Department of Cardiology, Heartcentre, University Medical Centre St. Radboud, P.O. Box 9101, Nijmegen 6500 HB, The Netherlands
Received October 8, 2002;
accepted October 9, 2002
* Corresponding author. Tel.: +31-24-3614533; fax: +31-24-3540537
f.verheugt{at}cardio.umcn.nl
Of the 18 presentations at the three HotlineSessions of the 24th European Congress ofCardiology, held in Berlin, August 31–September 4, 2002, 16 are summarised, since two of the Hotline presentations have been published recently(Lancet, 2002; 360: 743–751, 752–760). Theauthors collected the information given during the presentations of the studies, as well as from press releases prepared by most of the speakers. This report only shows preliminary results.
During the first Hotline Session, studies on early treatment of acute coronary syndromes werepresented.
Professor Francisco Fernandez-Aviles fromValladolid, Spain, presented the GRACIA study. To 500 patients with ST-segment elevation acutemyocardial infarction, front-loaded rt-PA wasadministered within 12h of symptom onset. About 3h following thrombolytic therapy, patients were randomised to early angiography and subsequent percutaneous intervention to be performed within 24h, or to an ischaemia-guided conservativestrategy. The average time to percutaneous intervention in the invasive group was 17h afterfibrinolysis. In the conservative arm 19% of patients underwent revascularisation during hospital stay, but this was not considered an endpoint in this study. The primary endpoint of 30-day death,reinfarction and (re-) revascularisation wasreduced by 20%, from 6.0% in the alteplase groupto 4.8% in the alteplase plus intervention group 
. Thirty-day mortality was similar in both groups (2.5 and 2.0%) as was major bleeding (1.6 and 1.6%). The patients who required periprocedural abciximab, had nearly 3% bleedingversus 1% in those who did not need abciximab.
These results show that percutaneous intervention after fibrinolysis beyond the time of myocardial salvage is feasible and safe. Mortalitywas similar and astonishingly low for a fibrinolytic trial. More studies on an early invasive strategy after fibrinolysis in a less selected population are warranted.
The second study was presented by Professor Petr Widimsky from Prague, Czech Republic. In the PRAGUE-2 study 850 patients with acute ST-elevation myocardial infarction were randomised in hospitals without intervention facilities to either streptokinase, or to transport to an intervention centre for prompt primary percutaneous coronary intervention. Despite a 74-min delay in time from randomisation to initiation of reperfusion therapy, primary percutaneous coronary intervention after transport diminished the combined endpoint (30-day death, reinfarction and stroke) by 44%, from 15.2 to 8.4% 
. Symptom-to-balloon time was 277min and estimated time from symptoms to reperfusion was 245min in the streptokinase arm (60min after initiation of fibrinolysis). Mortality was reduced by 32%, from 10.0 to 6.8% 
. Transport proved to be safe.
The results of this trial corroborate well withthe recently presented DANAMI-2 study,1 where a benefit was also found for patients undergoingprimary coronary intervention after transport to an intervention centre. However, time to intervention in PRAGUE-2 was longer (277 versus 220min) anda less potent, first generation fibrinolytic wasapplied. Apparently, transport to an intervention centre in acute ST-elevation myocardial infarction seems to be feasible and safe, and reduces ischaemic events. However, angioplasty procedures for failed thrombolysis were extremely low in both trials and neither DANAMI-2 nor PRAGUE-2 reaches a statistically significant mortality benefit.
Dr Elliott Antman from Boston, MA, USA, presented the results of the MAGIC trial. In 6213high-risk patients with ST-elevation myocardialinfarction magnesium sulphate or placebo wasinfused, after a bolus injection, for 24h. Median time of treatment was 3.8h and infusion was complete in 91% of patients. Thirty-day mortality was similar in both groups: 15.3% in the magnesium group and 15.2% in the placebo group 
. No difference was found for other ischaemic complications of myocardial infarction either. Magnesium was well tolerated and there was no significant side effect compared to placebo.
