CDU Executive Editor
There is no doubt concerning what was the "blockbuster" news out of this year's Congress of the European Society of Cardiology (Sophia Antipolis, France) in Vienna earlier this month. Drug-eluting stent (DES) devices are safe.
Well maybe . . . it all depends . . . and what are the specific circumstances in terms of patients, their exact type of heart disease, their co-morbidities, for the best use of DES devices vs. bare metal stent (BMS) devices?
The report of broad safety was literally blockbuster news, given that it deals with a blockbuster product and the profits — and, more recently, profit declines — that go with it.
In summary, the researchers developing the Swedish Coronary Angiography and Angioplasty Registry (SCAAR) issued a report at the meeting pushing back on the original findings from the research in an attempt to assure the cardiology community that DES is safe.
That conclusion appeared to disagree with the initial findings from the SCAAR study indicating that the broad use of DES devices had resulted in increased rates of complications, primarily increased thrombosis, with that thrombosis related to increased rates of mortality. That report was one of the first of a continuing series of studies on DES use pointing to similar results in certain populations and a rapid trend downward in DES use.
In Sweden, DES use plummeted, it was estimated, from 60% to around 15%. In the U.S. the uptake had been much greater, as much as 90% in some hospitals. There, use dropped to 80% or as low as 60%, according to some reports. Then DES use in Sweden was hit by an official barrier: the Swedish National Board of Health and Welfare in early 2007 recommended that DES devices should be used only when a physician considered that use medically necessary
But the newer analysis presented at ESC should serve to calm the fears of patients concerning DES, according to Stefan James, MD, of Academic Hospital (Uppsala, Sweden), who presented the findings, though it is much to early to see any change in Sweden's medical guidance.
James described the newer data as "good news" for patients. While James acknowledged "an increased risk of late stent thrombosis" in DES implantation, he said that this "doesn't seem to translate into an increase risk of death or MI [myocardial infarction] long-term." He then added two caveats: "I think there is still a concern: we haven't solved the problem of late thrombosis, and the patients are dependent on long-term treatment with dual antiplatelet therapy."
An even larger umbrella caveat made by James was to emphasize that the newer findings did not constitute a contradiction of the earlier findings concerning SCAAR. ". . . I don't think we have really backed off, but over time [mortality risk] is no longer significant."
Original and now new report
The original data out of SCAAR included percutaneous coronary intervention procedures done from 2003 to 2004, reporting 1,424 deaths and 2,463 MIs in 19,771 enrollees in the study. These figures indicated a reduced number of events upon six-month follow-up, but then an increasing number of deaths and MIs at three-year follow-up. In contrast, the new analysis looked at a great many more patients, 35,000, over one to four years of follow-up. As compared to the earlier findings, the data now showed reduced death among the enrollees implanted with DES devices from one to five years of follow-up.
The study underlined another important point that can't be considered a boon to the DES-supporting community: The new data showed no essential difference in the rates of death between DES-implanted and BMS-implanted enrollees.
This serves as counter-point to the original single-standard selling point for DES, that these devices greatly reduced the risk of restenosis compared to BMS. That argument tended to "sell" the technology's benefit to all parties — including the Centers for Medicare & Medicaid Services — but there had been no longer-term studies concerning what might be reasonably assumed as a much more critical endpoint for patients: mortality.
The various nuances of the study, however, didn't seem to influence media coverage of the positive analysis. And the Street picked up on the overall message of DES safety, with both Johnson & Johnson (New Brunswick, New Jersey)/Cordis (Miami Lakes, Florida) and Boston Scientific (Natick, Massachusetts), manufacturers of the leading DES devices, seeing up-ticks in their share prices following the report.
Explaining the desynchrony
The question hovering around the initial and then newer data was, of course: Why the desynchrony in the two conclusions?
James offered a variety of possible explanations, primarily focusing on the more careful selection of patients and the greater experience by interventionalists in the techniques for implanting the devices.
