September 1st, 2013
An Almost Striking Start to ESC
Paddy Barrett, MB BCh BAO MRCPI MCTI
Several Cardiology Fellows who are attending ESC.13 in Amsterdam this week are blogging for CardioExchange. The Fellows include Paddy Barrett, Louis Handoko, and Amanda Vest. For more of our ESC.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our Coverage Headquarters.
Amsterdam hosts the ESC congress this year, a fantastic city which I have had the fortune to visit many times over the years. My arrival this year, however, was almost my last, due to some significant wind shear on landing at Schipol airport which brought me the closest I’ve ever been to a wing strike. Happily, I survived the landing and made it to the start of the congress.
There are two certainties at ESC each year. Firstly, I make out my schedule for the conference and promptly realize that most of my selections are running concurrently and I will disappointedly miss out on much of what I had hoped to attend. Secondly, within seconds of taking my seat I will rediscover the incredible depth and breath of content that ESC delivers every year. This year has been no different.
Practice-Changing Research
Another constant has been the presentation of some potentially practice-changing data. One of the first trials presented at the Hotlines session was the PRAMI trial, which looked at the treatment of non culprit lesions in acute STEMI patients. Both the European and US guidelines are clear on this point: Beyond a set of limited scenarios such as ongoing cardiogenic shock, PCI of the non-culprit lesion is not advised. This 600-patient trial, however, demonstrated a 65% risk reduction in MACE. The timing of intervention resulted in almost immediate benefit, but the primary investigator, Dr. David Wald, noted that although the guidelines are explicit in terms of the immediate management of non-culprit lesions, the management strategy of these lesions in the post-MI period is somewhat less clear. Although PRAMI is a small trial, the significant risk reduction achieved will likely heavily influence the writing of the next STEMI management guidelines.
On the basis of findings from CURE and other studies, the practice of pretreatment of patients presenting with acute coronary syndrome with a second antiplatelet drug has become a cornerstone of cardiology practice. However, the ACCOAST trial raises some provocative questions to this approach, at least with the use of prasugrel. The trial randomized NSTEMI patients to pretreatment with prasugrel or placebo in addition to standard of care. Unexpectedly, not only was there no difference in ischemic end points, there was a significant increase in bleeding events. Although patients were initially pretreated with a smaller dose of prasugrel than conventionally used (30 mg), the pharmacodynamic studies performed concurrently demonstrated effective platelet inhibition. I would have to agree with Dr George Dangas’s point that the intervention community needs to look at the positive aspects of this study in so far as the safety of giving our patients a second antiplatelet only at the time of angiography. Whether this trial will substantially influence the content of the next NSTEMI guidelines remains to be seen and will likely require some additional investigation.
Basic Science and Incredible Imaging
Beyond the presentation of novel, late-breaking findings, the congress is awash with incredible clinical and basic science content. On a personal topic of interest, the staff at University Hospital Zurich gave a fantastic overview of atherosclerotic plaque vulnerability assessment and potential for management. Our ability to identify the vulnerable plaque has improved enormously, but how to selectively manage these lesions remains uncertain. Not all plaques are vulnerable, not all vulnerable plaques rupture, and even those that lose endothelial integrity do not result in infarction. We have moved the needle here but we still have a lot to learn. What is clear is that beyond some incredible science of atherosclerotic plaque vulnerability, this is an area which produces some of the most visually pleasing imaging; OCT to me is as if Pixar got a hold of routine angiography producing some of the most stunning imagery in cardiology today.
As ever, ESC has not failed to deliver a fantastic program covering a huge range of topics. More than anything, I’m reminded of how much I enjoy the field, and excitingly, we get to be part of the evolution of our specialty. After today, we are all certainly a little wiser. Tomorrow, we will be a little bit more, and I am indeed looking forward to it.