After the promising results from smaller, earlier trials in the 1980s both the huge ISIS-42 and MAGIC trials have brought about a definite end to magnesium intervention in acute myocardial infarction. Possibly, the earlier trials were positive, because aspirin, beta-blockers and ACE-inhibitors were not standard therapy in those days. On the other hand, these findings suggest that magnesium sulphatecan be given safely to acute myocardial infarction patients with low magnesium blood levels and ventricular arrhythmia.
In the glucose–insulin–potassium (GIPS) study, Dr Felix Zijlstra from Zwolle, The Netherlands, randomised 940 patients undergoing primarypercutaneous coronary intervention for acute ST-elevation myocardial infarction to a glucose–insulin–potassium infusion or control treatment. Thirty-day mortality—the primary endpoint of the study—was decreased by 17%, from 5.8 to 4.8% by the infusion 
. In the 90% subset of patients in Killip class 1 at admission the benefit was large (a 71% mortality reduction from 4.2 to 1.2% 
), whereas the patients with Killip class more than 1 at admission fared worse with the glucose–insulin–potassium infusion. Mortality went up from 26.5% in the control group to 36.0% in the glucose–insulin–potassium infusion group 
.
This provocative study shows a large benefit of adjunctive glucose–insulin–potassium infusion in the subset of patients in Killip class 1 undergoing primary percutaneous coronary intervention for acute ST-elevation myocardial infarction. It seems that in patients with heart failure, glucose–insulin–potassium may be hazardous and counterproductive due to fluid overload. However, these observations should be interpreted with caution, as randomisation in this study did not include a stratification on Killip class. Clearly, more studies are necessary for the identification of the role of glucose–insulin–potassium infusion as adjunct to reperfusion therapy in acute myocardial infarction.
The topics of the second Hotline Session were coronary artery disease and rhythm disorders.Professor François Schiele from Besançon, France, presented the BEST study. This multicentre study randomised 254 patients eligible for percutaneous coronary intervention to either IVUS-guided balloon angioplasty or systematic stent-implantation. The rates of stent-implantation were 44 and 100%,respectively. Reasons for stenting in the IVUS group were mainly incomplete result (38%) or occlusion (7%). In the stent group procedures were quicker with better immediate result. With respect tothe restenosis rate at 6 months (primary endpoint) IVUS-guided balloon angioplasty was not inferior to systematic stenting: 16.8 versus 18.1%. The upper limit of the 95% confidence interval of the observed –1.3% difference was +7.1%, which was below the prespecified non-inferiority border of +8%. Rates of death, myocardial infarction, unstable angina or revascularisation were also similar: 16 versus 20% 
.
Vigorously discussing these results, Dr Bernie Meier from Bern, Switzerland, pointed out that although IVUS-guided angioplasty challengesunconditional stenting, it is a complex, time-consuming strategy which may even be more costly than currently emerging strategies using drug-eluting stents.
Professor Petr Widimsky from Prague, CzechRepublic, presented the PRAGUE-4 study. In this single centre study 400 consecutive low-riskpatients, who were clinically and angiographically suitable for CABG, were randomised by a cardiologist to either coronary surgery with cardiopulmonary bypass pump 
or ‘off-pump’ CABG 
. Of the patients randomised to off-pump surgery 84% were operated using this technique. Including cross-overs 203 patients underwent the classical operation and 185 were operated off-pump. The composite primary endpoint of death, myocardial infarction, stroke and newly required haemodialysis occurred in 3.8% of patients randomised to the classical operation versus 2.9%in patients randomised to off-pump surgery (intention-to-treat-analysis, 
). Hospital costs were lower with off-pump surgery: 3777 versus 5757 
.
The main conclusion of this study is that off-pump surgery is safe and widely applicable inselected low-risk patients.
Professor Patrick Serruys from Rotterdam, The Netherlands, presented the EURO-SPAH study. This prospective, double-blind study was performed in 23 European hospitals and included 403 patients with stable and unstable angina or silent ischaemia. After successful stenting of a de novo lesion in a major epicardial vessel patients underwent intravascular sonotherapy (1MHz) or sham treatment in a double-blind manner. The primary endpoint was to achieve with sonotherapy a reduction of late-loss by off-line quantitative coronary angiography at6 months of at least 25% or an absolute 0.21mm. At angiographic follow-up late loss was 0.86mm inthe sonotherapy group and 0.94mm in the sham group 
. Major adverse cardiac events (death, myocardial infarction or revascularisation) occurred in 18.8 and 25.9% of patients, respectively .
