper we report the cross-sectional analysisof haemostatic factors in 3043 patients, who underwent coronaryangiography due to angina pectoris. Fibrinogen levels were higherin patients with one or more coronary stenoses of at least 50%than in patients without, by an average of 0.16 g. l^–1(P <0.0001). Depressed fibrinolytic activity due to higherlevels of PAI was also associated with the presence of coronarystenoses. There was no association with the extent of coronaryarteriosclerosis, as assessed by the number of involved arteries,except that patients who had more vessels with total occlusionshad higher fibrinogen levels. Depressed fibrinolytic activitywas also clearly associated with diabetes, obesity, higher triglyceridelevels, smoking and impaired cardiac pump function as assessedby ejection fraction. Cholesterol levels were particularly correlatedwith protein C and plasminogen.     

Doppler haemodynamic assessment of clinically and echocardiographically normal mitral and aortic Allcarbon valve prostheses

Doppler echocardiographic characteristics of normally functioningAllcarbon prostheses were studied in 149 consecutive patientswith 157 valves in the mitral (n=73) and aortic (n=84) positionswhose function was considered normal by clinical and echocardiographicevaluation. In the mitral position, the mean gradient and theeffective mitral orifice area were not significantly differentin either the 25-mm or the 31-mm size valves (from 5±1to 4±1 mmHg and from 2.2±0.6 to 2.8±0.9cm², respectively; P=ns for both). Conversely, peak gradientwas significantly and inversely correlated to actual orificearea (r=–0.70; P<0.0006), decreasing from 15±3mmHg in the 25-mm size valve to 9±1 mmHg in the 31-mmsize. In the aortic position, the mean gradient was 29±8 mmHgin the 19-mm size valve; it decreased to 8±2 mmHg inthe 29-mm size. Effective prosthetic aortic valve area, calculatedusing the continuity equation, ranged between 0.9±0.1cm² for the 19-mm size valve to 4.1±0.7 cm² for the 29-mmsize. By analysis of variance, effective prosthetic aortic valvearea differentiated various valve sizes (F=25.3; P<0.0001)better than peak (F=5.34; P=0.012) or mean (F=4.34; P=0.0052)gradients alone, and it correlated better with actual orificearea (r=0.89, r=–0.70 and r=–0.65, respectively).This study provides the normal range for Doppler haemodynamiccharacteristics of the various sizes of the Allcarbon valvein the mitral and aortic positions so that prosthetic malfunctioncan be identified.     

Utilization of coronary angioplasty and cost of angioplasty disposables in 14 western European countries

An inventory has been made of the practice of angioplasty in14 European countries from 1985 onwards. The numbers of proceduresperformed varied in 1985 from 3 to 186 per million inhabitants,in 1991 from 52 to 716. All countries showed a steady increase,but the highest performer, Belgium, achieved only 55% of thenumber of angioplasties performed in 1991 in the U.S.A. No relationwas found between the number of angioplasties and death ratefor ischaemic heart disease, national income, number of cardiologistsor spending on health care. The number of catheterization laboratorieswas related to the number of procedures. Prices of angioplasty disposables varied widely between countries.In 1989 Italy and Spain had very high costs, averaging almost2500 ECU and 2000 ECU for ACS and Schneider balloon cathetersrespectively, while Switzerland and the U.K. were cheap withcosts between 700 ECU and 500 ECU for the same products. In1991 average prices for balloon catheters fell by 25% in Spain,while in Switzerland average prices increased by 10%, bringingthe almost four-fold price difference in 1989, down to a differenceof 2.5 in 1991. If the U.S.A. is taken as a standard and set against the deathrate from ischaemic heart disease in Western Europe in 1991the number of ‘missing’ angioplasties was 215 500,the U.K. accounting for 42% of this deficit.     

Viral safety of a pasteurized, monoclonal antibody-purified factor VIII concentrate in previously untreated haemophilia A patients

The efficacy and viral safety of a pasteurized, immunoaffinity-purified procoagulant factor VIII protein (FVIII:C; Monoclate-P) was studied in two multicentre, prospective, open-label trials in 30 previously untreated patients, 18 with severe (< 1% FVIII:C activity), and 12 with moderate (1% to 5% FVIII:C activity) haemophilia A. Clinical assessments, performed at screening and regularly thereafter for 6 to > 24 months (maximum 34 months), showed that none of 24 assessable patients acquired illnesses consistent with monitored transfusion-transmissible diseases. No patients acquired hepatitis B surface antigen, or antibodies against hepatitis B core antigen, hepatitis C, or human immunodeficiency virus. Likewise, no patients acquired treatment-related hepatitis A antibodies or sustained elevations of alanine aminotransferase levels. The safety profile for Monoclate-P is brought about by a multi-step safety system that incorporates viral inactivation (through a combination of immunoaffinity chromatography and pasteurization) plus donor screening, plasma testing, and quality assurance. The inhibitor development rate (13% low titre, 10% high titre) was similar to that reported in the literature for other FVIII concentrates (24% to 52%). The most frequently reported adverse events were related to typical infant and childhood diseases. Monoclate-P was effective in all patients treated according to protocol, except in two, who developed inhibitors.