31-08-2013 t/m 4-09-2013 ESC Congres 2013 Amsterdam (NH)

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Prof Lüscher / Prof. Fox

ESC TV 2013 - Big hits at ESC Congress 2013

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AMSTERDAM, The Netherlands – Sunday 1 September 2013: Treatment with the oral anticoagulant dabigatran etexilate resulted in a higher number of thromboembolic and bleeding events compared to warfarin treatment in patients with mechanical heart valve replacements, according to results of the RE-ALIGN (Randomized, phase II study to Evaluate the sAfety and pharmacokinetics of oraL dabIGatran etexilate in patients after heart valve replacemeNt) trial presented here at the European Society of Cardiology congress.

In December 2012 the European Medicines Agency and the U.S. Food and Drug Administration issued a contraindication for the drug in this patient population after RE-ALIGN, a phase II dose-validation trial, was voluntarily discontinued by the drug’s manufacturer Boehringer Ingelheim.

“The RE-ALIGN trial results do not support the use of dabigatran etexilate in patients with mechanical heart valves” confirmed lead investigator Frans Van de Werf, MD, PhD, from the Department of Cardiovascular Sciences at University Hospitals Leuven, Belgium.

RE-ALIGN, a prospective, randomized, open-label, blinded-endpoint trial was conducted at 39 centres in 10 countries, and was intended to validate a new dabigatran dosing regimen for the prevention of thromboembolic complications in patients with mechanical heart valves.

Two populations comprising a total of 252 patients were investigated; those who had undergone mechanical aortic and/or mitral valve replacements within 7 days after surgery and those who had received a mechanical mitral valve replacement at least 3 months earlier. Treatment with dabigatran etexilate for at least 12 weeks was compared to warfarin, which is the standard of care.

An interim analysis by the trial’s Data Safety Monitoring Board revealed a higher rate of strokes and major bleeding in patients on dabigatran (5.4% and 4.2% respectively), compared to those on warfarin (0% and 2.4%), although there were fewer deaths in patients treated with dabigatran (0.6% vs 2.4%). The results of the RE-ALIGN study will be published on line in the New England Journal of Medicine on September 1, 2013.

Dabigatran is currently approved in more than 95 countries worldwide for venous thromboembolism prophylaxis after hip- and knee-replacement surgery, but is not approved in the US for this indication. In the US and elsewhere, it is approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.

“Dabigatran etexilate has been shown to be effective and safe in other indications, and there are several potential reasons for these results ” said Prof. Van de Werf.
“The presence of a mechanical heart valve is a clinical condition distinct from atrial fibrillation,” he explained. “In patients with a mechanical heart valve, coagulation activation and thrombin generation seem to be partially induced by the exposure of blood to the artificial surfaces of the valve leaflets and sewing ring (“contact thrombosis”), whereas in atrial fibrillation, under low blood flow conditions, thrombin generation is believed to be triggered by blood stasis and endothelial dysfunction.”

A likely explanation for why warfarin is more effective in the setting of mechanical valves is that “warfarin also inhibits synthesis of factor IX of the contact pathway while dabigatran exclusively inhibits thrombin,” he added.

If this hypothesis is correct, “the consequence could also be that factor Xa inhibitors such as rivaroxaban or apixaban won’t work for this indication and that patients with a mechanical heart valve will have to take warfarin or other vitamin K antagonists for the next 5 to 10 years,“ he said.

Sources of Funding: The study was funded by Boehringer Ingelheim.

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AMSTERDAM, The Netherlands – Sunday 1 September 2013: In the treatment of venous thromboembolism (VTE), the oral anticoagulant edoxaban resulted in equal efficacy and better safety compared to standard warfarin when either drug was used with initial low molecular weight heparin (LMWH), according to the results of the Hokusai-VTE trial.

In the landscape of new trials with oral anticoagulants, the Hokusai-VTE findings offer fresh insight into a previously under-represented subgroup of patients with pulmonary embolism (PE), suggesting that treatment for this group might need to be different than for other VTE patients, said lead investigator Harry R. Büller, MD, who presented the findings here at the European Society of Cardiology Congress.

