By DON LONG, OMAR FORD
And AMANDA PEDERSEN
In the acronym-heavy world of clinical studies, the cardiovascular research arena stands out via both the number and variety of such trials.
Results from a wide range of such studies involving cardio topics have been reported in recent weeks.
Several involved the seemingly never-ending topic of coronary stents, whether of the bare-metal or drug-eluting variety. A look at some of the most recent research findings follows.
Fewer adverse effects with CABG than PCI
Newly released results of a trial that compares the impact of coronary-artery bypass graft surgery (CABG) and percutaneous coronary intervention (PCI) show that patients who underwent the former have fewer adverse effects than those who underwent the latter.
The findings could give patients a far better alternative than drug eluting stent (DES) procedures.
The SYNTAX trial evaluated 1,800 patients throughout the course of a year in an international, multicenter, randomized controlled comparison of CABG, vs. PCI with drug-eluting stents. All of the patients suffered from left main or three-vessel coronary artery disease. In all there were 85 sites throughout 17 countries in Europe.
Patient groups had a far more complex anatomy and advanced disease than those studied in prior drug-eluting stent clinical trials.
The trial was sponsored by Boston Scientific (Natick, Massachusetts).
The trial's principal investigators are Friedrich Mohr, MD, program director of the Heart Center/Cardiothoracic Surgery at the University of Leipzig (Germany) and Patrick Serruys, MD, PhD, chief of interventional cardiology at the Thoraxcenter of Erasmus University (Rotterdam, the Netherlands).
During that year, authors of the study were searching for four main adverse events death, myocardial infarction; stroke and revascularization. The authors looked for a combined end point of any one of the four events occurring within a year of randomization.
Results were presented in the New England Journal of Medicine.
"The main bottom-line results of the study were that, at one year, about 12% of the CABG patients had had one of these four adverse events," said Dr. David Hillis, chairman of medicine at the University of Texas Health Science Center (San Antonio), during a webcast presented by NEJM. "In contrast, 18% of the PCI patients had had one of those adverse events. So the bottom-line conclusion of the authors was that CABG remains the standard of care for patients with left main and three-vessel coronary artery disease."
The SYNTAX trial shows that major adverse cardiac or cerebrovascular events at a year were higher in the PCI group because of an increased rate of repeat revascularization.
But while that statement looks as though it could be the final nail in the coffin for PCI, a closer look at the data provides a bit of a boon for those still backing DES.
"If we look at the primary end point ... which was a combination of death, MI, stroke and the need for revascularization, if we drill down further, there was no difference between the two groups in death, MI and stroke at one year," Dr. Elizabeth Nabel, director of the National Heart, Lung and Blood Institute, said during NEJM's webcast. "The primary end point was really driven by an increased need for revascularization in the PCI group. So that is an important distinction that we must remember. Furthermore, if we look at the complication rate, there was a 1.6% higher incidence of stroke in the CABG group, compared to the PCI group."
Specifically the rate of stroke was .6% for PCI compared to the 2.2% rate of occurrence in CABG.
This is the main focus of Boston Scientific, a developer of the Taxus Express2 Paclitaxel-Eluting Coronary Stent System, which was used during the trial.
"While CABG may still be the preferred treatment in many patients with complicated disease, some patients may now be candidates for a less-invasive alternative offered by stents," Ted Feldman, MD, director of the cardiac cath lab at NorthShore University HealthSystem (Evanston, Illinois), said in a release.
When pressed for further comment, a spokesman for Boston Scientific declined, saying the company's position was covered in a press release it sent out yesterday.
The company first began enrolling patients in the SYNTAX trial in April 2005. It completed enrollment in April 2007.
It can scarcely be considered a secret that stenting procedures (particularly drug eluting stents) have come under fire in the past few years. It all began right about the time Swedish doctors openly questioned the efficacy of DES and said that such procedures have a higher rate of death at the September 2006 European Society of Cardiology (ESC; Sophia Antipolis, France) conference.
The reports at the time indicated DES devices may increase the risk of potentially fatal blood clots in the form of late thrombosis. As a result, the worldwide use of DES went into a sharp decline, with sales going from $5.1 billion in 2005 to 3.9 billion in 2007, according to the Thomson Reuters agency Research Markets.
Whether or not the results of SYNTAX will continue to erode the DES market remains to be seen. What can immediately be gleaned from the study is that patients now have greater insight on which procedure they should undergo.
