BB&T

BARCELONA, Spain - Three years after he helped send sales of drug-eluting stents (DES) plummeting with a presentation challenging their long-term safety, Eduardo Camenzind, MD, was back at the European Society of Cardiology (ESC; Sophia Antipolis, France) to say in an opening plenary session that he is unrepentant.

The use of DES results in a decrease in restenosis at the price of increased late stent thrombosis, Camenzind, from University Hospital (Geneva, Switzerland) said, providing a critical review of studies published in the wake of the safety scare he set off in 2006.

DES sales peaked in 2006 at almost $6 billion worldwide.

Following the firestorm from Barcelona where Camenzind's concerns were amplified by findings from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR), European usage of DES dipped slightly, staying between 40% to 50% of percutaneous coronary interventions (PCI), while sales in the U.S. crashed from over 90% usage in early 2006 to around 55% before the end of that year, where it plateaued.

Camenzind acknowledged that there is greater understanding today of late stent thrombosis for DES patients, and that its causes are due to the convergence of multiple factors.

He also noted that in the three years since his presentation of safety concerns, the issues have only been complicated by the number and diversity of stents introduced to European practice.

Camenzind complained the raft of papers published over the intervening three years only contribute to clinical suspicions saying that reassuring findings about DES are coming from underpowered studies and dubious data with a failure to report p-values that mask their statistical significance.

Camenzind concluded that his doubts about total death and myocardial infarction in potent DES, as compared with bare-metal stents, "cannot in my view be definitively dissipated since Barcelona 2006," according to Heartwire.

For Camenzind, guidance for use of DES in practice centers on the potency of the DES and whether the stent leaves a polymer coating permanently in the patient's artery.

The discussion then took a powerful reversal in tone with a presentation by Adnan Kastrati, MD, of Deutches Herzzentrum (Munich, Germany) who said the idea of DES being the source of stent thrombosis, which was "born in Barcelona in 2006, is already dead," according to TCTMD, a publication of the Cardiovascular Research Foundation.

"We have to bury this in exactly the city where it was born," he said.

Reviewing data from randomized trials, Kastrati said evidence coming from randomized clinical trials and meta-analyses generally confirm the efficacy and safety of DES, including for high-risk patient groups, such as those with diabetes and myocardial infarction.

He ceded the point, however, that none of the randomized trials had enough power to reliably evaluate the safety of DES, and those meta-analyses compiling these study results are not a substitute for a large specific trial on stent thrombosis with long-term follow up.

Acknowledging the rapidly evolving technology of DES, and the need to distinguished between these different types of DES, he nonetheless reached the opposite conclusion of Camenzind saying there are good reasons to believe the benefit of DES for stemming restenosis is not achieved at the expense of compromised safety.

In a press conference ahead of the plenary session, Stefan James, MD, from the Uppsala Clinical Research Center (Uppsala Sweden) said the controversy sparked in Barcelona in 2006 provided a much-needed wake-up call for PCI practitioners

"All of us interventional cardiologists were overly enthusiastic," he said to reporters, "we thought that DES would solve everything and we started to stent patients we never should have stented."

The warning about DES safety resulted in closer scrutiny, "making us think about how to improve techniques, the antiplatelet therapy, and the selection of patients to get it right," he said.

In his plenary presentation James reviewed updated data from the 2006 SCAAR registry, which was used as part of an FDA hearing and showed that during almost three years of follow-up the rates of adverse events, including death, were significantly higher among patients receiving a DES than among patients receiving a bare-metal stent (BMS).

With data now running out to five years, James reported SCAAR data shows no difference between the two patient groups for adverse events.

Yet the opening plenary session, titled "Is it time to turn the page on Barcelona 2006?" ended in a draw among the nearly 5,000 cardiologists in attendance.

The co-chairs for the session, Michal Tendera, MD, from the Silesian School of Medicine (Katowice, Poland), and Anthony Gershlick, MD, from University Hospitals (Leicester, UK) called for a vote among audience members both before and after the debate, asking whether cardiologists continue to believe DES safety is a valid clinical controversy.

The vote was split both before and after the discussion, and one panel member, David Holmes, a cardiologist at the Mayo Clinic (Rochester, Minnesota), suggested the debate was far from over.

"We need to come back to Barcelona in three years in order to discuss this important topic again," he said.