He said that the earlier alarms about increased thrombosis may have guided a more careful identification of patients for DES implant, and the emphasis on the more rigorous patient compliance with anti-platelet therapy probably had resulted in physicians pushing its longer use and providing better oversight of compliance. As to implant technique, he speculated that the use of higher balloon pressures and greater care in the sizing of stents to vessels was being practiced by implanting physicians, to good effect.
Overall, the impact of the report is likely to be increased emphasis on even more careful identification of those patients considered most likely to benefit from DES implantation and offer much lower risk of thrombosis. The best profile for this patient, according to James, is the non-STEMI patients who will be most likely, and able, to be compliant with follow-on anti-platelet therapy (a factor often inter-mixed with the ability to pay for expensive pharmaceuticals, and insurance coverages).
Perhaps the largest qualifier offered to the overall upbeat study results and more positive recommendation for DES use was James' response to an ongoing drive by some European countries to follow Sweden's lead and develop guidelines that put a lid on widespread use of DES. "Considering the risks of stent thrombosis, considering the moderate benefit regarding restenosis, and the associated cost, it's a reasonable way of thinking," James said, once again underlining the need for careful patient selection.
Another, post-MI, DES-implant, caveat
As further background serving to "nuance" — and greatly modify — the optimism out of the new SCAAR analysis were a variety of other studies on DES at the ESC meeting. Those studies served as the less-reported back story to the rave reports by the media concerning SCAAR.
Professor Gabriel Steg of Hôpital Bichat-Claude Bernard (Paris) presented study data underlining the conclusion of increased possibilities for late stent thrombosis occurring "abruptly" more than one year after DES placement in those suffering MI. Steg acknowledged that this late thrombosis following DES placement is rare but that when it does happen it results in death in up to 45% of all cases. Steg's analysis used the database from the Global Registry of Acute Coronary syndromEs (GRACE), collected in 94 hospitals in 14 countries across four continents (Americas, Europe, Australia/NZ) to compare the survival up to two years of patients treated with BMS only or receiving at least one DES. Survival appeared similar in the six-months following discharge, but thereafter mortality was greater in patients treated with DES.
Important to note is that this difference was entirely related to patients treated for acute MI and was associated with an increased risk of late reinfarction, suggesting that it may indeed be related to late stent thrombosis, according to Steg.
Steg said that the risk of such late stent thrombosis may be greater in the context of acute coronary syndromes, but that there has been little data, thus far, from rigorous clinical trials comparing DES and BMS, in the context of acute MI. Such trials focused on this issue have been on fewer than 1,000 patients implanted with DES and only studied via short-term follow-up.
The ESC issued a statement urging caution in analyzing an observational study such as GRACE (noting that the patients in the DES and BMS groups were not similar), but said that this survival difference suggests that DES should be used with caution in patients with acute MI until more, longer-term safety studies are developed.
Ongoing since 1999, the GRACE registry is supported by Sanofi-Aventis and coordinated by the Center for Outcomes Research, University of Massachusetts Medical School (Worcester).
OPTIMIST not optimistic, re: thrombosis
Still another study presented at the meeting, looking at the issue of thrombosis whether following DES or BMS use, came from researchers at Hospital, Catholic University of the Sacred Heart (Rome), and its conclusion is that this is a serious concern in the context of percutaneous coronary intervention (PCI) in emergency situations. The data reported came from the OPTIMIST study which looked at the issue of thrombosis following emergency PCI, without distinguishing between rates of thrombosis between DES and BMS devices.
OPTIMIST was developed to collect data on the clinical outcome of patients with stent thrombosis following urgent PCI in order to add to an area of concern where such data is lacking. "We discovered," the researchers said, "that the clinical outcome during the six-month follow-up, despite good utilization of all the best pharmacological and technical resources, was a disappointing 17% mortality rate and 29% rate of major adverse coronary or cerebral events (death or myocardial infarction or stroke or necessity of a new interventional procedure). These results show that stent thrombosis is not a benign disease and emergency PCI in this setting is still associated with unsatisfactory outcome."