"I think that patients should have a chance to articulate their preferences and weigh the risk of stroke versus risk of other kinds of outcomes," said Dr. Tom Lee, an associate editor of NEJM. "The SYNTAX trial will surely make those discussions much more informed and probably make them happen much more reliably."
Stent use for delayed MI treatment narrows
The use of stents to treat blockages of vessels supplying blood and oxygen to the heart was the major, most publicized development in the cardiovascular sector and the device sector as a whole at the end of the 20th century. And it was given a further booster shot at the century's close with the development of drug-eluting stents (DES) that reduced the necessity to redo initial stenting.
The result has been continuing sector skirmishing between drugs and devices, with the balloon/stenting combination (or PCI for percutaneous coronary intervention) frequently presented to patients as a quickly assumed treatment offering the best path to recovery and longer life compared to the use of drugs.
Over time the enthusiasm for stents so enthusiastic for DES, in particular, that the Centers for Medicare & Medicaid Services provided reimbursement for these devices immediately upon FDA approval has eroded as a routine choice, especially with increased emphasis on more careful patient selection of patients for PCI.
That erosion may continue with a just-released report revising previous assumptions.
The researchers conclude that PCI offers no particular advantage over drug therapy for those patients who receive delayed treatment for a myocardial infarction (MI), or heart attack. This category of patients may do just as well on optimal drug therapy, they conclude, though one of the lead researchers, Daniel Mark, MD, is not sure what impact the findings will have on actual interventional practice.
The study appearing in the New England Journal of Medicine reverses the conclusions of earlier analysis of the Occluded Artery Trial (OAT), issued two years ago. That study found that patients who receive delayed treatment for a heart attack did just as well with drugs alone as they do with a drug/PCI combination to open blocked arteries.
Now, further analysis of a smaller number of that population indicates that the drug option is cheaper and that there is no meaningful long-term difference in quality of life between the two strategies.
This is a different study than the SYNTAX trial reported on above.
Mark, a member of the Outcomes Research Group at the Duke University Clinical Research Group (Durham, North Carolina), and lead study author, said the revision of the earlier finding "is just one more reason to question the use of routine stenting in late-treatment patients when cheaper, less-invasive options are just as effective."
The study population receiving drug/PCI therapy received mostly bare metal stents, just 8% DES devices. But Mark said he did not feel that broader DES use would have made any difference in the conclusions, since the impact of that technology has not been lengthened life but only on reducing the need for redo procedures.
Importantly, the new analysis, besides offering a look at longer-term outcomes, takes a close look at quality-of-life issues and overall costs.
Besides concluding that the use of drugs for these patients costs less, the study found that patients receiving stents enjoyed a no better quality of life, over time, than those treated by drug therapy alone.
The study population consists of patients who began receiving therapy beyond the optimal treatment window for those with arterial blockage, considered within two hours or less following the appearance of first symptoms. But in actual practice one-third of all patients receive initial treatment more than 12 hours or more following the onset of symptoms, the study notes.
Mark said that it has been considered fairly obvious that opening a clogged artery with a stent would benefit these patients, but that cardiologists have been seeking some clear direction that this is, or is not, the case.
With catheterization of these patients, many are found to have a 100% blockage in one of their arteries.
But if a patient survives with this amount of blockage, and is generally stable, with no great angina, what's primarily needed, he said, is "to halt the progress of atherosclerosis that causes these heart attacks in the first place" and can be done with drugs and without stenting.
He added, more succinctly: "You can't make them feel better by messing around with their plumbing."
In the initial OAT trial, Mark and Judith Hochman, MD, of New York University, presented findings from a study of 2,166 patients showing that the two strategies, were equally effective in stable heart attack patients and that the drug/PCI group had some "modest" benefit over the drug-alone group, but not over a longer term.
In their follow-up analysis of 951 patients of the OAT trail, the investigators examined how patients felt about their lives and the cost of the two approaches, including patients who had suffered a heart attack anywhere from three to 28 days prior to enrollment who had a completely blocked artery but who were clinically stable and experiencing no chest pain.
Investigators found that at four months, patients in the drug/PCI group reported less chest pain and scored higher on quality of life measures. But those differences were small and disappeared over time. And by the end of the study, patients in the medical therapy group appeared to be doing just as well as those in the stented group.
