Crash & Burn: A surprising number of trials fail at ESC, offering lessons—and controversy—for all

AMSTERDAM—Studies don’t always turn out as expected, but this year’s European Society of Cardiology (ESC) meeting featured several spectacular failures. Yes, good news is great to hear, but let’s face it: trying to understand why fine ideas fizzle can be interesting—and teach us a lot.

TASTE Results: Hard to Swallow?

Based on the largest randomized trial reported to date, aspiration thrombectomy as an adjunct to primary PCI is not superior to primary PCI alone in reducing mortality at 30 days in patients with ST-elevation acute coronary syndrome (STE-ACS). However, it was a new type of randomized clinical trial, and some critics are finding fault with the TASTE trial.

The rationale for intracoronary thrombus aspiration seems strong: a significant proportion of patients with STEMI have persistent impairment of microvascular blood flow despite successful reperfusion. Small trials suggested that removing thrombus, whether mechanically or manually, might reduce distal embolization and reduce microcirculatory injury. Such injury leads to greater ischemic insult to the myocardium, possibly contributing to larger infarct size, increased predisposition to ventricular arrhythmias, heart failure (HF), cardiogenic shock, recurrent myocardial infarction (MI), and death.

However, studies of thrombus aspiration have been inconsistent, although the results have been particularly negative regarding mechanical thrombus removal, which seems to show little benefit. Following the results of the TAPAS trial and subsequent meta-analyses, aspiration thrombectomy (but not mechanical thrombectomy) was given a Class IIa recommendation in the current ACCF/AHA PCI guidelines.

The TASTE trial was a multicenter, prospective, randomized, controlled clinical open-label trial that used the national Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Investigators evaluated 7,244 patients with STEMI undergoing PCI who were randomized to manual thrombus aspiration and PCI versus PCI alone. That makes this trial larger than all the previous aspiration trials combined.

The results: There was no significant difference in mortality at 30 days nor was there any reduction in hospitalization for MI or stent thrombosis at 30 days. Also, there was no reduction of other important clinical endpoints during hospitalization and no subgroup that seemed to benefit. Speaking on behalf of the investigators, Ole Fröbert, MD, PhD, Örebro University Hospital, Sweden, said, “We have a very clear message from the TASTE trial. We asked one simple question: Is thrombus aspiration life-saving? And we have one very clear answer: No, it’s not.”

During an online highlights program that was broadcast a week after ESC, University of Oxford Professor Barbara Casadei, MD, said, “I am puzzled by the results. My colleagues are always showing pictures of all the garbage they aspirate and it makes a cardiologist feel good to take all that out. Why doesn’t it help the patient?”

Peter Clemmensen, MD, University of Copenhagen, Denmark, said the TASTE investigators “had a signal from their registry that thrombus aspiration was not favorable for their patients and then they did a large clinical trial with hard outcomes. This is the way it should be done.”

He added that interventionalists know when working in the arteries “the result is often unpredictable whether you can aspirate a thrombus or not. Sometimes you can push it farther downstream and get distal emboli.” At least one good thing about this trial: aspiration appeared safe.

“A New Concept for Clinical Research”

Dr. Clemmensen said guidelines will need to be rewritten to discourage aspiration. However, Sanjit Jolly, MD, McMaster University, Hamilton, Ontario, said it may not be quite that cut-and-dry. The trial had a unique design: a registry randomized controlled trial, meaning the trial was nested within the larger SCAAR registry. Indeed, a separate TASTE presentation at ESC discussed prospective registry-based randomized clinical trials as “a new concept for clinical research.”

Based on the design of TASTE, randomization was appropriate, said Dr. Jolly, but the study was not blinded and there was no independent adjudication of events. Interventionalists recorded their own data in the registry which, he noted, increases the risk of bias. He also said the TASTE trial was underpowered for mortality, plus he pointed out that the ACC’s National Cardiovascular Data Registry® indicates that US clinicians use thrombus aspiration in only about one in five cases where patients have a heavy thrombus burden—not routinely, as evaluated in the TASTE trial.

Finally, previous studies suggested a mortality benefit at 6-12 months and not acutely at 30 days. If thrombectomy permits better sizing of stents, then longer-term stent thrombosis and target lesion revascularization may be improved over time, but not necessarily by 30 days.