An initial observation from the study was that stent thrombosis, even if it is a rare event, accounted for 3.6% of the emergency PCI performed in patients with acute MI. "This data reinforces the perception that stent thrombosis has more than a negligible impact on the contemporary health system and further investigations on its causes and management are called for," the researchers wrote.
They said that the data collected did not provide any clarifying look at whether thrombosis is higher for DES vs. BMS implantation, but the researchers said that the data supported the hypothesis that stent thrombosis "may have different mechanisms of occurrence in different types of stents. "Indeed, DES thrombosis, compared to BMS, happened more often after 30 days of implantation or after 15 days of anti-platelet drug therapy withdrawal. On the other hand, once stent thrombosis has occurred, we observed that the clinical manifestations, the procedural and the clinical outcomes, are not influenced by the type [DES or BMS] of previously implanted stent."
OPTIMIST is an independent, large-scale, multi-center study conducted by 11 hospitals in urban Rome. During the years 2005 and 2006 all patients who were admitted to participating hospitals with stent thrombosis and treated by PCI were enrolled.
The clinical and procedural data were recorded on a detailed questionnaire and the clinical outcome up to six months after intervention was assessed by ambulatory visit or phone contact, and the efficacy of the procedure to re-establish optimal coronary blood flow was assessed by performing detailed analyses in an independent core laboratory.
During the study, 110 patients were enrolled. This constituted, the researchers said, the largest series of patients with stent thrombosis ever collected.
Additional analysis of OPTIMIST showed:
- that mortality is significantly higher when stent thrombosis occurred one year after stent implantation ("very late" thrombosis);
- when the attempted PCI result was not optimal; and
- when a further stent was implanted during the PCI.
The data concerning mortality was interpreted by the investigators as indicating that clinical surveillance after a successful PCI should not be reduced after one year and that the possible value of long-term anti-thrombotic drug administration should be investigated.
"The other two factors may together provide some interesting suggestions to the interventional cardiologists who must perform emergency PCI procedures in patients with stent thrombosis. Indeed, it seems that they should aim to re-establish optimal coronary blood flow and not to eliminate any residual coronary vessel narrowing by further stent implantations," the investigators said.
OPTIMIST also evaluated the efficacy of novel techniques of PCI in the high risk scenario of stent thrombosis. Previous studies have suggested that thrombus removal by devices specifically designed for this procedure may facilitate restoration of coronary blood flow in thrombotic lesions by reducing thrombotic debris.
In OPTIMIST, one of every four patients was treated using thrombectomy devices as a first strategy. Though the patients treated by thrombectomy were sicker than the others, the data should no increase in adverse events.
Patients with absence of shock treated by thrombectomy had a fivefold improved rate of optimal coronary flow restoration, "suggesting that the role of distal embolization and its prevention may be important only before advanced heart damage has been established," according to the researchers.
If emergency angioplasty/stenting needed, do quickly
As with the reports concerning DES, emergency angioplasty received a type of point-counterpoint from the ESC conference, indicating that angioplasty/stenting on an emergency basis has the best outcomes when done very quickly, and that patients needing this procedure should be immediately transferred to a hospital where this can be done, if he or she isn't there already.
Professor Carlo Di Mario of the United Kingdom, presented data indicating that patients who are transferred and receive angioplasty immediately after the use of thrombolytics are much more likely (4.1% vs. 11.1% at 30 days, p<0.001) to be free from another MI, another acute episode of chest pain and ECG changes requiring urgent angioplasty. This advantage was present despite the fact that all the patients (36% of the entire conservative group) randomized to the group of more conservative treatment (no immediate transfer) were also promptly referred during the first hours post treatment if there was no evidence in their ECG/clinical status that the lytic drugs had open the occluded artery.
He said that the implications are that when a patient cannot receive direct angioplasty — noting that this still includes the majority of the patients with acute MI in most European countries — the current practice in most hospitals in Europe is to administer lytics and wait, watching the effect of the drug on ECG and patient's symptoms.