“I think our findings are going to shake things up a little bit,” said Dr. Büller, from the Department of Vascular Medicine at Academic Medical Center in Amsterdam.
“What makes this study unique is new insight that there are subgroups in which we might need to revisit what we currently think about the treatment of VTE.”

The Hokusai-VTE trial included a broader spectrum of VTE patients compared to those included in other recent oral anticoagulant trials, including a large subgroup (30%) of patients with PE and right ventricular dysfunction, and another subgroup (20%) at high risk for bleeding due to renal impairment and low body weight.

In total, 4921 patients with deep-vein thrombosis and 3319 with pulmonary embolism received initial  subcutaneous LMWH therapy and were then randomized to receive either 60 mg of edoxaban daily (30 mg for those at higher risk for bleeding, ie., creatinine clearance 30-50 mL/min or body weight below 60 kg), or warfarin (per standard of care) for 3 to 12 months.

For the primary efficacy endpoint of recurrent symptomatic venous thromboembolism,In terms of efficacy the  study found that edoxaban was non-inferior to warfarin, with the primary endpoint of recurrent symptomatic VTE occurring in 3.2% vs 3.5% respectively (P<0.001 for noninferiority).
However, in the subgroup of patients with pulmonary embolism and evidence of right ventricular dysfunction, efficacy was superior with endoxaban (3.3% vs 6.2%, hazard ratio 0.52).

For the principal safety outcome of clinically relevant bleeding edoxaban was superior with a rate of 8.5% compared to 10.3% in the warfarin group, (P=0.004 for superiority).

And among the sub-group of patients ay high risk for bleeding, “by halving the daily dose of edoxaban to 30 mg, efficacy was maintained with significantly less bleeding than observed in the warfarin group,” he said. In this high-risk subgroup clinically relevant bleeding occurred in 7.9% of those treated with edoxaban, compared to 12.8% of those treated with warfarin, while superior efficacy was maintained in the edoxaban arm (3.0% vs 4.2%).
Previous trials of oral anticoagulants have not identified these specific sub-groups, noted Dr. Büller.

“It was a nice and surprising finding that the combination of LMWH and edoxoban in the PE group resulted in a highly significant and clinically relevant reduction of about 50% in recurrent disease.”

“Our findings are likely to be generalizable. In a global setting,” he added.  “We included patients with both provoked and unprovoked venous thromboembolism and treatment durations varied from 3 to 12 months at the discretion of the treating physician.”

The success of edoxaban compared to warfarin is good news in the quest for simplified treatment of VTE, said Dr. Büller. “The problem with warfarin is that food and alcohol and many, many medications interfere with the level and so therefore you’re obliged to do careful laboratory testing every 3 to 4 weeks or even more frequently to measure the INR (international normalised ratio) and adjust the dose,” he said. “The great advantage of the new oral anticoagulants is they have very predictable kinetics and dynamics and therefore can be given in a fixed dose and do not need monitoring.”

But, along with enthusiasm for oral anticoagulants, there is also growing hope in the field that injectable heparin might also be safely eliminated, thus switching 2 inconvenient therapies for one pill said Dr. Büller.

“Two previous oral anticoagulant studies have omitted LMWH altogether (EINSTEIN PE and AMPLIFY) and were applauded because of the simplicity of just giving pills, ” said Dr. Büller, who was the lead author of one of those studies (N Engl J Med 2012; 366: 1287–97).

But, both EINSTEIN PE and AMPLIFY were criticized for under-representing the severely ill sub-groups that make up a large part of the Hokusai-VTE population, he said.

“The whole field was rushing to the conclusion that we could get rid of both heparin, and warfarin, but I think the findings of the Hokusai-VTE study show that in these subgroups it looks like it would be pretty unwise to omit heparin. Our study adjusts that thinking just a little bit, and may start us reconsidering.”

Sources of Funding: The study was supported by Daiichi Sankyo.

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AMSTERDAM, The Netherlands, 1 September 2013 – Aspiration of the blood clot or “thrombus” that causes a heart attack before re-opening a patient’s artery with a balloon catheter does not improve survival compared to performing balloon dilation and stenting alone according to the results of the Thrombus Aspiration in ST- Elevation myocardial infarction in Scandinavia (TASTE) trial.