CRT trial challenges ICD dominace

A clinical study presented at the meeting has the potential to rewrite practice guidelines worldwide for implantation of devices to assist heart failure patients.

Panos Vardas, president of the European Heart Rhythm Association (EHRA), tried to slow the enthusiasm among presenters by stressing during a press conference that the results of the trials, which he acknowledged are practice-changing, need to be validated by publication in peer-reviewed journals.

The MADIT-CRT study, sponsored by Boston Scientific (Natick, Massachusetts), investigated whether patients with mild heart failure do better if they are implanted with a cardiac resynchronization therapy defibrillators (CRT-D) device, combining cardiac resynchronization therapy with defibrillation, than if they only receive the traditional and widely used implantable cardioverter defibrillator (ICD) device.

The trial, led by Arthur Moss, MD, from the University of Rochester Medical Center (Rochester, New York), enrolled 1,820 patients from 110 centers in 14 countries who were randomized to receive either CRT-D or ICD.

Early intervention with CRT-D in mild heart failure slows the progression of heart failure, Moss reported, producing significant reductions in death and heart failure interventions, according to results from the MADIT-CRT trial.

Moss reported to colleagues at ESC 2009 that during a follow-up period that averaged 28 months, 17.2% of patients in the CRT group experiences either a heart failure event or death, compared to 25.3% in the ICD group.

The superiority of CRT-D therapy was found to be present in all patient sub-groups, including those with ischemic and non-ischemic types of heart disease, as well as in males and females, younger and older patients, and those with mild and more advanced heart dysfunction.

"Cardiac resynchronization therapy was dramatically effective in this large study population, with a 34% reduction in the risk of all-cause mortality or heart failure," he said, adding "The benefit is dominated by a 41% reduction in heart failure events. "

"This result validates a new indication for cardiac resynchronization therapy in the prevention of heart failure in at-risk asymptomatic or mildly symptomatic cardiac patients," said Moss.

"It seems likely that this preventive CRT-D therapy will have widespread application and utilization," he concluded.

Around half of all patients with heart failure die suddenly due to ventricular arrhythmias, leading to the recommendation in both European and American clinical practice guidelines that survivors receive an ICD.

About one third of patients with low ejection fractions have abnormal electrical activation of the left ventricle resulting in dyssynchronous contraction of the walls of the left ventricle, leading to suboptimal ventricular filling, decreased stroke volume facilitation of mitral regurgitation, increased wall stress, and delayed relaxation, which has been associated with increased morbidity and mortality.

CRT-D was designed to simultaneously pace both the left and right ventricles in a synchronized manner, resulting in acute hemodynamic benefits.

"MADIT-CRT is providing insight into the potential of CRT-D therapy to intervene earlier in the natural progression of heart failure," said Vardas, adding that about 60% of all heart failure patients in Europe fall into the criteria used for patients enrolled into the study.

Vardas also expressed a concern that it may prove difficult to have CRT-D technology implemented throughout Europe.

"Currently, huge differences exist in the implementation of the guidelines from country to country," he said.

Biodegradable stent coatings pass first trial

So far, so good for drug eluting stents (DES) with a biodegradable polymer.

A full year of follow-up with patients receiving the novel stents have shown results comparable, or non-inferior, to stents with permanent polymer coatings in a presentation at ESC.

DES have proven effective in preventing the re-narrowing of an artery after it is opened in a percutaneous coronary intervention (PCI) procedure and the current market for these devices is estimated at almost $2 billion in the U.S. alone in 2008.

Yet several studies have shown persistent risk of blood clot formation inside DES over a longer time period after implantation than observed with bare metal stents.

Recent angiographic studies have also shown a scar tissue accumulation can be seen up for up to two years after implantation of DES, and further, that the risk of late in-stent blood clotting may be caused by a delayed healing process or a persisting inflammatory response to the permanent polymer that controls the drug-release from the surface of stent.

A biodegradable polymer DES specially developed for the Individualized Drug-Eluting Stent System to Abrogate Restenosis (ISAR) project, consists of a sand-blasted, stainless-steel stent coated with a polymer that dissolves over nine weeks.

The ISAR-TEST-4 study then randomized 2,603 patients assigning half to receive the new biodegradable stent and dividing the other half between the Xience DES from Abbott (Abbott Park, Illinois) and the Cypher DES from Cordis (Miami Lakes, Florida), a unit of Johnson & Johnson's (New Brunswick, New Jersey), both of which feature permanent polymer coatings.