He said the data indicates this practice is wrong "and all patients should be transferred immediately for angioplasty after thrombolysis is started. He pointed to ESC guidelines which recommend this, may be based on a 2006 study published in the Lancet (2006;367:569-68) from trials indicating that the administration of "lytics" immediately before PCI can be deleterious and increase the risk of adverse events, such as bleeding, the need for emergency angioplasty and possibly death.
"We had an opposite result, and we believe the reason is the type of lytic treatment used — not just a thrombolytic drug, but a cocktail of a powerful intravenous anti-platelet agent called abciximab, and a reduced dose of a fibrin specific lytic drug called reteplase," Di Mario said.
He called this combination "very powerful and rapid in its action, with a synergistic effect demonstrated in previous trials and in in vitro models, and achieved restoration of flow in the occluded artery in 85% of cases by the time patients reached the hospital where angioplasty was performed.
"Its main advantage is, however, the ability to inactivate platelets during the subsequent angioplasty, the opposite of the result observed when only lytics are given which tend to activate platelets instead."
The interval between administration of the thrombolytic and angioplasty was greater than 120 minutes in more than half of the patients (median 136 minutes), meaning that they were not candidates for primary angioplasty under the current guidelines which require an interval of less than 90 minutes between first qualified medical contact and direct angioplasty. The current fear to give thrombolytics before angioplasty is challenged by the low incidence of bleeding observed in this trial (0.8% intracranial hemorrhages and 2.9% bleedings requiring 1 or more transfusions, with no difference between patients transferred for immediate angioplasty and patients who remained in the hospital of initial admission).
The trial, conducted in Italy, Poland and France, involved various networks of community hospitals referring to a larger hospital with a 24/7 availability for direct PCI of acute MI. Patients were randomized by telephone at the time of admission, with all adverse events blindly reviewed by an independent committee for adjudication and all ECG and angiograms analyzed by an independent core laboratory unaware of the treatment received.
The study was sponsored by the Italian Society of Invasive Cardiology (GISE; Rome), with data entry and analysis performed blind to the randomization code by the Clinical Trial Unit of the Royal Brompton Hospital (London).
Di Mario emphasized that the trial results should be noted in particular because of the number of patients living in rural areas or in mountainous regions, with an expected delay greater than 90 minutes to reach a center able to perform angioplasty. He said that even in the best models of angioplasty network (for instance in the recently reported experience of the Minnesota-AMC Minneapolis acute MI networks, using medically equipped helicopters for patient transferred in >70% of cases), almost half of the patients reached the cath lab of the receiving hospital in more than 120 minutes, suggesting that "facilitated angioplasty has great potential applications."
Taxus, Cypher: thrombosis differences
Among the various DES studies presented at the ESC meeting, one focused specifically on the issue of late thrombosis shown between the two stents approved in the U.S., the Cypher and the Taxus. Renu Virmani, MD, of the CVPath Institute (Gathersburg, Maryland) presented data indicating "inherent differences" for each of the stents in man, with fibrin deposition being more frequent in the Taxus while inflammation, especially eosinophilic infiltrate and giant cell reaction, being greater in the Cypher.
Noting the association between DES and late thrombosis, Virmani said that the mechanisms causing this are not well understood but can best be analyzed using pathologic studies.
"We have studies at autopsy of 83 patients (117 lesions) with DES in place for >30 days implanted in patients with coronary artery disease. Of 33 lesions with either luminal thrombus (n=25 lesions) or organized thrombus (n=eight lesions) six lesions (five patients) showed a hypersensitivity reaction (five for Cypher, one for Taxus).
These stents had been in place from 112 to 940 days; three patients died suddenly, and two presented with acute myocardial infarction. "From these data it appears that the response is limited to the area of the stent and that there is extensive eosinophilic and T-cell infiltration. There may or may not be a granulomatous reaction."