Quality-of-life measures included the Duke Activity Status Index (DASI), which reflects cardiac function; the Medical Outcomes Study 36-Item Short-Form, assessing pain, physical limitations, social function and vitality; and the Mental Health Inventory, which assesses psychological well-being. The questionnaires were administered face-to-face or by telephone upon study enrollment, and at four, 12, and 24 months following.
The researchers also compared the costs of the two treatments and the use of healthcare resources among a subgroup of patients in the U.S.
They found that during the first month of treatment, members of the PCI group stayed in the hospital 1.2 days longer than those in the medical group, mostly reflecting longer-time in intensive care.
They also found that the mean cost for hospital and physician care during the first 30 days after starting treatment was $22,859 for the PCI group and $12,683 for the medical therapy group. Cumulative two-year costs were about $7,000 higher in the PCI group.
In summary, Mark said that drug therapy "is one of those cases where less is more. While it may seem that going an extra step in opening up clogged arteries even days after a heart attack, we know that clinically, it doesn't seem to offer the advantages we expected. Coupling that with the higher cost, we now know that adding PCI to standard medical care in opening blocked arteries more than a day after a heart attack is not good value. In an era when the high cost of healthcare is the subject of intense debate, this study offers us one way we can offer high quality care for less money."
The National Heart, Lung, and Blood Institute's Nabel, whose agency supported the study, said, "Medical care is not just about immediate results and survival, but it is also about providing good quality of life and minimizing medical costs."
Mark said he could not predict what effect the more recent conclusion would have on actual practice but any change would likely not be quick.
"I've been around my interventional colleagues long enough not to expect any miraculous shift. The process of developing information and having it filtered down to what doctors do on a daily basis takes longer than you would expect."
And he called any change in practice a "wild card" given "current economic chaos [putting] pressures on medical issues in general."
But, he added: "over time, people tend to move toward what we have the best evidence for."
Six-year data show sustained benefits for DES
The first company to receive FDA clearance for a drug-eluting stent has released six-year follow-up data on that device. The clinical benefits of the Cypher sirolimus-eluting coronary stent compared to a bare-metal stent (BMS) were sustained, according to data presented at the Cardiovascular Revascularization Therapies (CRT) conference in Washington.
The data is significant considering the many ups and downs the DES market has seen in the six years since Johnson & Johnson's (New Brunswick, New Jersey) Cordis (Miami Lakes, Florida) unit received clearance for the Cypher stent. The past six years in DES history has been characterized by data questioning the safety and effectiveness of the devices compared to their bare-metal cousins.
Sidney Cohen, MD, vie president-clinical at Cordis, noted in his presentation at CRT a copy of which was provided to Cardiovascular Devices & Drugs that no differences were observed between the Cypher stent and the BMS in the safety measures of heart attack, death or blood clots.
"These data are important for several reasons. First, the six-year results have remained consistent over time and continue to show the sustained patient benefits of the Cypher stent for patients," Cohen said in response to an CD&D question. "As the longest running randomized clinical trial of a drug-eluting stent, only the SIRIUS trial can provide six-year clinical data. Second, the results from SIRIUS confirm the overall safety of Cypher over a six year time period and that too is unmatched by any other drug-eluting stent."
At six-year follow-up, patients in the Cypher stent arm of the SIRIUS trial experienced significantly lower rates of target vessel failure (TVF), the primary endpoint of the trial, than those who received the BMS (26.1% for the Cypher vs. 39.9% for the BMS). TVF was defined as a composite of cardiac death, myocardial infarction and target vessel revascularization (TVR, or re-treatment of the blocked vessel).
The sirolimus-coated BX Velocity Balloon-Expandable Stent in Treatment of Patients with De Novo Coronary Artery Lesions (SIRIUS) trial, sponsored by Cordis, served as a pivotal study for the U.S. approval of the Cypher stent in 2003 and is the longest-running, U.S.-based study for a DES.
In the double-blinded, multi-center randomized trial, patients were divided into two treatment groups: 533 patients received the Cypher and 525 patients received a BMS. Of the original 1,058 participants, only about 50% (271 patients receiving the Cypher and 255 patients receiving a BMS) participated in the six-year follow up.
"The six-year results of the SIRIUS trial demonstrate that the treatment benefits and safety of the Cypher stent are preserved in longer-term follow-up," Cohen said. "The Cypher stent remains the most proven and studied drug-eluting stent in its class and physicians can trust in the long-term safety profile and sustained patient benefits associated with the Cypher stent."