This study shows that intravascular sonotherapy seems safe and feasible, but does not reducelate/oss after stent-implantation. In the discussion Dr Karl Karsch from Bristol, UK, questioned the rationale of the study, since the exact mechanism of benefit of sonotherapy is still unknown. Also, the optimal ultrasound power and the mandatory duration of administration are not established as yet.
The results of the ACE trial were presented byDr Christoph Stellbrink from Aachen, Germany.This prospective, open-label, multicentre non-inferiority study compared the efficacy and safety of weight-adjusted subcutaneous enoxaparin (1mg/kg s.c. b.i.d. for the first 3–8 days, followed by 40 or 60mg b.i.d.) to conventional anticoagulation with intravenous unfractionated heparin (bolus 80IU/kg, 
72h infusion, initial rate 18U/kg/h,aim 2–3 times prolongation of aPTT) followed by phenprocoumon (target INR 2.0–3.0) in 496 patients undergoing cardioversion for atrial fibrillation. In the vast majority of patients (87%) transoesophageal echocardiography (TEE) was performed prior to cardioversion. The combined primary endpoint was the incidence of stroke, peripheral emboli,major bleeding and death at 28 days post cardioversion. In the per-protocol analysis enoxaparin was not inferior to conventional anti-coagulation: the primary endpoint occurred in 3.2% (7/216) and 5.7% (12/212) of patients, respectively (
, test for non-inferiority). Findings at intention-to-treat-analysis corroborated well: 2.8% (7/248) versus 4.8% (12/248).
Given its favourable profile of subcutaneousadministration, allowing out-patient therapywithout the need for monitoring, enoxaparin therefore may be an attractive alternative for conventional antiocoagulation. However, in this study event rates were low and TEE was performedfrequently. Therefore, the results of the ACEtrial need confirmation in larger studies without TEE prior to cardioversion under adequateanticoagulation.
The next speaker was Professor John Cleland from Kingston upon Hull, UK, presenting theresults of TEN-HMS. This international multicentre randomised study addressed the use of a remote Telemonitoring system (Philips Medical Systems) in the patients' home to reduce the number of days spent in hospital in 428 NYHA classes II–IV congestive heart failure patients with left ventricular systolic dysfunction. With the Telemonitoring system patients' ECG, blood pressure and weight were checked twice daily for early recognition and if possible, prevention of adverse events. Telemonitoring was randomly compared to nursetelephone monitoring, consisting of monthlytelephone contact, and to a reference groupreceiving usual care. With respect to the primary endpoint of the study, bed-days occupance,expressed as days alive and out-of-hospital, telemonitoring did not differ from nurse monitoring, but both were superior to usual care. Interestingly, at 400-day follow-up mean survival time was shorter with usual care: 295 days, as compared to 340 days with nurse monitoring and 347 days with telemonitoring 
.
Thus, in the outpatient setting heart failurepatients may benefit from regular monitoring,either by nurse telephone contact or a telemonitoring system.
The results of the ACTION study were alsopresented by Professor Patrick Serruys fromRotterdam, The Netherlands. This single-blindmulticentre trial studied the use of actinomycin-coated 18mm stents in 360 patients with a single de novo lesion in a major coronary vessel. Two doses of the cytotoxic antibiotic actinomycin, 2.5 and 10µg/cm2, were compared with control. The composite primary endpoint of this study was safety, expressed as the 30-day incidence of death, myocardial infarction and target lesion revascularisation. At interim-analysis the data safety monitoring board called for accelerated patient follow-up based on high revascularisation rates in the actinomycin groups. Finally, the primary end-point occurred in 10.2% of patients in the control group as compared to 18.3% in the 2.5µg/cm2actinomycin group and 28.1% in the 10µg/cm2actinomycin group 
. This difference was mainly due to a difference in target lesion revascularisation: 9.1% for control versus 17.5 and 23.1% in the low and high-dose actinomycin groups, respectively. At angiographic follow-up restenosis rates were 14, 27 and 28%, respectively. In a couple of patients receiving actinomycin-stents 6-monthIVUS showed the so-called ‘black-holes’, which have been associated with ‘malignant’ intimalhyperplasia.