Other morphologic changes that predispose stent thrombosis are malapposition (n=8), stenting of bifurcation lesions (n=7), AMI patients (n=8), and overlapping stents (n=4). All showed delayed healing, further exaggerated either from turbulent flow at malapposition or bifurcation sites or poor healing at sites of plaque rupture, and overlapping stents. "Excessive length (>30 mm) is a correlate of LST as well as presence of uncovered stent struts. Uniformly all cases with thrombi have presence of fibrin, poor stent coverage by neointima, and less endothelialization."
All 78 lesions that were patent (and DES was not the cause of death) and had been in place for >30 days showed less neointima as compared to BMS thus suggesting that DES are effective in reducing neointimal thickness. A parameter, which is uniformly observed in BMS is that the neointimal formation (smooth muscle cells in matrix) around the circumference of the stent tends to be uniform in distribution. In DES there is heterogeneity of healing with areas showing excessive fibrin and others with smooth muscle cells within matrix and uneven luminal endothelialization.
The researchers concluded from these histologic studies that because of underlying atherosclerotic plaque morphology differences, variability in healing from patient to patient, and a hypersensitivity in some patients, DES technology may have to be tailored to individual patient characteristics, rather than "one stent fits all."
Cardio-conference must: gender differences
Another topic increasingly being featured at cardiovascular conferences is the difference between men and women in terms of presentation of symptoms, differences in the rates of heart disease between the genders, and differences in the types and rates of treatment.
Antonio Abbate, MD, said that women "have been neglected in several fields of medicine for too long. I think that cardiology is only one of the many fields in the past where the male predominance was obvious."
He pointed to the increasing awareness that women are poorly represented in clinical studies and that this has "generated the idea that women were less likely to be affected [by heart disease] and because they presented differently from men were labeled as 'atypical presentation.' In reality we never had enough data to define what 'typical' angina in women really is."
He said the differences between men and women are heightened by "the differences in epidemiology and prevalence in risk factors, incidence of the inciting event, differences in the response to the insult, and differences in outcome, making therefore even more complex to appreciate true gender-dependent differences."
Several studies, he said, indicate "that women with MI are usually diagnosed late during the course, are often misdiagnosed at first, are less likely to receive optimal medical care, and in many series their crude mortality is higher than men."
This, Abbate said, encourages the view that women are disadvantaged. "Indeed they are disadvantaged if they are diagnosed late and if they are treated less aggressively," which he termed a social disadvantage. "The question whether they are biologically disadvantaged, on the other hand, is still debated." But he said it is "plausible that female gender is protective toward adverse remodeling."
After an insult (such as ischemia, infarct or pressure overload), the heart attempts to compensate by remodeling which usually entails hypertrophy of the walls and enlargement of cavity. This process, although initially beneficial in maintaining an adequate cardiac output eventually leads to unfavorable outcome, he said. "It has been described that females [both human and animal] tend to have a prevalent hypertrophic response rather than dilatation of the cavity and this associated with preserved contractile function and overall better outcome." Abbate said.
He said that there may "indeed be a gender-dependent difference in the pathway dominating the remodeling process."And he said that while several molecules have been proposed as candidates to address these pathway differences, "no definite data are available. An increased resistance to apoptosis in females is suggested."
Study finds 'harm' for women
Another report launched from the concept that the genders are "lumped together" — and trying to avoid that — was made by Profesor Eva Swahn of University Hospital (Link ping, Sweden). She reported that in patients with a non ST-elevation (NSTE) acute coronary syndrome (ACS), subgroup analyses from several trials have shown a reduction of death and MI with an early invasive treatment (PCI or bypass operation) among men, but "sugggested" a trend for harm amongst women.
Women who were randomized to an early invasive strategy had more bleedings and died more frequently than women who were randomized to the "wait and see" group. "With these alarming results in this very small trial, we need to conduct a large randomized trial to determine the safety and efficacy of an early invasive approach in women."