“We believe that TASTE questions the usefulness of thrombus aspiration as a routine adjunct and the recommendation for its general use in international guidelines should probably be down-graded,” said lead author Ole Fröbert, MD, PhD,  from the Department of Cardiology at Örebro University Hospital, in Örebro, Sweden.

The multicenter, prospective, randomized, controlled open-label trial enrolled 7244 patients with STEMI from Sweden, Denmark and Iceland who had a diagnosis of ST-elevation myocardial infarction (STEMI).

Half of the patients were assigned to balloon treatment only (known as percutaneous coronary intervention, or PCI) and the other half had their blood clot aspirated before PCI.
The mortality rate at 30 days post-procedure was not statistically different between the groups (3.0% versus 2.8% respectively).

Similarly, there was no difference between the two groups for secondary endpoints including risk of new heart attack, stroke and complications related to the treatment.

Even high risk groups such as smokers, patients with diabetes or patients with large clots had similar results with either approach.

“Our findings do not support a role for this additional procedure as a routine future treatment,” said Dr. Fröbert.
The study results will likely have an immediate impact on clinical practice, he added.

Current European Society of Cardiology guidelines on treatment of patients with ST-elevation myocardial infarction (STEMI) recommend that thrombus aspiration should be considered and “most opinion leaders advocate its use,” said study co-chair Stefan James MD, PhD, from the Department of Cardiology and Uppsala Clinical Research Center at Uppsala University Hospital in Uppsala, Sweden.

Since the presentation of the TAPAS trial that suggested a mortality benefit (N Engl J Med 2008;358:557-67) thrombus aspiration has “gained an enormous popularity,” he explained. ”The therapy is so popular among interventional cardiologists because it intuitively feels beneficial to aspirate the clot that closes the artery.”

But recent research has suggested that thrombus aspiration also carries risks. In 2012, a meta-analysis associated the procedure with a borderline significantly higher rate of stroke (Int J Cardiol 2012;166:606-12.) and another study showed that systemic embolization can occur as result (Circ J 2009;73:1356-8).

The TASTE trial is the first large-scale randomized trial of thrombus aspiration for STEMI to be large enough to reveal meaningful findings on mortality and morbidity.

It enrolled more patients than all previous randomized trials of this procedure combined and included a much broader range of patients in order to make the results relevant to everyday clinical practice.

“An even more far-reaching impact is that our trial is the first trial ever to use the registry based trial concept, which we invented, “ added Dr. Fröbert.

The study’s unique Registry-Based Randomized Clinical Trial (RRCT) protocol used national registries as on-line platforms for randomization, case record forms and follow-up, making the trial economically and administratively feasible.

“This concept reduces costs to 1% or less of a conventional randomized trial and enables the testing of treatments that have no revenue potential. since commercial interest is often the main incentive behind large-scale randomized clinical trials,” he said. “In general fewer of these trials are being performed because of the huge costs involved. This trial concept can help to break the deadlock of clinical trials.”

Sources of Funding: The Swedish Association of Local Authorities and Regions; the Swedish Heart-Lung Foundation, The Swedish Research Council and by unrestricted grants from Terumo Medical Corporation, Medtronic and Vascular Solutions.

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Amsterdam, The Netherlands - Sunday 1 September 2013 – Mechanical chest compressions with defibrillation during ongoing compressions are just as effective, but not superior to manual compressions, for delivering cardiopulmonary resuscitation (CPR) to patients in cardiac arrest, according to the results of the LUCAS in Cardiac Arrest (LINC) study.

"The study was designed to show a better 4-hour survival in the group treated with mechanical chest compressions, and this was not achieved,"
said lead investigator Sten Rubertsson, MD, PhD, professor and specialist consultant at Uppsala University and Uppsala University Hospital.

"But we now have the scientific support to allow us to use mechanical chest compressions and defibrillate during ongoing compressions,"
he said, adding that this could potentially increase the efficiency and safety of emergency personnel as they deliver care during transportation of patients.

