Trials and Tribulations: Hits and Misses from ESC and TCT

Cover Story | This year, the European Society of Cardiology (ESC) and the Transcatheter Cardiovascular Therapeutics (TCT) scientific symposia were held just days apart, but jet lag can't slow us down! Here are some highlights from both the 2014 ESC and TCT meetings.

"Less Is More" May Apply to AF Ablation

In the largest randomized trial to examine outcomes of ablation in persistent atrial fibrillation (AF) (N = 589), patients with persistent AF were randomized to either pulmonary vein ablation (PVA) alone, PVA plus ablation of atrial regions of the heart that produce abnormal electrograms, or PVA plus ablation of linear lesions in the left atrium.

The Substrate and Trigger Ablation for Reduction of Atrial Fibrillation Part 2 trial results were presented at ESC. "The more complex ablation procedures took almost an hour longer with about 33% more X-ray exposure for both operator and patient," Atul Verma, MD, Southlake Regional Health Centre, Newmarket, Ontario, Canada, said when he presented the data. "And yet they offered absolutely no increased benefit over the more minimal procedures. If anything, the more minimal procedures had a better outcome, although the differences were not statistically significant."

But Maybe More is More with Revascularization

There is primary percutaneous coronary intervention (PPCI) and now preventive PPCI (which we hope does not get abbreviated PPPCI). The issue: whether or not to target non-culprit lesions while the interventionalist is nearby working on opening the infarct-related artery (IRA). Preventive PPCI is not recommended in current guidelines, mostly owing to a lack of evidence with respect to the value of this strategy. Maybe the CvLPRIT trial offers a good start to answering that question.

Prior to treatment with PPCI, 296 patients in the United Kingdom were randomized to either IRA-only revascularization or complete revascularization of both the IRA as well as all non-IRAs shown to be significantly blocked.

"CvLPRIT demonstrated a 55% reduction in MACE in those patients presenting for primary PCI when their non-infarct-related artery was also treated on the index admission," according to Anthony Gershlick, MD, University Hospitals of Leicester, NHS Trust, Glenfield Hospital, United Kingdom. "I would suggest that this strategy may need to be considered by future STEMI guideline committees."

Compared to FFR, the Eyes Don't Have It

Colin Berry, PhD, Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom, presented the FAMOUS-NSTEMI trial results in Barcelona. "The assessment of an angiogram involves visual interpretation and this is subjective and potentially leads to suboptimal decision-making. Accordingly, there is a desire for increased objectivity in this setting." More objective, like fractional flow reserve (FFR).

The study involved 350 patients with acute non-ST-elevation myocardial infarction (NSTEMI) and either urgent invasive management planned within 72 hours of their MI or a history of recurrent symptoms within 5 days. Additionally, angiography needed to show at least one coronary artery for which FFR measurement might have diagnostic value, meaning blockage of at least 30% and normal blood flow.

A decision to treat with drug therapy, stents, or surgery was made by the attending physician based on assessment of each subject's baseline angiogram. Participants were then randomized to either receive this treatment (n = 174) or to receive a subsequent diagnostic FFR (n = 176), which would refine the treatment decision.

FFR better differentiated patients who don't need revascularization. More than one fifth had a revised treatment plan and ultimately more received drug therapy (i.e., avoided revascularization) than the angiographically-guided group (22.7% vs. 13.2%; p = 0.022). At 12 months, revascularization trended lower in the FFR group (79.0% vs. 86.8%; p = 0.054). Dr. Berry said, "FFR was feasible in 100% of patients in whom it was attempted and it was also safe, with guidewire-related dissections occurring in .03% or 2 patients. This resulted in a reduction in the need for unnecessary stenting and open heart surgery in one-fifth of the patients we evaluated."

Need more proof of the value of FFR? In the October 21 issue of JACC, Johnson et al. present an elegant analysis of FFR data collected over the past 20 years. Using meta-analysis techniques, they show a continuous relationship between measured FFR and patient outcome. While the statistics may be a bit daunting, in an accompanying commentary, John McB. Hodgson, MD, professor of medicine at Case Western Reserve School of Medicine, Cleveland, Ohio, wrote that the message is quite clear: "When FFR values are low, patients benefit from revascularization and when FFR values are high, we can do harm by proceeding with revascularization."