These results show that the use of actinomycin-coated stents leads to higher rates of targetlesion revascularisation and restenosis. Although the exact impact of ‘black-holes’ may yet be unclear, their occurrence raises doubt on the overall safety of stents eluting cytotoxic agents.
The third Hotline Session consisted of trials on hypertension, left ventricular dysfunction and heart failure. The session was opened by Dr S. Kjeldsen from Oslo, Norway, who presented a substudy on 1326 patients from the LIFE study with isolated systolic hypertension. Inclusion criteria for this substudy were age 55–80 years, systolic blood pressure 160–200mmHg, diastolic blood pressure <90mmHg and electrocardiographic criteria for left ventricular hypertrophy. Patients were randomised to treatment with either losartan (50–100mg), or atenolol (50–100mg), which was combined with hydrochlorothiazide (12.5–25mg) in 90% ofpatients, aiming at a systolic blood pressure of 140mmHg. In both groups the mean systolic blood pressure was reduced from 174 to 145mmHg. The primary endpoint, a composite of cardiovascular death, stroke and myocardial infarction at 66-month follow-up, occurred in 12% of patients on losartan and 17% of patients on atenolol (risk reduction 26%, 
). The incidence of new diabetes was lower on losartan (risk reduction 38%, 
). The protective effect of losartan with respect to cardiovascular mortality in the LIFE study was particularly present in elderly patients with isolated systolic hypertension and electrocardiographic signs of left ventricular hypertrophy (
for treatment interaction). These results suggest that losartan may be more beneficial than atenolol in these relatively high-risk patients. However, in the absence of placebo-controlled trials with beta-blockers in patients with isolated systolic hypertension, it will be of interest to see how losartan compares to drugs with proven benefit in thissubset of patients.
Professor Willem Remme from Rhoon, TheNetherlands, presented the CARMEN study. This multicentre, double-blind trial studied the effects on left ventricular remodelling of carvedilol (25mg b.i.d.), enalapril (10mg b.i.d.) or the combination in 572 patients with stable NYHA II–III heart failure and a left ventricular ejection fraction <40%. In two-thirds of patients, previous ACE-inhibitor therapy was stopped 2 weeks before the study treatment phase. Primary endpoint was the difference in left ventricular systolic volume index (LVSVI) assessed by echocardiography at 18 months as compared to baseline. When compared to enalapril alone, combination treatment significantlyreduced LVSVI: –6 versus –1ml/m2
. The reduction in LVSVI with carvedilol alone did not differ from that on enalapril: –3 versus –1ml/m2. In this trial with a high proportion ofpatients recently withdrawn from ACE-inhibition, within-group differences in LVSVI at 18 months in patients on combination therapy or carvedilol alone were statistically significant. Enalapril alone did not reduce LVSVI, which may be explained by a difference in baseline LVSVI between the treatment groups.
Thus, the combination of carvedilol and enalapril significantly reduced the surrogate endpoint of left ventricular remodelling expressed as LVSVI as compared to enalapril alone. Further researchis warranted to study whether carvedilol aloneis equally effective as combination therapy inpatients with mild heart failure.
Dr Ralph Zahn from Ludwigshafen, Germany, presented the ANTIBIO study. This multicentre, randomised trial studied the effects of themacrolide antibiotic roxithromycin on the clinical outcome in 872 patients admitted to a German hospital within 48h of symptoms of acute ST-elevation or non-ST-elevation myocardial infarction. Within 5 days of admission patients were randomised to 6 weeks double-blind treatment with roxithromycin 300mg or placebo in addition to the usual care. There was no difference between groups in the primary endpoint of 12-month mortality: roxithromycin 6.5% versus placebo 6.0%
. The combined secondary endpoint consisting of 12-month death, myocardial infarction, revascularisation, stroke and post-infarction angina pectoris did not differ either: 27.8 versus 23.2% 
.