September 1st, 2013
A World Conference in My Backyard
M. Louis Handoko, MD PhD
Several Cardiology Fellows who are attending ESC.13 in Amsterdam this week are blogging for CardioExchange. The Fellows include Paddy Barrett, Louis Handoko, and Amanda Vest. For more of our ESC.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our Coverage Headquarters.
Dear Reader,
My name is Louis Handoko, and I am a cardiology resident at the VU University Medical Center, Amsterdam, The Netherlands. For the coming days, I will share with you my experiences at the ESC. This year, the ESC happens to be in my home town, which is very convenient.
It is not the first time that I have attended a major conference like this one. Nevertheless, and especially on the first day, I feel a great sense of excitement:
- Will it be busy?
- What news will this conference bring?
- Shall I meet interesting people?
And, in the afternoon, I also have some of my own research to present.
I decide to go to a pro/con session on endocarditis first. When I enter the room, the debate on the role of transesophageal echocardiography in S. aureus bacteriemia has just started. I like this discussion very much. It is clinical problem I regularly face on the ward, and at the end of the discussion, a useful diagnostic algorithm is provided.
The second debate is on the role of early surgery in infective endocarditis. At my hospital, I find the surgeons are very conservative, so I hoped to find some arguments to convince them in the future. Instead, the first speaker rushed through 100 slides in fifteen minutes, and I am dazzled by the information. The second speaker explains to me that the role of surgery is nowadays not an issue at all, and only discussed the timing of the surgery (early or too early?).
After lunch, it is time for some action of my own. I have a moderated poster on fluid challenge in pulmonary hypertension. In my session, the best poster will be awarded a prize: a free ticket to the ESC next year. Of course, I am stoked!
The interest in my poster is quite good, and I receive several good suggestions to improve my work in the future. The presentation went even better…unfortunately, no prize for me. But as Coubertin has said: “The most important thing in the Games is not winning but taking part.”
It was a good first day, see you tomorrow!
September 1st, 2013
Pretreatment with Prasugrel Not Indicated in NSTEMI
Larry Husten, PHD
For more of our ESC.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our Coverage Headquarters.
Although current guidelines strongly recommend that dual antiplatelet therapy be administered early in treating patients with non-ST-segment-elevation acute myocardial infarction (NSTEMI), it is unclear whether pretreatment is beneficial,especially with the newer, more potent and more rapidly acting antiplatelet agents prasugrel and ticagrelor. Now a large new study, ACCOAST, presented at the European Society of Cardiology in Amsterdam and published simultaneously in the New England Journal of Medicine, offers strong evidence that pretreatment with prasugrel should not be performed in this situation.
Near the end of the enrollment period, the trial was stopped prematurely on the advice of the independent data and safety monitoring committee because of an increase in major and life-threatening bleeding, but no reduction in cardiovascular events, among patients in the pretreatment group.
A total of 4033 patients scheduled for coronary angiography were randomized to receive pretreatment with prasugrel or no prasugrel. There were no significant differences in the primary endpoint, (death from CV causes, MI, stroke, urgent revascularization, or glycoprotein IIb/IIIa bailout at 7 days). However, TIMI major bleeding was significantly more common in the pretreatment group at 7 days. Similar findings were observed at 30 days.
- Primary endpoint: 10.0% in the pretreatment group versus 9.8% in the control group (hazard ratio, 1.02; 95% CI, 0.84-1.25; P=0.81)
- TIMI major bleeding: 2.6% versus 1.4% (HR, 1.90; 95% CI, 1.19-3.02; P=0.006)
No benefit of pretreatment was observed in the subgroup of patients who underwent PCI. The pretreatment group had a 3-fold excess in major bleeding not related to CABG and a 6-fold increase in life-threatening bleeding not related to CABG.
That authors write, “Our results support the administration of prasugrel when the coronary anatomy is known and after PCI is selected as the treatment strategy.” They noted that prior to catheterization the risk for ischemic complications is very low.