He added, "One is left wondering: what part of the FFR link don't interventional cardiologists understand? The data are clear; the cardiology community should not tolerate continuing to ignore it."

ATLANTIC: Pre-hospital Ticagrelor Drowns in ATLANTIC

Pre-hospital administration of anti-clotting agents such as fibrinolytics or glycoprotein IIb/IIIa inhibitors has been associated with improved coronary reperfusion and better outcomes in ST-elevation myocardial infarction (STEMI) patients. However, in this multicenter, double-blind study of 1,862 patients with an ongoing STEMI, a loading dose of 180 mg ticagrelor in the ambulance was safe but not superior to treatment upon hospital arrival. One explanation: pharmacodynamics and electrocardiogram findings suggested that the maximal effect of pre-hospital administration of ticagrelor occurred after the end of the procedure. This may help explain the finding that rates of definite stent thrombosis were lower in the pre-hospital group versus the in-hospital group at both 24 hours (0% vs. 0.8%; p = 0.0008) and 30 days (0.2% vs. 1.2%; p = 0.02).

Gilles Montalescot, MD, PhD, Institut de Cardiologie of Pitié-Salpêtriėre Hospital, Paris, France, said, "This was a kind of 'world record' in terms of the timing of the transfer of patients in this study." What the investigators observed was "the effect of ticagrelor after PCI on platelet function and on stent thrombosis as most of the events occurred within the first 24 hours." Despite it being clearly a negative trial, Dr. Montalescot said that this approach is safe, and because it may reduce long-term outcomes, consideration should be given to initiating ticagrelor as early as possible. (The ATLANTIC trial was simultaneously published in The New England Journal of Medicine.)

Five-Year PARTNER Results: "Hard to Deny This Therapy"

New data from the landmark PARTNER I trial were presented at TCT and show that after 5 years, transcatheter aortic valve replacement (TAVR) demonstrated a persistent mortality benefit, improved functional status, and a lower rate of repeat hospitalizations when compared with standard therapy for patients with severe aortic stenosis who are not candidates for surgery.

Consistent with the very high risk nature of the patient population, the 5-year all-cause mortality (the primary endpoint) was 93.6% in the standard therapy group versus 71.8% in the TAVR group (p < 0.0001). Median survival was less than a year with standard therapy compared with more than 2 years in the TAVR group (11.1 vs. 29.7 months; p < 0.001).

Similarly, at 5 years, re-hospitalizations were nearly half as frequent in TAVR compared to standard therapy patients (87.3% in standard group vs. 47.6% with TAVR; p < 0.0001). Valve durability was demonstrated with no increase in transvalvular gradient or attrition of valve area over the 5-year period.

Lead investigator Samir Kapadia, MD, director of the Sones Cardiac Catheterization Laboratory at the Cleveland Clinic, noted, "What this study says is that you can have these patients live longer, they are already reasonably functional, and even if they only live 2 years, they will be living outside of the hospital. So, it's very hard to deny this therapy to any patient who is otherwise reasonably functional, socially and otherwise."

Jeffrey Popma, MD, St. Elizabeth Hospital and professor at Harvard Medical School, Boston, agreed. "This is going to change my practice because I was more hesitant in doing (aortic stenosis) in patients who I thought were very high risk," he said. "What I learned from this trial is that I should be looking longer term because I am impressed that there is still a benefit from TAVR between year 2 and year 5."

CLEAN-TAVI: Protecting the Brain During TAVR

While overall results have been mixed for use of cerebral protection devices during interventions, a first-of-its-kind study finds such a device deployed during TAVR significantly reduces the number and volume of cerebral lesions in high-risk patients.

A total of 100 patients with severe aortic stenosis at increased surgical risk were randomly assigned in a 1:1 ratio to TAVR with cerebral protection (device group) or TAVR alone (control group). Patients underwent magnetic resonance imaging of the brain before and 2-7 days after TAVR.

After 2 days, the median number of lesions in the protected regions (the primary endpoint) was significantly lower in the device group (4 vs. 10 in the control group, respectively; p = 0.009). At 7 days post-TAVR, the median lesion number continued to be significantly lower with the device (3 vs. 7; p = 0.0023). In addition, the median total lesion volume in the protected area was significantly smaller in the device group compared to the control group at 2 days (246 mm3 vs. 527 mm3, respectively; p = 0.0023) and at 7 days (101 mm3 vs. 292 mm3; p = 0.002).