These negative results suggest a lack of benefit from roxithromycin after acute myocardial infarction. In contrast, several smaller previous studies on antibiotics in acute coronary syndromes were positive,3,4 and although larger trials were overall negative,5,6 benefit was shown in specific subgroups.6 It is noteworthy that ANTIBIO was anunderpowered study with early discontinuation due to slow recruitment and a lower than anticipated 12-month mortality rate in the placebo arm: 6% versus an estimated 10%. Hopefully, the results of currently running megatrials, including PROVE-IT and AVES (UK), involving over 20,000 patients,will give a definite answer about the role of antibiotics in the treatment of cardiovascular disease.
Professor Tomasz Siminiak from Poznan, Poland, presented a feasibility study and phase I clinical trial results on transplantation of autologousskeletal myoblasts to improve left ventricular function in patients with post-infarction heart failure. This study included nine men and one woman witha documented myocardial infarction who were scheduled for CABG and who had 1–3 a- or dyskinetic segments without signs of viability atdobutamine stress echocardiography. Patientsunderwent biopsy of the vastus lateralis muscle with isolation of skeletal myoblasts, which were cultured and up to 2x107cells were grown. After construction of the anastomoses during CABG,myoblasts were injected into the damaged myocardium. One patient died 1 week after the operation from a new myocardial infarction in an area of the left ventricle that was different from theinjected segment. The first two patients had sustained ventricular tachycardias, which were thought to be injection-related rather than due to re-entry, after the procedure. In the remaining eight patients no ventricular tachycardia wasobserved after prophylactic administration of amiodarone. In this uncontrolled study all patients had improvement of left ventricular function at 5-month echocardiography.
These initial results show that autologous skeletal myoblast transplantation in non-viable myocardium is a feasible method, which requires further study with respect to both efficacy and safety.
Dr Neil Sulke from Eastbourne, UK, presented the results of the prospective, single centre, randomised EASYAS trial. This study included patients with two previous syncopal episodes in the past year, who presented acutely with syncope and in whom no conclusive diagnosis was established within 24h of presentation. Patients with an indication for pacemaker therapy were excluded. A total of 201 patients were randomised to either subcutaneous implantation of a loop recorder for ECG-registration (‘Reveal Plus’, Medtronic, USA) or conventional treatment. After follow-up of at least 6 months both time to first ECG diagnosis (primary endpoint) and time to ECG driven therapy were shortened with the loop recorder. The main loop recorder diagnoses were bradycardia (26%) and sinus rhythm (47%) duringvaso-vagal collapse. Surprisingly, the time torecurrent syncope after diagnosis did not differ between groups.
Thus, the use of an implantable loop recorder expedited diagnosis in patients with unexplained syncope, but did not affect recurrence rate. Whether the improved diagnostic capability of loop recorders with subsequent earlier initiation of therapy will reduce the incidence of recurrentsyncope remains to be determined.
The last study at this year's Hotline Sessions was the EARTH trial, presented by Dr Inder Anand from Minneapolis, MN, USA, and Professor Thomas Lüscher from Zürich, Switzerland. This placebo-controlled trial studied the effects of five doses (10, 25, 50, 100 and 300mg) of the selective endothelin-A receptor antagonist darusentan on LV remodelling in 642 NYHA II–III heart failure patients with an ejection fraction <35% and a left ventricular end diastolic diameter index >3.0cm/m2. At study entry all patients were on stable standard heart failure treatment for at least 1 month. Primary endpoint was the change in left ventricular end-systolic volume (LVESV) at magnetic resonanceimaging performed after 24 weeks of therapy, as compared to baseline. There was no significant difference in the change of LVESV between placebo or either of the active treatment groups. When compared to placebo, darusentan did not improve performance at the 6-min walk test (secondary endpoint) either. Overall, darusentan was welltolerated, the incidence of adverse events did not differ from placebo.
These results demonstrate that in a heterogeneous group of heart failure patients on stable standard therapy, treatment with darusentan is safe,but does not affect left ventricular remodellingor exercise performance. Whether endothelinreceptor antagonists may be more beneficial in a less ambitious study population with patients, in whom left ventricular remodelling still can beprevented, i.e. patients with a recent myocardial infarction, remains to be determined.
References