In an accompanying editorial, John Keaney, Jr, writes that ACCOAST “may streamline the care of patients with NSTEMI in the hospital” and allow cardiologists to “safely pursue a more parsimonious approach of reserving prasugrel adminstration until after angiography.” By delaying administration of a P2Y12 inhibitor, patients who require CABG will no longer suffer long delays and “P2Y12 treatment can be limited to patients who will be undergoing PCI.”
For an interview with the lead investigator of the ACCOAST trial, click here.
September 1st, 2013
ESC.13 Headquarters
CardioExchange Editors, Staff
CardioExchange is dedicated to bringing you the latest from ESC.13. Check out our coverage of the conference ─ and some of the great debates these posts have sparked ─ then tell us what you think!
News:
- A Disruptive TASTE of the Future?
- Pretreatment with Prasugrel Not Indicated in NSTEMI
- Disappointing Results with Dabigatran for Mechanical Valves
- Positive Results for Edoxaban in VTE/PE
- Cardiovascular Outcome Studies in Diabetes Drugs Finally Arrive
- Automatic Wireless Monitoring Shows Benefits in Chronic Heart Failure
- Losartan Reduces Aortic Enlargement
- Study Fails to Support Broader Patient Population for Cardiac-Resynchronization Therapy
- Speedy Tour de France Racers Slower to Die
- New Dual Biomarker Test Could Speed Rule-Out of MI in the ED
Analysis:
- A TASTE of Registry-Based Randomized Trials
- Inside the ACCOAST Trial of Pretreatment Prasugrel
- Is It Time to RE-ALIGN Our Thinking About Direct Thrombin Inhibitors?
- For CRT, Let ECG — Not Echo — Be Your Guide
- EchoCRT Trial — Going Narrow Doesn’t Broaden CRT Population
Follow our Fellows:
September 1st, 2013
Inside the ACCOAST Trial of Pretreatment Prasugrel
Gilles Montalescot, MD, PhD, John Ryan, MD, Richard A. Lange, MD, MBA and L. David Hillis, MD
CardioExchange’s John Ryan, Rick Lange, and David Hillis interview Gilles Montalescot, lead investigator of the ACCOAST trial, about why prasugrel pretreatment did not benefit patients with non–ST-segment elevation acute coronary syndromes. The study, published in The New England Journal of Medicine, was presented at the European Society of Cardiology conference in Amsterdam.
THE STUDY
In a study funded by the manufacturer of prasugrel, researchers randomized 4033 patients with NSTE acute coronary syndromes and a positive troponin level who were scheduled to undergo catheterization to receive either placebo or a 30-mg pre-angiography loading dose of prasugrel. The two groups did not differ significantly in the primary composite endpoint of death from cardiovascular causes, myocardial infarction, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor rescue therapy through day 7. Major bleeding was significantly more common with pretreatment than without it. The findings persisted at 30 days and in prespecified subgroups.
THE INTERVIEW
CardioExchange: In the patients pretreated with prasugrel, did the low (i.e., 30-mg) loading dose provide adequate antiplatelet activity to influence ischemic events before cardiac catheterization?
Montalescot: Yes! See the pharmacodynamic substudy (graph in the article’s appendix) with significant antiplatelet effect at the time of catheterization in the pretreatment group. Moreover, if this group had more bleeding, it is likely that pretreament with 30 mg was effective.
CardioExchange: Pretreatment with aspirin and a P2Y12 antagonist is common practice for NSTE patients. Your study shows that pretreatment with prasugrel did not limit ischemic events in these patients. Under what circumstances, if any, should dual antiplatelet therapy be administered to NSTE patients before coronary angiography?
Montalescot: The value of pretreatment with clopidogrel is controversial with several negative randomized trials (CREDO, PRAGUE 8, ARMYDA5) and a meta-analysis showing no effect on mortality; our study shows no benefit of prasugrel pretreatment. Ticagrelor has not been tested as pretreatment. Everyone must now draw his own conclusions.