In this long-term follow-up, the Cypher stent also demonstrated lower rates of target lesion revascularization (TLR, or re-treatment at the same arterial site) and major adverse cardiac events (MACE), which include heart attack and death, compared to the BMS. The TLR rate for the Cypher stent was 11.9% vs. 27.9% for the BMS, and the MACE rate for the Cypher stent was 22.6% vs. 37.2% for the BMS.
Cohen noted during his presentation that the six-year clinical follow-up was completed on only half of the originally enrolled patients and that, while Kaplan-Meier analysis partially adjusts for this, bias cannot be ruled out, as patients who did receive follow-up were not a random subset of the original cohort.
"It is important to note that both the absolute reduction in key endpoints between the Cypher stent and the control, and the increment in these numbers due to underlying cardiovascular disease progression, remains consistent over the six-year timeframe. This demonstrates there is no 'late catch-up' in the patients receiving the Cypher stent," Cohen concluded.
In addition, there was no significant difference in the mortality or the heart attack rates between the Cypher stent and the BMS at six-year follow-up. The mortality rate was 8.9% for those receiving the Cypher stent compared to 9.4% for those receiving BMS. The myocardial infarction rate for the Cypher was 6.4%, compared to 7% for the BMS.
According to Cohen's presentation at CRT, there was no significant difference in the overall rate of stent thrombosis between the Cypher stent and the BMS, regardless of the definition of stent thrombosis employed. The definitions include the original SIRIUS trial protocol definition and the Academic Research Consortium (ARC) definition. At six years, the protocol definition identified a rate of 1.2% stent thrombosis for the Cypher stent vs. 0.8% for the BMS. The definite/probable ARC definition identified a stent thrombosis rate of 1.2% for the Cypher stent vs. 2.1% for the BMS. There was no trend for an increase in ARC-defined definite or probable very late stent thrombosis rates between 1 and 6 years (0.8% in Cypher arm vs. 1.0% in the BMS arm), Cordis noted.
Last year second-generation drug-eluting stents hit the U.S. market, first Medtronic's (Minneapolis) Endeavor zotarolimus-eluting stent, which won approval in February, then with Abbott's (Abbott Park, Illinois) Xience V everolimus-eluting stent getting approval five months later.
Both the Endeavor and Xience are expected to elbow aside the first-generation DES devices, the Cordis Cypher and the Taxus from Boston Scientific, which was approved in 2004.
Abbott also supplies a private-label version of Xience V to Boston Scientific called the Promus.
According to Cordis, the Cypher stent has been used to treat some 3 million patients with coronary artery disease. A robust clinical trial program that includes more than 70 studies that examine the performance of the Cypher stent in a broad range of patients, the company said, supports the safety and efficacy of the device.
The next version of a sirolimus-eluting stent, the Cypher Select sirolimus-eluting coronary stent, was launched in Europe, Asia Pacific, Latin America and Canada in 2003. The Cypher Select Plus stent, the third version of a sirolimus-eluting coronary stent, received the CE mark in 2006 and is currently available in many markets outside the U.S.
Studies back biventricular support
It probably goes without saying that if a heart failure patient is going to develop right ventricular (RV) failure after receiving a left ventricular assist device (LVAD), that patient should have received biventricular support from the start. The problem is, predicting post-LVAD RV failure requiring mechanical support is anything but easy.
Data published in the December issue of the Journal of Heart and Lung Transplantation (JHLT) highlights this problem, as one article in the journal finds that RV dysfunction develops in 20% to 50% of LVAD patients and a second article finds that 37% of LVAD recipients later require a RV assist device (RVAD).
What happens is when the LVAD is implanted it begins to assist the left side, which powers up the body and moves blood back to the right atrium, and the right ventricle can't keep up with the assisted left ventricle, explained Roger Ford, CEO of SynCardia Systems (Tucson, Arizona), the company that makes the CardioWest temporary Total Artificial Heart.
"The mystery is how in the heck can you determine whether you have a poor function right and left side before you assist the left side? Nobody knows, some people think they know but nobody really knows," Ford told CD&D.
One article published in JHLT is from the German Heart Institute Berlin. It suggests that RV dysfunction develops in 20% to 50% of patients after LVAD implantation, leading to prolonged ICU stays and elevated mortality, according to the study authors. The article concludes that pre-operative evaluation of tricuspid incompetence and RV geometry may help to select patients who would benefit from biventricular support.