The study, an all-comers trial where the cohort were non-selected patients undergoing PCI in de novo native-vessel coronary lesions, was conducted at two tertiary medical centers, the Deutsches Herzzentrum and the Medizinische Klinik of the prestigious Klinikum rechts der Isar, both in Munich, Germany.

The primary endpoint was a composite of cardiac death, myocardial infarction (MI) related to the target vessel, or revascularization related to the target lesion (TLR) at one year.

The results, published online simultaneously in the European Heart Journal, indicate that safety and efficacy outcomes at one year are comparable with those of permanent polymer-based DES.

"These results now provide a framework for testing the potential clinical advantage of biodegradable polymer DES over the medium- to long-term," according to lead investigator Julinda Mehilli, MD, from the Deutsches Herzzentrum.

In a press conference ahead of the presentation, Mehilli told reporters, "At the moment, all I will say is that a bioerodable polymer seems as good as the permanent polymer, and that I need a longer-term follow-up to say that we have better safety with this stent."

"But probably the bioerodable-polymer stent will be the DES of the future," she added.

Blood thinner reduces risks from stents

One study presented at ESC strongly suggests that reducing stent thrombosis and other adverse cardiac events following stent implantation may be as simple as taking a pill, or rather two pills.

Shamir Mehta, MD, with McMaster University (Hamilton, Ontario) delivered reassuring news for cardiologists and great news for the two pharmaceutical companies that manufacture the blood thinner clopidogrel, reporting that doubling the dosage significantly reduced the risks of myocardial infarction (MI) and stent thrombosis for patients.

With 25,087 patients participating the CURRENT OASIS 7 trial - clopidogrel optimal loading dose usage to reduce recurrent events/optimal antiplatelet strategy for interventions)- is the largest clinical trial aimed at evaluating different dosing regimens for the blood thinner in a broad range of acute coronary syndrome (ACS) patients.

"Virtually every interventional cardiologist is using clopidogrel," Mehta said at the press conference ahead of his presentation.

"After the results of this trial are presented, they will have to decide what to do," he said, predicting that the trial results will require an adjustment to current guidelines for prescribing clopidogrel.

"It's a simple change to institute," said Mehta. "It means going from one pill to two pills a day, with cost implications that are virtually negligible while the benefits are great," improving patient outcomes in PCI.

Among the PCI patients in the study population receiving the higher dose of clopidogrel there was a 15% reduction in the composite endpoint of cardiovascular death, heart attack, or stroke at thirty days.

The major contributor was a 22% reduction in MI and what was called a highly significant 42% reduction in the risk of stent thrombosis, which was a secondary endpoint.

A further finding in the study data revealed that the patient group given a higher dose of aspirin consistently did better.

"There was no downside to using the higher dose aspirin and there may have been a benefit," Mehta reported.

The study was sponsored by Sanofi-Aventis (Paris) and Bristol-Myers Squibb (New York), co-commercialization and co-development partners for clopidogrel under the brand name Plavix.

Data describes Europe's 'burden of heart failure'

About 25,104 physicians and surgeons attending the ESC meeting participated in 600 hours of scientific sessions listening to presentations delivered by 3,800 speakers.

A key touchstone for presenters is the rapidly aging population of Europe that will only increase the burden of cardiovascular disease for national health systems, which is estimated to cost the economies of the 27 members of the European Union e192 billion ($275 billion) per year with 57% of that figure accounted for by direct healthcare costs.

At ESC 2009, a recently completed analysis of more than one million hospital cases in Sweden over 16 years revealed that the impact of heart failure is as great as the most common and feared forms of cancer in respect to the risk of being hospitalized for the first time, poor overall survival and the number of premature life-years lost.

The ratio of heart failure to cancer cases overall was 1.5 to 1, and 59% of patients with heart failure died within five years of their first hospital admission, a lower survival rate than for the combined cancer population.

The estimated cost of heart failure due to loss of life and quality of life combined was SEK 16.4 billion ($2.3 billion) compared to SEK 5.3 billion ($746 million) and SEK 4.1 billion ($577 million) for lung and prostate cancer, respectively.

Novel study looks at AF on a global scale

The Thrombosis Research Institute, a charitable foundation affiliated with Queen Mary University of London reported an innovative research initiative to understand the burden of atrial fibrillation (AF) called GARFIELD, the Global Anticoagulant Registry in the Field.