CardioExchange: Your study’s mean time from randomization to cardiac catheterization was very short (median, 4 hours), even though most patients were not considered “high risk” (only one fourth had a GRACE score >140). Does this reflect real-world experience? What antiplatelet regimen would you recommend for centers that perform angiography 24 to 48 hours after patient presentation?
Montalescot: Median time to catheterization in ACCOAST was similar to that in CURRENT, ACUITY, PLATO-NSTEACS PHOENIX, and TRACER — all had delays <5 hours. One fourth of patients with a GRACE score >140 is also similar to other studies such as TIMACS. All our patients had a positive troponin a marker of poorer prognosis (most previous studies did not require positive markers for inclusion). Our population is an intermediate- to high-risk cohort. ACCOAST allowed catheterization up to 48 hours, and the results are the same when examined by quartile of timing. So our results are also applicable to centers that perform angiography 24 to 48 hours after patient presentation. We do not know beyond 48 hours.
CardioExchange: The study was stopped early, in November 2012, because of increased harm (i.e., excessive bleeding) in the patients pretreated with prasugrel without public disclosure. Was the sponsor obliged to divulge and disseminate the results as soon as it had a reasonably reliable estimate of the harm?
Montalescot: You should ask the sponsor of the study about the necessity of a press release in this situation. Investigators, authorities, and the clinical-trials website all were informed. The harm was not for the on-label use of the drug, as determined by the TRITON study.
JOIN THE DISCUSSION
Are you surprised by the findings from the ACCOAST trial? Why or why not?
September 1st, 2013
Is It Time to RE-ALIGN Our Thinking About Direct Thrombin Inhibitors?
Judith Andersen, AB, MD
Findings from the RE-ALIGN study, presented at ESC 2013, indicate that dabigatran is associated with increased rates of thromboembolism and bleeding, compared with warfarin, in patients with mechanical heart valves. Judith Andersen offers her take on the research.
THE RE-ALIGN TRIAL
In a phase 2 dose-validation study of dabigatran, funded by the drug’s manufacturer, researchers enrolled patients who had undergone recent aortic- or mitral-valve replacement within the past 7 days, as well as patients who had undergone one of those procedures at least 3 months earlier. Participants were randomized, in a 2:1 ratio, to receive either dabigatran or warfarin. The dabigatran dose (150, 220, or 300 mg twice daily) was determined by a patient’s kidney function and adjusted to obtain a trough plasma level of ≥50 ng/mL. Warfarin dosing was adjusted to achieve a target INR of 2 to 3 or 2.5 to 3.5, depending on thromboembolic risk.
The trial was terminated prematurely after 252 patients were enrolled, because of excess thromboembolic and bleeding events in the dabigatran group. In an as-treated analysis, 32% of dabigatran recipients required dose adjustment or discontinuation of the drug. Ischemic or unspecified stroke occurred in 5% of dabigatran recipients and in no warfarin recipients; major bleeding (always pericardial bleeding) occurred in 4% and 2% of patients, respectively. Most thromboembolic and bleeding events occurred in patients who had undergone valve replacement within 7 days before randomization.
A CLINICIAN’S PERSPECTIVE
Judith Andersen: I have a prolonged love–hate relationship with dabigatran, which I don’t use for any other indication than atrial fibrillation, for reasons that make me suspect all direct thrombin inhibitors (DTIs) as universal anticoagulants: Bleeding and clotting complications are frequent attendees.
Atrial fibrillation is an invitation to thrombosis formation, but a weak one, such as stimulus rate. Stasis is permissive but not productive. Chance activation of the clotting system can create issues, but it does so in an episodic manner. Valve issues, in contrast, create constant mechanical and flow difficulties. Stasis, chamber dysfunction, mechanical heart-valve characteristics, and dysrhythmias are permissive and require constant, consistent prevention.