The LINC study included 2,589 patients from six European sites who had suffered an out-of-hospital cardiac arrest and needed resuscitation.

Manual chest compressions were started on all patients as soon as EMS personnel arrived on the scene.

Patients were then randomized to either be kept on manual chest compressions (n=1289) or be switched to mechanical compressions with defibrillation during ongoing chest compressions (n=1300). Mechanical chest compressions were delivered with the LUCAS Chest Compression System (Physio-Control/Jolife AB, Lund Sweden), a piston-driven device with a suction cup designed to deliver compressions according to resuscitation guidelines.

In both groups, ventilation and drugs were given according to guidelines.

The study showed that four hours after the initiation of CPR, survival rates were similar in both the mechanical and manual CPR groups (23.6% versus 23.7%).

Later outcomes were also similar, including the rate of restoration of spontaneous circulation (ROSC), the number of patients who arrived at the emergency room with a palpable pulse, the number of patients who survived until discharge from intensive care, and neurological outcomes at one and six months.

Theoretically, mechanical chest compressions should offer an advantage over manual chest compressions because the latter often have insufficient depth, incorrect rate and frequent interruptions, explained Dr. Rubertsson.

"The efficacy of traditional manual chest compression is heavily dependent on the skills and endurance of rescuers, and is compromised by periods of hands-off time and transportation interruptions,"
he said. Even at high efficiency it delivers only approximately 30% of normal cardiac output, resulting in decreased blood flow to vital organs." Mechanical compressions should theoretically improve CPR, but to date there is no definitive evidence from large randomised trials to show this.

Two randomized pilot studies of out-of-hospital cardiac arrest patients have compared mechanical chest compressions with mechanical compressions from the LUCAS device (1-2), and neither study found any significant difference between groups; however, the study populations were small.

The results of the current study suggest clinical equipoise, said Dr. Rubertsson - although, he said slight adjustments to the treatment algorithms might result in clinically significant differences in the future.

"With the algorithm we used for mechanical CPR we found that time to first defibrillation was delayed compared to manual CPR and this could explain why we were not able to show improved outcome. Therefore in the future we will recommend defibrillation without delay, before deployment of the device."

Regarding safety, "I would say that we can deem the device is safe, based upon the low number of severe adverse events and adverse events reported in the study, " he said.

"Survivors at 6 months had good neurologic outcome (99% in the mechanical group and 94% in the manual) and in a previously published pilot study of 85 patients we did not find any difference between groups in injuries at autopsy. What remains to be finally analysed is the cohort of 200 patients within LINC that underwent autopsy."

Evidence showing equal efficacy for both manual and mechanical compressions is an added benefit to Emergency Medical Systems (EMS) workers.

"EMS workers can now use a device to provide CPR which means they have an extra pair of hands available for other possible interventions,"
said Dr. Rubertsson.

"Safety during transportation in the ambulance can also be improved since now the crew can have safety belts and still provide CPR."

He emphasized that the results of the LINC trial are only applicable to the LUCAS device and cannot be generalized to other mechanical chest compressors.

Funding: The LINC study was initiated by Uppsala University and sponsored by Physio-Control/Jolife AB.

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Amsterdam, The Netherlands - Sunday 1 September 2013 – Heart attack patients with ST elevation who undergo a preventive procedure to unblock additional coronary arteries have significantly better outcomes than those whose treatment is confined to the culprit blockage only, according to the results of the Preventive Angioplasty in Myocardial Infarction (PRAMI) Trial.

The findings, presented today at the ESC and published simultaneously in the New England Journal of Medicine, provide information that will help guide clinical practice and resolve uncertainty over how to approach percutaneous coronary intervention (PCI) for ST elevation myocardial infarction (MI).

“When a patient is admitted with an acute myocardial infarction, it is known that PCI to the blocked culprit artery is life-saving, but there is uncertainty as to whether doctors should undertake preventive PCI in vessels that are partially blocked but did not cause the myocardial infarction. This is a common clinical dilemma,” said the study’s lead investigator David Wald, MD, from the Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine, Queen Mary University of London and the London Chest Hospital.