The GARFIELD Registry will follow 50,000 patients newly-diagnosed with AF who are also candidates for anticoagulant therapy to prevent blood clots leading to stroke over a six-year period in 32 countries.

A set of patients from 1,000 centers in 50 countries will be included in the registry.

Clinical sites will be randomly selected to participate to avoid the selection of only sites expert in AF management in order to provide a real-world view of how the disease AF is being managed across all care settings, such as hospitals, emergency departments, anticoagulant clinics and general practice settings.

"We need to better understand AF if we are to begin tackling its consequences in a meaningful way," said Prof. Ajay Kakkar, the director of the institute and Professor of Surgical Sciences at Queen Mary University.

In the European Union 4.5 million people have persistent AF where parts of the atria emit uncoordinated electrical signals that cause the chambers to pump too quickly and irregularly, thereby not allowing blood to be pumped out of the atria completely.

As a result, blood may pool and lead to thrombosis, or creating clots that could potentially lodge in an artery particularly in the brain leading to a stroke.

People with AF have a five times higher risk of suffering a stroke than the general population, and are also at high risk for heart failure, chronic fatigue and other heart rhythm problems.

"Anticoagulant therapy may be necessary for preventing thromboembolic stroke, yet few at-risk patients probably receive appropriate and potentially life-saving prophylactic therapy," Prof. Kakkar said, adding that GARFIELD aims to better understand the effectiveness and application of therapies.

Monitoring of ICD patients speeds detection

The remote monitoring of patients with implantable cardiac devices (ICD) is believed to be a remedy for improving patient safety, streamlining hospital visits and enhancing the surveillance of both device- or patient-related clinical data.

Yet there has not been sufficient clinical evidence to support these assumptions about remote monitoring.

The TRUST trial presented at ESC 2009 claims to be the first prospective large scale effort to test such technology.

Centered on an internet-based, wireless remote monitoring system using the GSM telephone network called Biotronik Home Monitoring, TRUST is a randomized trial of 1,443 patients enrolled from 105 North American sites.

The study measured how reliably daily telemetric surveillance, which is automatic as it does not require patient activation, reported relevant clinical events, such as asymptomatic atrial fibrillation.

Niraj Varma, MD, with the Cleveland Clinic and the principal investigator for the TRUST trial reported that remote monitoring event notifications were evaluated in a median of three days compared to more than 30 days with conventional care, providing earlier detection and notification of both symptomatic and asymptomatic arrhythmic events and enabling earlier physician intervention.

The event notifications were triggered infrequently and did not overburden physician or clinic resources with distracting information, he reported.

Biotronik (Berlin) said it has an installed base of 200,000 home monitoring systems in 65 countries that are compatible with the company's pacemakers, ICD and cardiac resynchronization therapy (CRT) devices.

Abbott expands range of stents, scope of trials

Abbott reported at ESC 2009 the next generation in its family of DES stents, the Xience Prime, is now being widely distributed in European markets, and in select countries throughout Asia-Pacific and Latin America, on the heels of receiving the CE mark in June.

A cobalt chromium stent with what Abbott calls one of the thinnest strut designs available, the Xience Prime is articulated in a broad matrix of sizes, including the SV version for small vessels and the LL version for long lesions.

The Xience Prime also feature greater visibility under x-ray during stent implantation procedures.

These design features "make it easier for a physician to appropriately reach and treat a lesion in complex anatomy," said Patrick Serruys, MD, with the Thoraxcenter at Erasmus University Hospital (Rotterdam, the Netherlands), who is also the editor of EuroIntervention, a publication of the European Association of Percutaneous Cardiovascular Interventions (EAPCI).

Abbott also updated European cardiologists on the dizzying series of SPIRIT clinical trials that are designed as head-to-head competitors for the Xience stents, which remain in development and not available for sale, with the market-leading Taxus DES from Boston Scientific (Natick, Massachusetts)

The trials now included SPIRIT II through SPIRIT V and in June, Abbott reported the launch of a further trial, SPIRIT PRIME to continue hammering at Taxus.

Abbott trials have a total participation of some 22,000 patients, and data from the SPIRIT IV trial, one of the largest comparing Xience V to Taxus, will be presented at the Transcatheter Cardiovascular Therapeutics annual meeting later this month in San Francisco.