A second article, from the Hospital of the University of Pennsylvania (HUP; Philadelphia), found that of 266 LVAD recipients, 99 required a RV assist device (37%).
RV failure after LVAD placement is a "serious complication and is difficult to predict," according to the authors of the HUP article. "In the era of destination therapy and the total artificial heart, predicting post-LVAD RV failure requiring mechanical support is extremely important."
According to the HUP article, researchers reviewed patient characteristics, laboratory values and hemodynamic data from those 266 patients who underwent LVAD placement at the University of Pennsylvania from April 1995 to June 2007.
The researchers compared 36 parameters between LVAD and BiVAD patients to determine pre-operative risk factors for RVAD need. The study authors concluded that the most significant predictors for RVAD need were cardiac index, RV stroke work index, severe pre-operative RV dysfunction, creatinine, previous cardiac surgery and systolic blood pressure. Using these data, the researchers constructed an algorithm that can predict which LVAD patients will require RVAD with more than 80% sensitivity and specificity.
Both articles were presented at the 28th annual meeting of the International Society for Heart and Lung Transplantation (ISHLT; Addison, Texas) in April.
"The obvious point is, my goodness, 37% of people that got LVADs needed RVADs," Don Isaacs, director of communications for SynCardia, told CD&D. "If they could determine whether that patient would need an RVAD or not ... get more appropriate device, which for tiny patients would be a biventricular assist device and patients of any size would be a CardioWest total artificial heart."
SynCardia is in the process of developing a 50 cc version (compared to the 70 cc version) of its total artificial heart for smaller adults and adolescents. Ford said the development of the smaller device is on track to be completed by the third or fourth quarter of this year.
"Right ventricular failure in LVAD patients is tragic," said Jack Copeland, MD, chief of cardiothoracic surgery at University Medical Center (Tucson), who reports owning equity in SynCardia. "If it can be anticipated, the solution is bi-ventricular support from the start. If it becomes a crisis, in appropriate patients, the CardioWest temporary total artificial heart (TAH-t) may be life-saving."
Originally designed as a permanent replacement heart, the CardioWest artificial heart is currently approved as a bridge to human heart transplant for patients dying from end stage biventricular failure. The device is the only FDA, Health Canada and CE-mark approved total artificial heart in the world, the company notes.
"By replacing both sides of the dying heart, the CardioWest eliminates complications caused by failing ventricles, diseased valves, ventricle defects and electrical problems requiring a pacemaker and/or defibrillator," Copeland said.
Although the CardioWest device is approved as a bridge-to-transplant device, Ford said there are some patients in Germany with a CardioWest artificial heart implanted who have decided to "avoid the hospital and have been on our device for three years now."
Meanwhile, LVAD makers continue to release new and improved devices designed to support the left ventricle. Terumo Heart (Ann Arbor, Michigan) received the go-ahead from FDA in March 2008 to start its U.S. trial of the DuraHeart Left Ventricular Assist System (LVAS) as a bridge-to-transplant device.
Then, in August, the company reported that the first U.S. patient implanted with the DuraHeart had been discharged from the University of Michigan Health System (Ann Arbor) 15 days after receiving the device.
Terumo says the hockey puck-sized DuraHeart LVAS uses a new type of magnetic levitation technology (Mag-Lev) designed to eliminate mechanical contact within the blood flow path thus minimizing the chance of mechanical failure. Mark White, marketing manager for Terumo Heart, told CD&D at the time that the Mag-Lev technology is the core benefit of the DuraHeart, as it prevents a lot of the problems associated with other systems in which the impeller is suspended through pressure distribution.
That news came almost simultaneously with HeartWare (Farmingham, Massachusetts/Sydney, Australia) reporting that the first U.S. patient had received its LVAS at Washington Hospital Center (Washington), marking the start of its U.S. trial. Similar to the DuraHeart, the impeller that spins inside the HeartWare LVAS pump is also suspended by magnetic forces. Although both pumps are much smaller than earlier generation devices, the HeartWare is actually small enough to fit directly adjacent to the heart in the pericardial space. Most other systems, including the DuraHeart, are implanted into a surgically-created pump pocket in the abdomen.
Other companies developing similar devices include Ventracor (Chatswood, Australia), Abiomed (Danvers, Massachusetts) and Thoratec (Pleasanton, California).