The researchers said that the study was intended to evaluate whether a routine early invasive treatment was superior to a selectively invasive treatment in women.
The OASIS 5 Women sub-study randomized 184 women — 92 in each group — with NSTE ACS to either an early routine coronary angiography — and, if appropriate, coronary revascularization within seven days — or to wait and do a coronary angiography only if symptoms or signs of angina occurred. "We evaluated death, myocardial infarction, severe angina, bleeding and stroke at two-year follow-ups," the researchers said.
The mean age of enrollees was 68 in both groups, 80% of the patients had markers in the blood suggesting myocardial damage. In the early invasive group 58% were operated (PCI/bypass) compared to 31% in the selectively invasive group during the initial hospitalization.
At the one-year follow-up, eight patients in the early invasive group had died (all cardiovascular deaths), compared to one patient (from bleeding) in the selectively invasive group. There was no significant difference in either of the endpoints myocardial infarction worsening of angina or stroke. Major bleedings were more frequent in the early invasive group. The differences in deaths and major bleedings between the groups persisted at the two-year follow-ups.
A critical linkage: obesity, heart disease
The foundation causes of heart disease are more and more frequently being found in the increasing incidence of obesity, with researchers at ESC calling the epidemiological data and predictions concerning that association "alarming."
Worldwide it is estimated that one person in every eight is overweight and more than 300 million are obese. And data collected by the International Obesity TaskForce (IOTF) and by the World Health Organization (Geneva, Switzerland) suggests that more than half of the population in the European Union (EU) is overweight.
According to the IOTF, one person in three in Austria is overweight and one person in five is obese. It is predicted that the incidence of obesity will double in the next four decades in Europe.
Adding to this situation is the observation that in all countries where surveys have been performed, the numbers of overweight and obese children have increased dramatically. It is predicted that in the EU 26 million schoolchildren will be overweight by the year 2010, of which 6 million will be obese. By that time these numbers will grow each year by 1.3 million and 0.3 million, respectively.
Another research report focused on obesity/cardiovascular disease links in general and atherosclerosis in particular. Researchers studied cultured adipocytes from human adipose tissue and used them as a model to study effects of inflammatory mediators on the production of various adipokines by these cells.
The rationale for this approach is based on the notion that obesity is associated with a state of chronic inflammation, in contrast to acute inflammation, which is in most cases a life-saving defense reaction of the body against infection that leads to tissue damage and destruction. Such tissue damage is thought to be the initiating event in the development of atherosclerotic blood vessels.
Using this approach, the researchers said they were the first to show that certain inflammatory mediators increase the production of two key adipokines, namely plasminogen activator inhibitor type-1 (PAI-1) and vascular endothelial growth factor (VEGF) by adipocytes. PAI-1 is a prothrombotic protein that promotes the development of blood clots.
The development of such clots in atherosclerotic blood vessels is a key event in cardiovascular diseases such as myocardial infarction. Thus, the researchers said that through their findings they have established a link between inflammation, adipose tissue and the development of cardiovascular disease.
In general, the research serves to underline the view, increasingly held, that adipose tissue is no longer seen merely as a mostly passive energy storage organ but is now also considered to be an active endocrine tissue that, by producing a variety of cytokines, hormones and other proteins, impacts on a multitude of physiological and pathophysiological processes in the human body.
According to the researchers, the adipocyte is the cellular factory that produces these proteins termed adipokines, its size and numbers increaed in obesity.
VEGF is a protein, which induces the growth of new blood vessels. And the researchers said it is believed that adipose tissue, when it increases in mass, needs additional blood vessels to secure its supply with nutrients and oxygen. Studies have shown that in mice, blockade of VEGF leads to decrease in adipose tissue mass in these animals.
"We were able to show in mice, for the first time, that inflammatory mediators injected into these animals led to increased blood vessel growth in adipose tissue. Such increase in blood vessel density in adipose tissue would then in turn result in better supply with oxygen and nutrients and could ultimately lead to growth of adipose tissue."