DTIs such as dabigatran reject short-term coagulation insults, but not consistently. These drugs abort many biologic antithrombotic mechanisms that may be necessary for long-term high-grade anticoagulation, such as that required by mechanical heart valves. Specifically, they inhibit protective mechanisms that depend on thrombin activation of downstream antithrombotic mechanisms, including the activation of protein C. Indeed, activation of protein C, a powerful inhibitor of hypercoagulability in turbulent coagulation areas, must be considered in circumstances related to mechanical heart valves. Given, too, that dabigatran must be taken twice daily, the issue of missed doses and inadequate coverage becomes important. Strong evidence from many studies suggests that moving from a once-daily medication strategy to twice — or thrice — daily creates a strong likelihood of missed doses and failed protection.
I was quite surprised that this trial was actually funded — and not surprised that it failed. It is both the best and the worst of anticoagulation strategies: It (1) inhibits local thrombin activity but (2) does not prevent thrombin generation and inhibits the physiologically inbuilt strategies to regulate thrombin activity — namely, protein C activation with subsequent inactivation of activated factor VIII and factor V — and other thrombin-mediated vascular control mechanisms. In this clinical situation, that is a combustive combination.
An inhibitor of thrombin generation — e.g., a powerful anti-Xa agent — would be a better alternative, as it would inhibit thrombin generation without also inhibiting protective mechanisms that would limit thrombin-mediated vascular hypercoagulability. A once-daily strategy would also make prevention more likely to be secure than reliance on twice-daily medication adherence.
JOIN THE DISCUSSION
How does the RE-ALIGN trial change your perception of dabigatran’s role in various clinical settings? Like Dr. Andersen, do you find the data unsurprising?
September 1st, 2013
Positive Results for Edoxaban in VTE/PE
Larry Husten, PHD
For more of our ESC.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our Coverage Headquarters.
A new entrant in the growing oral anticoagulant field shows promise for the treatment of venous thromboembolism (VTE) and pulmonary embolism (PE). The drug, edoxaban, is a new, once-daily Factor Xa inhibitor with a rapid onset of action that is under development by Daiichi Sankyo. Results of the Hokusai-VTE trial were presented at the European Society of Cardiology meeting in Amsterdam and published simultaneously in the New England Journal of Medicine.
The Hokusai-VTE investigators randomized 4921 patients with VTE and 3319 patients with PE to either warfarin or edoxaban. The trial differed from some earlier trials with new oral anticoagulants in that patients were treated following a lead-in period with heparin. In addition, patients were treated for as short as three months or as long as a year at the discretion of the physician, though patients were followed for a full year. Patients with low body weight or renal impairment received a half dose of edoxaban. The investigators said the design was intended to reflect the full spectrum of conditions clinicians see in real life.
- At one year, the primary efficacy outcome, recurrent symptomatic VTE, occurred in 3.2% of the edoxaban group and 3.5% of the warfarin group (HR 0.89, CI 0.70-1.13, p<0.001 for noninferiority).
- Major or clinically relevant nonmajor bleeding occurred in 8.5% of the edoxaban group and 10.3% of the warfarin group (HR 0.81, CI 0.71-0.94, p=0.004 for superiority).
- In the subset of 938 PE patients with right ventricular dysfunction, recurrent VTE was significantly lower in the edoxaban group (3.3% versus 6.2%, HR 0.52, CI 0.28-0.98).
Because it evaluated all patients at 12 months, regardless of treatment length, the investigators said that the trial design “allowed for a better understanding of the outcomes that may be expected in clinical practice.”
Primary results of the ENGAGE AF-TIMI 48 study of edoxaban in atrial fibrillation are scheduled to be presented in November at the American Heart Association meeting in Dallas.
September 1st, 2013
A TASTE of Registry-Based Randomized Trials
Ole Frobert, MD, PhD and Harlan M. Krumholz, MD, SM
CardioExchange’s Harlan M. Krumholz interviews Ole Fröbert, lead investigator of the TASTE trial, about his study group’s registry-based trial design. The article is published in The New England Journal of Medicine and was presented at the European Society of Cardiology conference in Amsterdam.