In February, Thoratec agreed to acquire HeartWare in a cash-stock deal valued at about $282 million. The company said it would pay about 50% in cash and the rest would be paid in shares of its common stock. Ford speculated that Thoratec was motivated to buy HeartWare because its device is small enough to fit directly in adjacent to the heart in the pericardial space, without the surgeon having to create a pump pocket in the abdomen.
"Thoratec had to get above the diaphragm to reserve their spot in the space because being above the diaphragm is where the surgeons want to go, it is a less invasive surgery ... put the pump right in the pericardial space," Ford said.
Identifying earliest heart disease in women
The trial name, STILETTO, has the quality of a neon sign. And Martha Gulati, MD, laughs when she reports that some of the women thinking of enrolling ask if their participation will get them a pair of high heels.
She tells them they won't get any shoes, spiky heels or otherwise, but she hopes that they'll feel better as a result if they are selected for the study, designed to explore a potential treatment for Syndrome X.
STILLETO stands for "Syndrome X Trial: Identifying underLying Endothelial dysfunction and Testing Treatment Outcomes in women," with Syndrome X being a group of cardiovascular symptoms thought to lead to worse heart disease.
To be conducted by physicians at the Bluhm Cardiovascular Institute of Northwestern Memorial Hospital (Chicago), the trial specifically is designed to explore options for treating women shown to have, specifically, endothelial dysfunction, and if that treatment has a longer-term preventive effect.
Gulati, MD, associate medical director of the Center for Women's Cardiovascular Health and assistant professor of medicine at the Feinberg School of Medicine (Chicago) of Northwestern University, is the lead investigator of STILETTO.
She told CD&D that Syndrome X is defined by three primary symptoms, angina, an abnormal EKG and abnormalities of the microvasculature (and different from metabolic syndrome which consists of having a group of five other high-risk conditions for heart disease, diabetes, high blood pressure, obesity, decreased HDL cholesterol and elevated triglycerides).
Gulati notes that women experiencing chest pain this very obviously and intuitively indicating a heart problem often are put through a variety of diagnostics, such as stress testing and cardiac angiography, but with those tests frequently showing no other evidence of coronary artery disease.
So they are often sent home with little direction, but subsequently experience similar symptoms and go on to develop worse problems, or even heart attack and death.
As a result, Gulati says that there are no clear guidelines for treating these women, and STILETTO is an attempt to fill that therapeutic gap.
Endothelial dysfunction is defined as a condition in which the outer layers of vascular cells are not functioning properly, and she says there is a body of research indicating that this condition is the earliest stage of coronary artery disease in women.
While the research points to such a relationship, she says, "We're not 100% certain." Thus, STILETTO, the name constructed to underline its focus on women, will explore the possibility of a cause/effect relationship.
It will first identify the presence of endothelial dysfunction in a group of women presenting with Syndrome X and then provide a two-pronged approach to stave off follow-on heart disease: guidance in making behavioral changes, such as with diet and exercise, and medical treatment consisting of a combination of basic cardio drugs.
The trial directly addresses the well-publicized disparities between men and women in the treatment of heart disease, with women frequently being diagnosed with heart disease more slowly than men and slower to receive necessary therapies, and as a result, dying of heart disease more often than men, it is thought.
Clearly underlying the reports of these disparities are two, often unstated possibilities: that doctors are treating women suspected of having heart problems less aggressively, due to some bias, or that cardiovascular science medicine has been slow to identify the ways in which heart diseases impact women in different ways than in men.
Gulati says she favors "the latter" of these explanations and that STILLETO is an attempt to better understand what may be a sentinel precursor of more serious disease in women and provide preventive measures.
The women in the trial which she describes as a pivotal study of only about 50 enrollees to begin with will be selected from those who appear with chest pain and then diagnosed as having endothelial dysfunction. The diagnosis will be made by an injection of acetylcholine, that drug serving to indicate vasoconstriction.
Once enrolled, the women will be guided in pursuing "aggressive" lifestyle changes and also receive treatment with what Gulati described as a "cocktail" of drugs developed by the trial investigators, primarily a combination of statins, beta blockers and aspirin, all cardio-therapeutic standards.
The enrollees will be followed for one year to determine if there is any improvement in symptoms, and Gulati acknowledges that a trial with much greater number of women, followed for a much longer period, is necessary to offer the power robust enough to determine the endothelial dysfunction/more serious disease combination and the efficacy of the therapies used.