Does it really matter? "Eventually, we may be able to show the filter has the potential to improve neurologic outcomes," said Axel Linke MD, University of Leipzig Heart Center, Germany, who presented the data. However, in a state-of-the-art review in JACC, the authors went through the data on silent brain injury after cardiac surgery in general and concluded that while this association between imaging results and cognitive dysfunction is plausible, it is not yet firmly established.1

Commenting on CLEAN-TAVI, Alexandre Abizaid, MD, PhD, Institute Dane Pazzanese de Cardiologia, Sao Paulo, Brazil, said, "This is clearly a positive study and it was reassuring to see that mechanistically, there is an advantage to protecting the brain."

By the By with Bioresorbable Stents, Biodegradable Polymers

Despite rapid dissemination of the everolimus-eluting bioresorbable Absorb stent, it has not been directly compared to its metallic stent counterpart (Xience, both from Abbott Vascular, Santa Clara, California). At TCT, Patrick Serruys, MD, PhD, Imperial College, London, United Kingdom, presented the ABSORB II trial results. Patients with one or two de novo native lesions in different epicardial vessels were randomly assigned (2:1) to the bioresorbable-scaffold group (n = 335 patients; 364 lesions) or the metallic-stent group (n = 166 patients; 182 lesions).

Although acute lumen gain was lower for the bioresorbable scaffold by quantitative coronary angiography (1.15 mm vs. 1.46 mm; p < 0.0001), at 1 year the cumulative rates of first new or worsening angina from adverse event reporting were lower (72 patients [22%] in the bioresorbable-scaffold group vs. 50 [30%] in the metallic-stent group; p = 0.04). However, performance during maximum exercise and angina status (by the Seattle Angina Questionnaire) were similar.

The 1-year composite device-oriented endpoint was similar between the bioresorbable-scaffold and metallic-stent groups (16 [5%] vs. 5 patients [3%]; p = 0.35). There were 17 (5%) major cardiac adverse events (MACE) in the bioresorbable-scaffold group compared with five (3%) events in the metallic-stent group, with the most common adverse events being MI (15 cases [4%] vs. 2 cases [1%], respectively) and clinically indicated target-lesion revascularization (4 cases [1%] vs. 3 cases [2%], respectively).

Dr. Serruys said, "When we started this trial, investigators were somewhat afraid of the fragility of the polymer, but that is something we have corrected. We know that the preparation of the lesion has to be impeccable and then the scaffold will deploy easily." Referring to Dr. Serruys' group, David Rizik, MD, Scottsdale Healthcare Heart Group, Arizona, noted, "This is the birthplace of good, high-level science of bioresorbable stents. There have been retrospective analyses with lower levels of evidence that suggested safety concerns, but this is a higher level of science and it is very reassuring in terms of reinforcing the safety of this device at least, in this cohort."

Dr. Rizik added, "What I find most compelling about this study is the reduction in angina. Those of us who are implanting this bioresorbable scaffold had noticed this empirically and now we have two datasets presented at this meeting—the ABSORB II and the ABSORB EXTEND data—and both really do show similar striking reductions in angina episodes at 1-year with the bioresorbable scaffold."

ABSORB EXTEND, also presented at TCT, is an interim report on the 36-month clinical outcomes from the first 250 patients enrolled. After propensity-score matching, the angina had occurred in 25.8% of the ABSORB EXTEND participants versus 41.3% of patients undergoing Xience stenting in SPIRIT IV (p = 0.005).

Finally, at ESC, investigators presented the results of BIOSCIENCE, evaluating a thin-strut biodegradable polymer (as opposed to a biodegradable platform) sirolimus-eluting stent compared to a thin-strut durable polymer everolimus-eluting stent. It is one of the first trials pursued in a patient population with minimum exclusion criteria powered for clinical endpoints. Patients were randomly assigned to the biodegradable polymer stent (1,063 patients;1,594 lesions) or everolimus-eluting stents (1,056 patients; 1,545 lesions). The sirolimus-eluting biodegradable polymer stent was noninferior to the durable stent for the combined safety and efficacy outcome of target lesion failure at 12 months. In a pre-specified analysis, the biodegradable polymer stent showed a benefit in terms of better outcomes in patients with STEMI. However, only 19% of patients presented with STEMI, so this parameter needs further study.