THE STUDY
Researchers in Sweden conducted a multicenter, prospective, open-label, randomized controlled trial to investigate the effect of thrombus aspiration on hard clinical endpoints in patients with ST-segment-elevation myocardial infarction (STEMI). They used the infrastructure of the population-based registry Swedish Coronary Angiography and Angioplasty Registry (SCAAR) to facilitate patient enrollment and data collection.
In all, 7244 patients with STEMI undergoing percutaneous coronary intervention (PCI) were randomized to undergo manual thrombus aspiration followed by PCI or PCI alone. All-cause mortality at 30 days was similar in the two groups — 2.8% of the thrombus-aspiration group and 3.0% in the PCI-only group — as was the rate of stroke or other neurologic complications at discharge. The thrombus-aspiration group had slightly but nonsignificantly lower rates of hospitalization for recurrent MI at 30 days (0.5% vs. 0.9%; P=0.09) and of stent thrombosis (0.2% vs. 0.5%; P=0.06). Findings were consistent across major prespecified subgroups, including those defined according to pre-PCI thrombus burden and coronary flow. No participants were lost to follow-up.
THE INTERVIEW
Krumholz: You have achieved a remarkable study at a low cost. What did you learn from this experience?
Fröbert: First of all that it is doable. The Scandinavian countries have a long tradition of health registries, some going back to the 1950s. More recently, several registries have become web-based, whereby a nurse or physician enters information while examining a patient. For some registries, entering information is compulsory and a prerequisite for administration. Personal identification numbers allow patients in Scandinavia to be tracked, and information on hard endpoints such as death and rehospitalization can be extracted from the same or other national registries. The quality and the fidelity are thus highly reliable.
Adding a randomization module to the existing SCAAR registry was a relatively minor alteration. All information already entered was able to serve as a substitute for case record forms, and all outcome information could be extracted from the registries when needed. Accordingly, administration related to conducting a registry-based RCT is negligible, with no need for dedicated follow-up. We also learned that if the additional work related to randomization is kept at a minimum (as in the TASTE trial), colleagues and hospitals that don’t often take part in clinical trials are eager to participate. Therefore, the spectrum of patients was broader and probably more representative than what conventional clinical trials typically have. With the costs reduced to <1% of the usual costs of an RCT, our concept opens up potentially new ways to conduct clinical trials and improve quality of care in areas with no or limited revenue.
Krumholz: Did you lose anything by taking this approach of building on the registry?
Fröbert: A strength of the registry-based RCT concept is that hard endpoints can be addressed with close to 100% accuracy. Surrogate endpoints such as ST-segment resolution or coronary flow are more susceptible to inaccuracy. Typically, this does not affect one group more than another in an RCT, but underreporting is a possibility. However, because enrollment in a registry-based RCT is simple for the physician, it is relatively easy to recruit enough patients and achieve sufficient power to learn whether the investigated treatment actually reduces mortality.
Krumholz: Is there anything you should have done differently?
Fröbert: The outcome in the TASTE trial was neutral, so additional surrogate endpoints might have been relevant in helping us learn more about the pathophysiology related to thrombus burden, distal embolization, and no reflow. In future trials, we will dedicate resources to adjudication of key surrogate endpoints to get a broader picture.
Krumholz: Are you conducting additional trials in this way?
Fröbert: Yes: Detox-AMI, which is already recruiting participants, will be a 6600-patient registry-based RCT of oxygen therapy versus room air in patients with suspected myocardial infarction. Additional trials on invasive therapies will start sometime soon.
Krumholz: What advice would you give the ACCF and AHA if they wanted to conduct RCTs on top of their registries?
Fröbert: In the U.S. and many other countries, the lack of personal identification numbers creates a challenge. However, given the amount of information being gathered in heart registries today, it seems relatively straightforward to conduct trials using existing registries such as the National Cardiovascular Data Registry, when key variables have accuracy above 90%, as platforms for RCTs. Strengths and weaknesses could be investigated in smaller pilot studies before launching larger trials.