The PRAMI trial was stopped early by the Data Monitoring Committee when a planned interim analysis showed a clear benefit in favor of preventive PCI that was evident within 6 months of the procedure and maintained thereafter.

“The results of this trial show that in this situation preventive PCI, in this situation, reduces the risk of cardiac death, a subsequent myocardial infarction or angina resistant to medical therapy, by about two-thirds.” With this new evidence, “consideration can be given to revising current guidelines,” he added.

Current guidelines recommend culprit-only PCI for patients with ST elevation myocardial infarction and multivessel disease, because until now there was a lack of evidence in favor of preventive PCI.

In the trial, patients undergoing emergency PCI for acute ST elevation (462) or left bundle branch block (3) myocardial infarction and multivessel coronary artery disease were randomized while in the catheterization laboratory to either preventive PCI (234), or culprit-only PCI (231).

Patients were eligible for the preventive procedure if their culprit artery had been treated successfully and they had a blockage (stenosis) of 50% or more that was treatable by PCI in another or several other coronary arteries.

After a mean follow-up of 23 months (67% of patients had at least one year, and 46% at least 2 years, of follow-up) a total of 21 patients in the preventive PCI group and 53 in the culprit-only group had experienced a primary outcome event (cardiac death, nonfatal myocardial infarction or refractory angina) showing an absolute risk reduction of 14 per hundred patients in the preventive PCI group [hazard ratio 0.35 (95% CI 0.21-0.58), p<0.001], and a relative risk reduction of 65%.
The rate of complications was similar in the preventive and culprit-only PCI groups (procedure related stroke 2 vs 0; bleeding requiring transfusion or surgery, 7 vs 6; and contrast-induced nephropathy requiring dialysis, 1 vs 3).

Procedure time, fluoroscopy dose and contrast volume were increased in the preventive PCI group (median 63 vs 45 minutes, median 90.1 vs 71.4 Gycm2, and median 300 vs 200 mL).

“The results show that on average, preventive PCI extends the procedure time by about 20 minutes, uses an extra 100mls of contrast (the dye used in angiography) and exposes the patient to an X-ray dose equivalent to an angiogram,” said Dr. Wald, adding that” the initial costs of preventive PCI are higher but there will be reduced costs thereafter, with a reduced need for subsequent hospital admissions, cardiac investigations and revascularisation procedures.”  

Funding: Barts and London Charity; ISRCTN number, 73028481

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AMSTERDAM, The Netherlands, Sunday 1 September 2013 – A shortened pre-surgical interruption of anti-thrombotic therapy, compared to the more traditional one-week interruption, has no influence on perioperative complications in cardiac patients, according to the results of the PRAGUE 14 trial.

“Thus, there is no evidence to support changing the traditional approach of interrupting antithrombotic therapy one week before surgery,” said lead investigator Petr Widimsky, MD., DrSc., from the Cardiocenter of Charles University, in Prague, Czech Republic.

The results shed light on a persistent dilemma for surgeons and the dueling risks faced by cardiac patients undergoing surgery.
 
While treatment for most cardiac patients involves antithrombotic therapy which can pose a cardiac risk if interrupted, the continuation of such medications before surgery may also be problematic because they can increase the risk of surgical bleeding, said Professor Widimsky.

“The risk of surgical hemorrhage is increased by 20% in patients taking aspirin and 50% in those taking dual antiplatelet therapy,” he explained. “Is it better to withdraw the drugs and reduce the hemorrhagic risk or to maintain them and reduce risk of a myocardial ischemic event ?”

As a compromise for these competing concerns, antithrombotic therapy is often interrupted for a period of one week prior to surgery, but the ideal duration of such an interruption remains undetermined, he said.

To explore this, the PRAGUE 14 study enrolled 1,200 consecutive cardiac patients (mean age 74 years) who were undergoing non-cardiac surgery at a large tertiary university hospital between 2011 and 2013.

The majority (83.7%) of patients had been receiving antithrombotic medication within the month before surgery, with the most common drug being aspirin (53.3%), followed by warfarin (23.4%), thienopyridine derivatives (ticlopidine or clopidogrel, 1.7%), dabigatran (0.3%), or dual antiplatelet therapy (5%) – which is a combination of aspirin and one other antithrombotic medication.