Thomas Pilgrim, MD, Swiss Cardiovascular Center, University Hospital, Bern, Switzerland, presented the data and said in a press conference, "The biodegradable polymer itself may attenuate the inflammatory response after stent implantation and reduce the risk of very-late stent thrombosis."

A Hit or a Miss for Extended Therapy?

Length of time for antiplatelet therapy engenders much debate and even the experts can't agree. For example, the ACC/AHA guidelines currently recommend 12 months of DAPT in patients treated with drug-eluting stents (DES) "if the patient is not at high risk of bleeding," while in Europe, the ESC guidelines stress that "routine extension of DAPT beyond 6 months after new-generation DES implantation in stable coronary artery disease cannot be recommended and observational data suggest that even shorter durations of DAPT may be sufficient."

The SECURITY trial was a randomized study aiming to address the need for prolonged use of DAPT following implantation of second-generation DES. A total of 1,399 patients were randomized: 682 assigned to a 6-month and 717 to a 12-month regimen.

At 1 year, the incidence of the primary endpoint was 4.5% in the 6-month group compared to 3.7% in the 12-month group (FIGURE 1). After 24 months, both groups showed similar incidences of cardiac death (0.9% for 6 months of therapy vs. 0.8% in the 12-month arm; p = 0.925). Results of the trial were simultaneously published in JACC.

In ISAR-TRIPLE, the largest randomized trial to date investigating triple therapy after stenting and the first trial evaluating the duration of triple therapy, investigators evaluated 614 patients who require oral anticoagulation therapy and are candidates for dual antiplatelet therapy (DAPT) after DES implantation. Six weeks of drug therapy was not superior to 6 months of therapy with regard to net clinical outcomes (FIGURE 2). After 9 months, the primary endpoint occurred in 9.8% of patients in the 6 week group and 8.8% of patients in the 6 month group (p = 0.63). There also was no difference in major bleeding: 5.3% of patients in the 6-week versus 4.0% in the 6-month group (p = 0.44).

Lead investigator Nikolaus Sarafoff, MD, Deutsches Herzzentrum and Klinikum der Universität Munich, Germany, said, "The shortening of triple therapy neither reduced the incidence of TIMI major bleeding nor increased the incidence of the composite of ischemic events. These results suggest that physician should weigh the trade-off between ischemic events and bleeding risk when choosing the shorter or longer duration of triple therapy."

Practitioners are Translating the Data Appropriately

The largest prospective longitudinal study of acute MI patients offers unique insight into the use, safety, and effectiveness of blood thinners prasugrel and clopidogrel in hospitals across the United States. Importantly, the data also underscore that, in a real-world setting, clinicians are following the guidelines and responding to important clinical trial findings.

Investigators evaluated the comparative effectiveness and safety of prasugrel versus clopidogrel therapy when used in routine clinical practice in the United States. TRANSLATE-ACS looked at physician-directed patterns of prasugrel versus clopidogrel use among 11,969 patients treated with PCI at 233 hospitals. Prasugrel patients (n = 3,123, 25.5%) were younger (median 57 vs. 61 years; p < 0.0001), more likely to present with STEMI, and less likely to have prior MI (14.6% vs. 21.3%; p < 0.0001) or diabetes (24.6% vs. 27.2%; p = 0.003) than clopidogrel-treated patients.

While unadjusted comparisons demonstrated lower MACE in patients receiving prasugrel versus clopidogrel, the difference was no longer significant after risk adjustment. On the other hand, after adjusting for patient risk, prasugrel was associated with significantly lower definite stent thrombosis (p = 0.02). Among all-comers, adjusted bleeding risk was significantly higher with prasugrel.

Tracy Wang, MD, Duke University, Durham, North Carolina, said the results show that practitioners are listening to the data. "They are using prasugrel in patients who are younger, male, STEMI patients—these are the patients we think would stand to benefit the most from more potent antiplatelets." She added, "My take-home message from this is that, in routine practice, we are following the guidelines. I find these data help convey a reassuring safety signal for how we are employing these therapies in routine practice."

Have Pleiotropic Effects of Statins Crossed the River STICS?

Small randomized trials had suggested that perioperative statin therapy might prevent in-hospital complications after cardiac surgery. However, in 1,922 patients undergoing elective cardiac surgery, there was no benefit to rosuvastatin 20 mg daily—starting up to 8 days before surgery and continuing until the 5th postoperative day—compared to placebo. That included no benefit for the co-primary outcomes (new-onset AF or serum levels of troponin I) or secondary outcomes (including length of hospital stay, major in-hospital cardiac or cerebrovascular events, left ventricular (LV) function, and plasma creatinine).