JOIN THE DISCUSSION
What is your expectation about the future of registry-based randomized trials such as TASTE?
September 1st, 2013
A Disruptive TASTE of the Future?
Larry Husten, PHD
For more of our ESC.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our Coverage Headquarters.
A new study from Scandinavia may influence the treatment of acute myocardial infarction. But it also may end up having a much bigger impact on the entire field of medicine by pointing the way to an entirely new way of performing randomized clinical trials rapidly and inexpensively. One expert said the trial design may represent “a new paradigm,” and for once the use of the p-word may actually be appropriate.
Thrombus aspiration for ST-segment elevation myocardial infarction (STEMI) has been kicking around for a long time, but its utility has never been definitively evaluated. The procedure uses a dedicated catheter to suck the clot out of the vessel prior to stent implantation. In an accompanying editorial, Robert Byrne and Adnan Kastrati write that thrombus extraction “is an intuitively attractive strategy and one that is simple to carry out.”
The Scandinavian study has its origins in an earlier study, TAPAS, which found an unexpected benefit on mortality at one year for thrombus aspiration, though the trial was not designed to assess mortality. On the basis of TAPAS, thrombus aspiration was given a level IIA endorsement in both European and U.S. guidelines.
TASTE (Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia) was presented at the European Society of Cardiology meeting in Amsterdam and published simultaneously in the New England Journal of Medicine. The investigator-initiated randomized trial was performed as part of the Swedish Coronary Angiography and Angioplasty Registry (SCAAR), which in this case included 1 center each in Iceland and Denmark. After obtaining consent, patients were randomized through “an online randomization module within the SCAAR database.”
A total of 7244 STEMI patients were randomized, representing a striking 60% of all STEMI patients referred for PCI in Sweden and Iceland during the study period. All-cause mortality at 30 days was not significantly different between the two groups:
- 2.8% in the thrombus aspiration group versus 3% of the PCI-only group (hazard ratio 0.94, CI 0.72-1.22, p=0.63)
A similar result was observed in the per-protocol analysis.
There were no significant differences in the rate of rehospitalization due to reinfarction, stent thrombosis, target-lesion revascularization, target-vessel revascularization, neurological complications, or other clinical outcomes, though there were trends in favor of thrombus aspiration in hospitalization for MI and stent thrombosis. The results were consistent across all major subgroups.
In their editorial, Byrne and Kastrati hold out hope that thrombus aspiration may turn out to be beneficial. They predict that “many interventional cardiologists will continue to perform thrombus aspiration for now,” based on hints of efficacy and the lack of any safety issues found in the trial.
Furthermore, they write, 30-day followup may not be long enough to detect a benefit, since the benefit in the TAPAS trial only emerged at 1 year. They urge the TASTE investigators to report the 12-month findings of their trial, and note that another large-scale randomized trial is nearing completion. “For now,” however, “the hope that this simple, easy-to-use, intuitively attractive technology could save the lives of patients presenting with myocardial infarction remains an unmet aspiration.”
A New Paradigm?
But the sweetest part of TASTE may be that the investigators were able to conduct a rapid and low-cost trial utilizing a new model, “a registry-based randomized clinical trial,” by incorporating the trial within the already existing framework of SCAAR: “The data were monitored and adjudicated as part of the regular registry validation; we did not perform separate, dedicated monitoring and adjudication of the data for the TASTE trial.”
In an accompanying Perspective, Michael Lauer and Ralph D’Agostino, Sr. ask whether randomized registry trials may be “the next disruptive technology in clinical research.” Current trials are expensive and “too complex and difficult to apply.” The usual alternative, traditional observational studies utilizing registries, “lack the rigor of randomization.”
TASTE, they write, represents “a new paradigm… that can potentially release us from the circular (and expensive) trap of the randomized-versus-registry debate.”