Aspirin was stopped a median of 7 days prior to surgery, whilst warfarin and thienopyridines were stopped a median of 8 and 4 days respectively prior to surgery.

“This was a real life registry - the study design did not prescribe interruption, rather it was left to the discretion of the attending physician, so overall there is a continuous spectrum of interruption from 0 days to more than 10 days,” he explained.

The study showed that perioperative cardiovascular complications occurred in 7.6% of patients, and perioperative bleeding occurred in 13.3%.
Thirty-four of 91 patients (37.4%) with perioperative cardiovascular complications died, compared to only 2 deaths in 159 patients (1.26%) with perioperative bleeding complications.

Multivariate analysis revealed that “surprisingly, the length of aspirin interruption before surgery predicted neither perioperative cardiovascular nor bleeding complications,” noted Dr. Widimsky.

Instead, independent risk factors for perioperative bleeding complications were high platelet count and the presence of a prosthetic valve, while independent risk factors for perioperative cardiovascular complications included age, preoperative anemia, history of previous PCI, history of chronic heart failure, general versus other types of anesthesia and, acute surgery versus elective.
While antithrombotic interruption was not an independent risk factor, univariate analysis did show that a shortened pre-operative interruption of aspirin (a median of 2 days compared to 7) was related to more bleeding and cardiovascular complications.

“Most likely this is related to the fact that acute surgery, which has an inherently higher risk, was the reason behind most cases of shortened aspirin interruption,” said Prof. Widimsky.

The findings confirm that pre-operative antithrombotic therapy interruption should remain at a duration of one week, as currently recommended, he said.

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Amsterdam, The Netherlands, Sunday 1 September 2013: In patients with non-ST-elevation acute coronary syndrome (NSTE- ACS), pre-treatment with the P2Y12 antagonist prasugrel prior to catheterization, significantly increases the risk of life-threatening bleeding without reducing the risk of major ischemic events, according to the results of the ACCOAST (A Comparison of prasugrel at PCI or Time of Diagnosis of Non-ST Elevation Myocardial Infarction) trial.

The findings point to a "paradigm shift" away from pre-treatment in such patients which will not only be "hard to believe and destabilizing for many cardiologists, but may also be difficult to implement since the routine use of pre-treatment has been anchored for so long," said the study's lead investigator Gilles Montalescot, from the ACTION study group at the Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtriėre, in Paris, France.

Current ESC and ACCF/AHA guidelines recommend that pre-treatment with P2Y12 inhibitors should be added to aspirin as soon as possible before catheterization and maintained over 12 months, unless there are contraindications such as excessive risk of bleeding, explained Dr. Montalescot.

This strategy has been accepted for years based on the results of observational, subgroup and non-randomized analyses performed with the older drug clopidogrel,

But newer P2Y12 receptor antagonists such as prasugrel are more potent and have a faster onset of action, which makes these drugs well-adapted to PCI.

"With the rapid onset of action of the oral and intravenous P2Y12 inhibitors and the modern era of short delays between hospital admission and catheterization, the risk of an ischemic complication before catheterization is extremely low, suggesting that there is no longer a need for pre-treatment in NSTE-ACS patients to prevent ischemic complications while waiting for catheterization,"

he said.

"Moreover, there is also no benefit of pre-treatment on peri-PCI complications. Together, our findings suggest use of prasugrel should be considered only after the coronary anatomy has been defined."

Enrolment for ACCOAST was suspended by an independent data monitoring committee on November 16, 2012 when a planned interim analysis showed that pre-treatment with prasugrel was associated with an increased risk of major and life-threatening bleeding, although no increased rate of mortality.