But she says the women in such a study would not have to be tracked out to 20 or 30 years, only a much shorter time, given how aggressive heart disease sometimes attacks these women.
She told CD&D that STILETTO investigators are applying for additional grant monies to do an extension of the current trial.
Neil Stone, MD, medical director of the Center for Vascular Disease and professor of medicine at the Feinberg School of Medicine, underlined the importance of the study, saying that there "are currently no other randomized trials comparing the effectiveness of such therapy in women with cardiac symptoms, normal coronary arteries but evidence of coronary endothelial dysfunction."
STILETTO is supported by the Woman's Board of Northwestern Memorial Hospital.
Study cites favorable results with Impella
A study published in the February issue of the Journal of American College of Cardiology cites favorable results in the use of Abiomed's (Danvers, Massachusetts) Impella 2.5 system in patients undergoing high- risk percutaneous coronary intervention (PCI).
The study shows results from the Protect I trial, and concludes that the system is "safe, easy to use and provides excellent hemodynamic support during high-risk PCI."
The PROTECT I trial enrolled 20 patients undergoing high-risk PCI at seven centers between July 2006 and April 2007. Eligible patients had left ventricular ejection fraction (EF) of less than 35% and were required to undergo PCI on either an unprotected left main coronary artery or the last patent coronary conduit.
Patients with recent ST-segment elevation myocardial infarction or cardiogenic shock were excluded. The primary safety end point was the incidence of major adverse cardiac events at 30 days. The primary efficacy end point was freedom from hemodynamic compromise during PCI (defined as a decrease in mean arterial pressure below 60 mm Hg for more than 10 minutes).
The Impella 2.5 device was implanted successfully in all patients. The mean duration of circulatory support was 1.7 ± 0.6 h (range: 0.4 h to 2.5 h). Mean pump flow during PCI was 2.2 ± 0.3 l/min. At 30 days, the incidence of major adverse cardiac events was 20% (two patients had a periprocedural myocardial infarction; two patients died at days 12 and 14).
There was no evidence of aortic valve injury, cardiac perforation, or limb ischemia. Two patients (10%) developed mild, transient hemolysis without clinical sequelae. None of the patients developed hemodynamic compromise during PCI.
"The advantage to having a small heart pump is that it is minimally invasive," said a company spokesperson via e-mail to CD&D. "Other LVADs require a sternotomy, or cracking of the chest, for implantation. Impella 2.5 is implanted percutaneously via the femoral artery and up through the aorta, hooking into the left ventricle. Impella increases the blood flow and oxygen supply to the heart, while decreasing demand, essentially reducing the workload on the heart by doing 30% of the work for pumping blood, with a pump that is 100th the size of the heart."
The study shows that the Impella provides hemodynamic support by directly unloading the left ventricle and reducing oxygen demand and the work on the heart, while increasing oxygen supply.
The device was initially developed in Aachen, Germany, by Impella CardioSystems (Aachen Germany). Abiomed acquired Impella CardioSystems in the spring of 2005 for $1.8 million in cash.
The Impella device then received 510(k) clearance from the FDA in June 2008 for partial circulatory support for periods up to six hours.
Now approved in more than 40 countries, including in Europe under the CE mark, Impella 2.5 has been used to treat more than 1,700 patients worldwide and has been the subject of more than 50 peer-reviewed publications.
The company said that it also is conducting two U.S. pivotal studies comparing the Impella 2.5 to the IABP (Protect II for high-risk percutaneous coronary intervention, or PCI; and Recover II for acute myocardial infarction, AMI or heart attack).
There are an estimated 60,000 annual high-risk PCI patients and 100,000 AMI anterior infarct patients annually in the U.S.
Other companies developing similar devices include Ventracor (Chatswood, Australia) HeartWare (Framingham, Massachusetts/Sydney Australia) and Thoratec (Pleasanton, California).
Ventracor offers the VentraAssist, a VAD that operates on a hemodynamically-suspended titanium impeller. The VentraAssist has a CE mark, and is currently enrolling patients in a U.S. pivotal trial.
HeartWare developed its HeartWare Left Ventricular Assist System (LVAS) at Washington Hospital Center (WHC; Washington), which marks the start of the company's U.S. bridge-to-transplant clinical trial. Steven Boyce, MD, surgical director of the heart failure program at WHC, performed the surgery. The pump is small enough to fit in the pericardial space adjacent to the heart.