For example, in an elegant meta-analysis published 5 years ago, Bavry et al. reported that aspiration thrombectomy prior to PCI for acute STE-ACS can be beneficial. Now, they have updated their work with a completely new meta-analysis that included 5,534 patients in 25 trials. In the October 17, 2013, issue of JACC, the authors report no benefit in clinical outcomes at 30 days, but the story was different at 6-12 months for manual aspiration. Mechanical thrombectomy was not associated with significant benefit compared with conventional PCI alone, but manual catheter aspiration was associated with a reduction in MACE (RR = 0.76; p = 0.006) and all-cause mortality (RR = 0.71; p = 0.049).1

What’s next? Dr. Jolly is the principal investigator in the TOTAL study, a large, randomized, controlled trial of thrombus aspiration that is enrolling 6,700 patients in up to 18 countries worldwide. The TOTAL trial is evaluating differences in cardiovascular death, recurrent MI, cardiogenic shock, and new or worsening HF at 180 days. Results from this trial will likely be available in the summer of 2014. Until then, Dr. Jolly said, “Over the next 6 months while we wait for results from TOTAL, use [thrombus aspiration] when you feel it will be beneficial in subsets of patients. Outside of a trial, I tend to use it in patients where you’ve got a large thrombus burden and it allows you to perhaps use a shorter stent length and prevent no reflow.”

Marco Roffi, MD, director of interventional cardiology at University Hospital, Geneva, Switzerland, said, “Routine thrombus aspiration does not work. Whether it might work in selected patient population is still open, but it is difficult for me to imagine that [the TOTAL trial] will over-rule the findings of the TASTE trial.”

RE-ALIGN: Dabigatran in Patients with a Mechanical Heart Valve

Seems straightforward enough: simplify life for people with mechanical valves by using dabigatran, which has been shown to be superior to warfarin in nonvalvular AF (RE-LY; 150 mg dabigatran twice daily). However, the trial was terminated prematurely after enrollment of 252 patients because of an excess of thromboembolic and bleeding events among patients in the dabigatran group.2

Why did dabigatran produce no benefit and an excess risk in these patients? Possible explanations provided during the ESC presentation:

  • inadequate blood levels of dabigatran
  • play of chance with relatively few events seen in the warfarin arm
  • differences in the mechanism of action of dabigratran compared with warfarin

In terms of explaining the results, Dr. Clemmensen said, “By inhibiting thrombin you are only taking one step.” Unlike dabigatran, “Warfarin acts on multiple pathways,” he said, “and that may the secret as to why this trial was negative. Contact activation seems to be an important issue with mechanical valves.”

Discussant Alec Vahanian, MD, Bichat Hospital, Paris, France, said, “Obviously dabigatran should not be prescribed in patients with mechanical valve prosthesis.” Also, he noted one way around the issue: indications for mechanical prosthesis are continuously decreasing as bioprostheses are improving, patients with valvular heart disease are older, repair is catching up, and percutaneous techniques are steadily developing.

EchoCRT: Drop the Echo—and the CRT

Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in HF patients with a wide QRS complex. Many HF patients with a narrow QRS have mechanical dyssynchrony, a potential target for CRT. Off-label use of CRT has become common in this setting despite conflicting observational and randomized trials, creating an imperative for a definitive outcome assessment of CRT in patients with HF and a narrow QRS complex.

EchoCRT evaluated the effect of CRT in patients with New York Heart Association (NYHA) class III or IV HF, a left ventricular (LV) ejection fraction <35%, a QRS duration <130 ms, and echocardiographic evidence of LV dyssynchrony. All patients underwent device implantation (CRT with defibrillator capabilities) and were randomly assigned to have CRT turned on or off.

Investigators randomized 809 patients but the study was halted early on the basis of futility with a potential for harm. Specifically, compared to optimal pharmacologic therapy and an implantable cardioverter-defibrillator (ICD), the addition of CRT did not improve the primary combined efficacy endpoint of all-cause mortality and HF hospitalization. Plus, randomization to CRT ON appeared to increase mortality: there were 45 deaths in the CRT group and 26 in the control group (11.1% vs. 6.4%; p = 0.02).3

Dr. Casadei said “Maybe we should drop the ‘Echo’ and just refer to this as the ‘CRT’ trial.” Frank Ruschitzka, MD, the trial’s co-primary investigator, smiled and said, “That hurts me, Barbara. When Johannes Holzmeister and I designed EchoCRT in 2007, many people told us that the vast majority of people with narrow QRS had echo signs of dyssynchrony.