The phase 3, randomized, double blind, event-driven study conducted in 171 centers and 19 countries in Europe, Canada, Israel and Turkey, randomized 4033 patients to either pre-treatment with prasugrel or placebo at the time of NTSE-ACS diagnosis (n=2037) followed by prasugrel given selectively after the coronary angiogram to patients with a confirmed indication for PCI (n=1996). Patients in both arms also received aspirin and standard of care. Patients were to be scheduled to undergo coronary angiography/PCI within 48 hours from randomization. Patients In the pre-treatment arm received a 30-mg loading dose (LD) of prasugrel at the time of randomization and, if PCI was indicated, an additional 30-mg at the time of PCI, while patients in the no pre-treatment arm got a placebo dose at randomization, and, if PCI was indicated, a 60-mg LD of prasugrel at the time of PCI.

Ultimately, PCI was performed in 68.7% of subjects, while in the 7 days post-randomization coronary artery bypass surgery (CABG) was chosen for 6.2% and medical management for 25.1%.

For the primary endpoint, a composite of cardiovascular death, myocardial infarction, stroke, urgent revascularization or GPIIb/IIIa bailout at 7 and 30 days post-randomization, there was no significant difference between the pre-treatment and no pre-treatment groups (10.0% vs 9.8%, p = 0.812, and 10.8 vs 10.8, p = 0.976, respectively). However, the rate of all major bleeding, according to Thrombolysis in Myocardial Infarction (TIMI) criteria was almost double in the pre-treatment group at both 7 days (2.6% vs 1.4%, p = 0.006), and 30 days (2.9% vs 1.5%, p = 0.002). At 7 days, major and life-threatening TIMI bleeding not related to CABG procedures were increased by three-fold and six-fold respectively (1.33% vs 0.45%, p = 0.003; and 0.83% vs 0.15%, p = 0.002).

There was however, no excess of fatal or intracranial hemorrhage with pre-treatment. ACCOAST is the first randomized study of pre-treatment versus no pre-treatment in NSTE ACS before scheduled catheterization, said Dr. Montalescot. While the study looked specifically at prasugrel, the results, when considered alongside another recent study of pre-treatment with clopidogrel (JAMA. 2013;309(14):1461) are potentially applicable to the global concept of pre-treatment with a P2Y12 inhibitor.

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Amsterdam, The Netherlands, Sunday 1 September 2013 – Heart failure patients have significant survival benefits when their implanted cardioverter-defibrillators (ICD) or cardiac resynchronization therapy defibrillators (CRT-D) are fitted with telemonitoring technology that alerts medical experts to potential problems, results of the IN-TIME trial reveal. New technology that allows transmission of diagnostic data from implanted devices to a monitoring physician or clinic, as opposed to patients being followed via in-office visits, allows early detection of atrial or ventricular arrhythmias or specific trends in certain clinical parameters said lead investigator Gerhard Hindricks, MD, from the Heart Center Leipzig, Germany.

"The rapid transmission of information compared to traditional methods of monitoring patients gives physicians more time to intervene if necessary, thereby preventing serious or even fatal events."

The IN-TIME trial showed that at one-year, significantly more patients randomized to telemonitoring scored better on a composite endpoint that included all-cause mortality and specific cardiac measures. The prospective, randomized, controlled, multicenter trial analysed 664 patients, mean age 66±9 years, with chronic heart failure lasting for 3 months or more, class II or III New York Heart Association (NYHA) symptoms, and a reduced left ventricular ejection fraction (LVEF) of ≤35%.

Most patients included had ischemic heart disease (69%), mean LVEF was 26±6%, and heart failure medication diuretics (93%), beta-blockers (91%), and ACE inhibitors or angiotensin receptor blockers (89%). The primary endpoint of IN-TIME was the modified Packer score, a clinical composite score consisting of mortality, overnight hospitalization for worsened heart failure, and NYHA class global self assessment. A secondary endpoint of the trial was all-cause total mortality.

All patients were fitted with implanted devices that had a telemonitoring function, with 58% receiving a cardiac resynchronization device (CRT-D) and 42% an implantable dual chamber. Data transmission was initiated by a time trigger (e.g. 3 AM every day) or by a relevant arrhythmic or technical event, and was transmitted from the patient's implanted device to a central monitoring unit at the Heart Centre Leipzig. A run-in phase of one month was used to optimise patients' heart failure therapy and ensure that the device's transmission system was functioning after which patients were randomized to either telemonitoring (n=333) or standard care (n=331).