“The TASTE investigators designed a large-scale trial to answer an important clinical question and carried it out at remarkably low cost by building on the platform of an already-existing high-quality observational registry. With this clever design, which leveraged clinical information that was already being gathered for the registry and for other preexisting databases, the investigators were able to quickly identify potential participants, to enroll thousands of patients in little time…, to avoid filling out long case-report forms, to obtain accurate follow-up with minimal effort, and to report their findings, all for less than the amount of a typical modular R01 grant…”
For an interview with the lead investigator of the TASTE trial, click here.
September 1st, 2013
Disappointing Results with Dabigatran for Mechanical Valves
Larry Husten, PHD
For more of our ESC.13 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and blogs from our fellows on the most interesting presentations at the meeting, check out our Coverage Headquarters.
Despite being more durable than bioprosthetic valves, mechanical heart valves are often not chosen because of the requirement for lifelong anticoagulant therapy. It has been hoped that the newer generation of oral anticoagulants might eventually replace warfarin, making anticoagulation more tolerable and better accepted, since these agents don’t require continuous monitoring and have much fewer serious interactions with other drugs and food. So far, however, there has been no convincing demonstration that the the newer agents are as safe and effective as warfarin for this indication.
RE-ALIGN was a phase 2 dose-validation study of dabigatran in patients with mechanical heart valves. Results of the trial were presented at the European Society of Cardiology meeting in Amsterdam and published simultaneously in the New England Journal of Medicine. Patients in the trial were randomized to dabigatran or warfarin.
After 252 patients had been randomized, the trial was stopped early due to an increase in thromboembolic and bleeding events in the dabigatran group:
- Among the 162 patients who received dabigatran there were nine ischemic or unspecified strokes and three MIs, compared with no strokes or MIs among the 84 patients randomized to warfarin.
- Major bleeding occurred in seven (4%) patients in the dabigatran group versus two (2%) in the warfarin group. Twenty-seven percent of patients in the dabigatran group had a bleeding episode of any type, compared with 12% in the warfarin group. All the major bleeding episodes took place in the first two weeks after surgery.
The trial investigators reported that one-third of the dabigatran patients either discontinued treatment or required a dose adjustment. They speculated that warfarin may be more effective than dabigatran at suppressing the specific coagulation activity associated with valve surgery.
“The results of our study indicate that dabigatran is not appropriate as an alternative to warfarin for the prevention of thromboembolic complicaitons in patients who require anticoagulation after the implantation of a prosthetic heart valve,” they wrote. They also warned that the same fate may befall the factor Xa inhibitors, including rivaroxaban and apixaban, which, like dabigatran, have been approved as an alternative to warfarin for use in atrial fibrillation.
In an accompanying editorial, Elaine Hylek writes that the results may be explained in part by the high percentage of patients with recent surgery. “The early postoperative period may have been less than optimal for testing a new fixed dose regimen because of the enhanced thrombogenicity inherent in such patients.”
Hylek writes that another possible explanation is the use of target trough levels based on the RE-LY trial in patients with AF. “Translation of dose across indications is challenging, given the different mechanisms of thrombus formation in different vascular beds, differences in flow and shear stress… and patients’ characteristics.”
She strongly discourages the clinical use of the newer anticoagulants for this indication at the present time, but holds out hope for their eventual success: “Off-label use will place patients at undue risk and is rightfully prohibited. The results of RE-ALIGN are disappointing, but there is a palpable downside as well to potential premature abandonment of research into the use of such drugs in patients with mechanical heart valves.”
For a clinician’s perspective on the RE-ALIGN trial, click here.
NEJM Journal Watch — Recent Cardiology Articles- Does Use of Drug-Coated Devices Improve Outcomes in Chronic Limb-Threatening Ischemia?
- New Recommendations for Lipid Management in Patients with Acute Coronary Syndromes
- Postpartum Blood Pressure Control in Hypertensive Disorders of Pregnancy: Is Lower Better?
- Beta-Blocker Use After Takotsubo Syndrome
- CTA-Guided Care in Stable Angina: Long-Term Results