“One out of five CRTs in recent years was implanted in people with a narrow QRS. We did an adequately powered trial with 115 centers worldwide and we have closed the chapter on this. And it hurts me because these are the majority of HF patients and we are running out of options. They have a prognosis worse than cancer and I am sad we cannot bring them CRT because CRT is a life-saving device—one that we under-implement in patients with clear-cut indications. We learned one more thing from EchoCRT: ECG is back. Echo is out, but ECG rules.”

Time to Rethink Timing of Thienopyridines?

Thienopyridine pre-treatment in non ST-Elevation ACS (NSTE-ACS) has a class I recommendation, but no large randomized study has been conducted to assess the risk-benefit as well as the optimal dosage and timing of a thienopyridine in this patient population.

In the ACCOAST study, investigators enrolled 4,033 patients with NSTE-ACS who were scheduled to undergo coronary angiography within 2-48 hours after randomization. Patients were randomly assigned to prasugrel (a 30 mg loading dose; pretreatment group) or placebo (control group) before the angiography. When PCI was indicated, an additional 30 mg of prasugrel was given in the pretreatment group at the time of PCI and 60 mg of prasugrel was given in the control group.

Pretreatment had no significant effect on the rate of major ischemic events over the course of the 30-day study period.4 In fact, the trial was terminated because prasugrel pretreatment was associated with more bleeding events that were categorized as major or life-threatening. The bleeding also tended to be more systemic in nature (gastrointestinal or other internal bleeding) as opposed to access-site bleeds. No subgroup appeared to have a favorable risk-benefit ratio for pretreatment. On the other hand, among patients undergoing PCI, once the coronary anatomy had been defined, treatment with prasugrel was beneficial.

Speaking to the media, lead author Gilles Montalescot, MD, Pitie-Salpetriere University Hospital, Paris, France, said, “There was absolutely no benefit on the ischemic side, which was the primary endpoint of the study, but there was an excess of bleeding. So, we need to reevaluate our guidelines and our practice and imagine now a way to see the coronaries before treating patients with one of these drugs.”

According to John F. Keaney, Jr., MD, University of Massachusetts Medical School, Worcester, the ACCOAST study may streamline the care of patients with NSTE-ACS.5 He noted that up to 16% of patients with NSTE-ACS ultimately undergo coronary artery bypass grafting (CABG). Because current guidelines recommend P2Y12 inhibition soon after hospital admission, many patients with NSTE-ACS who need CABG will have received P2Y12 antagonists and evidence suggests use of these agents within 5 days before CABG leads to excess bleeding and prolonged hospitalization, prompting recommendations that CABG be delayed until 5 to 7 days after discontinuation of P2Y12 antagonists.

“As a consequence,” Dr. Keaney said, “early P2Y12-inhibition therapy is an important cause of delay in performing CABG, adding inefficiency and cost to the care of patients with NSTEMI.” But, he said, the ACCOAST results suggest that patients with NSTE-ACS who are selected for an early invasive strategy will be best served by administration of prasugrel only after angiographic definition of their coronary anatomy.


References

1. Kumbhani DJ, Bavry AA, Desai MY, et al. J Am Coll Cardiol. 2013 May 18. [Epub ahead of print]
2. Eikelboom JW, Connolly SJ, Brueckmann M, et al. N Engl J Med. 2013 August 31. [Epub ahead of print]
3. Ruschitzka F, Abraham WT, Singh JP, et al. N Engl J Med. 2013 September 2. [Epub ahead of print]
4. Montalescot G, Bolognese L, Dudek D, et al. N Engl J Med. 2013;369:999-1010.
5. Keaney JF Jr. N Engl J Med. 2013;369:1056-7.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Clinical Topic Collection: Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Valvular Heart Disease, Anticoagulation Management and ACS, Implantable Devices, SCD/Ventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Cardiac Surgery and VHD, Lipid Metabolism, Novel Agents, Acute Heart Failure, Interventions and ACS, Interventions and Imaging, Interventions and Structural Heart Disease, Angiography, Nuclear Imaging

Keywords: Thrombin, Electrocardiography, Angioplasty, Balloon, Coronary, Cardiac Resynchronization Therapy, Thienopyridines, Shock, Cardiogenic, Registries, beta-Alanine, Bioprosthesis, Benzimidazoles, Thrombosis, Taste, Acute Coronary Syndrome, Neoplasms, Off-Label Use, Piperazines, Pyridines, Myocardium, Burns, Stents, Sweden, Coronary Angiography, Thrombectomy, Microcirculation, Heart Failure, Heart Valve Diseases, Medical Futility, Embolism, Coronary Artery Bypass, Hospitalization, Defibrillators, Implantable


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