This meant that in the standard care group, telemonitoring data was still collected but was not accessible to the central monitoring unit or treating physicians until the end of the study. For these patients all treatment interventions were either patient-initiated or triggered by in-office follow-ups.

In contrast, for telemonitored patients, relevant observations such as frequency of ventricular extrasystoles, or atrial and ventricular tachyarrhythmia episodes were forwarded to the patient's treating physician, which could lead to additional follow-ups, and therapy changes at the physician's discretion.

At 12 months follow-up, significantly more patients in the control group as compared to the home monitoring group worsened according to the modified Packer score (27.5% vs 18.9%; p<0.05).

Moreover, there was a significantly lower rate of all-cause mortality as well as cardiovascular mortality in the telemonitoring arm compared to controls (3.4% vs 8.7%; P<0.01 ; p< 0.012 ).

"The next step is to carefully analyse triggers, events, medical actions and of course the time lines to better understand the mechanism(s) by which modified Packer score was improved and all-cause mortality was so strongly reduced in heart failure patients supported by home monitoring," said Dr. Hindricks.

"That will be the basis for the clinical application of the study results and of course for future research in the field."

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"The DECAAF results show that stage of atrial fibrosis prior to ablation is a new, powerful, independent predictor of outcome,” said lead investigator Nasir Marrouche, MD, from the CARMA Center at the University of Utah in Salt Lake City, USA.

"By performing this imaging before ablative treatment we can triage patients according to likelihood of treatment success, and avoid ablative procedures in those patients for whom it is unlikely to work. If a patient has late stage 3 or stage 4 fibrosis their chance of being cured is only 30-35% which is really low, but if they’re in an early stage their chance of cure is 60-80%,” he said.

The DECAAF trial included 260 atrial fibrillation (AF) patients with atrial fibrosis who were undergoing ablation. The patients, from 15 centers in USA, Europe and Australia were a mean age of 59 years, and 64.6% of them had paroxysmal AF.

High resolution Delayed Enhancement MRI (DE‐MRI) was performed up to 30 days before ablation in all patients to determine the presence and extent of atrial fibrosis, while post- ablation DE-MRI was performed at 90-days follow-up in 177 of the subjects, to determine the extent of residual ablation.

At the 90-day follow-up, recurrence of arrhythmia was noted in 88 of the 260 patients (33.8%) based on Holter monitors and electrocardiograms.

Multivariate analysis revealed two independent predictors of successful ablation or recurrent symptoms were stage of atrial fibrosis before ablation (P<0.001) as well as residual fibrosis after (P<0.001).

Specifically, patients whose pre-ablation fibrosis was stage 1 (defined as less than 10% damaged atrial tissue) had an 85.8% success rate, those with stage 2 (10% - 20% damage) had a 63.3% success rate, those with stage 3 (20% - 30% damage) had a 55% success rate and those with stage 4 (more than 30% damage) had a 31% success rate.

For every increased percentage of fibrosis before ablation, there was 6.3% increased risk of recurrent symptoms after ablation (hazard ratio 1.063), said Dr. Marrouche.

Similarly, for every percentage of residual fibrosis there was an 8.2% increased risk of recurrent symptoms (HR 1.082).

A secondary finding of the study, based on post-ablation imaging, showed that the type of ablation clinicians used also had an impact on success rates. The choice of procedure was not dictated in the study protocol and was left to the discretion of individual treating physicians.

After comparing pre-ablation images of fibrotic tissue, with post-ablation images showing the extent of residual fibrosis, a surprise finding was that pulmonary vein ablation, which is the standard-of-care in atrial fibrillation ablation candidates, is not the best ablative approach, said Dr. Marrouche.

“We do ablation around the pulmonary veins because we have assumed for years that the trigger for AF comes from the vein – that’s the standard of care,” he said. “But what we found in DECAAF is that ablation of the veins did not predict outcome. In fact, the most important predictor of outcome, along with stage of atrial fibrosis, was the degree of ablation of the fibrotic tissue. Rather than targeting the pulmonary veins, procedures which ablated fibrotic tissue produced better outcomes - the more that was targeted, the better the outcome.”