Barbara Casadei, MD, DPhil, John Radcliffe Hospital, University of Oxford, United Kingdom, put no spin on it when presenting the results to the media covering ESC. "There are many reasons why these patients should be put on statin treatment, but the prevention of postoperative complications is not one of them. I don't want this message to get mixed up with the need to treat these patients with a statin for the long-term effects of lowering LDL cholesterol. But for short-term effects, I think this is the end of the discussion around the pleiotrophic effects of the statins in terms of having an impact on clinical outcomes."

After the data were presented at an ESC Hotline Session, panel member Steven Nissen, MD, chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic, matched Dr. Casadei in frankness: "There is a lesson here—a terribly important lesson—which is the power of self-delusion in medicine. When we base our guidelines on these small, poorly controlled trials, we are often making mistakes. And this is one of a number of examples of where, when someone finally does a careful thoughtful trial, you find out that something that people believed just isn't true. We can't cut corners with evidence. We need good randomized controlled trials."

Rivaroxaban for AF Patients Undergoing Cardioversion

In the absence of specific evidence, many physicians have begun switching to the novel, non-vitamin K oral anticoagulants, like rivaroxaban, in AF patients undergoing cardioversion. Good news: this time, jumping the gun was not a bad idea.

X-VeRT is the first prospective, randomized trial to examine the safety and efficacy of rivaroxaban compared to vitamin A antagonist (VKA) therapy in patients undergoing elective cardioversion for the treatment of AF. The pharmacological characteristics of rivaroxaban might be particularly useful in this setting because it has a rapid onset of action—within 2-4 hours—that could expedite cardioversion.

The study included 1,504 patients scheduled for either electrical (almost 98%) or pharmacological cardioversion. Using established guidelines, patients were assigned to either early or delayed cardioversion. Compared to treatment with a VKA, rivaroxaban was associated with an overall 50% reduction in the risk of cardiovascular events and a 24% lower risk of major bleeding, the primary safety outcome. (While not powered for statistical significance, it was thought this large of a trial still would give clinically meaningful information.)

Riccardo Cappato, MD, University of Milan, Italy, said, "Many physicians are already switching to novel oral anticoagulants despite the absence of any information about their use. So we thought that bringing this methodologically sound information would provide more consistent evidence for those who are doing this anyway and a little bit more evidence for those who may be reluctant to use the novel oral agents."

IVUS- or Angiography-Guided Intervention for CTOs?

The IVUS-CTO study is the first randomized trial to examine the clinical impact of intravascular ultrasound (IVUS)-guided intervention in patients with chronic total occlusion (CTO). The prospective, multicenter trial randomized 402 patients with CTOs to either the IVUS- or angiography-guided groups after successful guidewire crossing. Patients were then additionally randomized to zotarolimus-eluting stents or biolimus-eluting stents.

The primary endpoint was the composite of cardiac death, MI, and target-vessel revascularization (TVR) at 12 months, which was significantly lower in the IVUS-guided group (2.6% vs. 7.1% with angiography-guidance; hazard ratio = 0.35; p = 0.035). Occurrence of the composite of cardiac death and myocardial infarction was also significantly lower in the IVUS-guided group (p = 0.045). IVUS guidance led to more aggressive balloon inflations during PCI. At follow-up, TVR was lower in the IVUS-guided group compared with the angiography-guided group, but not significantly so (2.6% vs. 5.2%; HR = 0.48; p = 0.186).

Commenting on the study, Dr. Rizik said this was another presentation that could be practice changing: "IVUS is grossly underused in my opinion in our cath labs—it's less than 20% and I think it is (only) 11%—and revascularization is an expensive proposition compared to the cost of using an IVUS. So, as we get deeper into studies like this and have more data, I think it will be practice-changing."

Quadriphonic Did Not Make it—How About Quadripolar?

Quadripolar cardiac resynchronization therapy (CRT) technology intuitively addresses some of the limitations associated with current CRT devices that feature standard bipolar leads. They offer more programming options—16 pacing configurations—as well as shorter spacing between the two center electrodes and less phrenic nerve stimulation, a potential side effect of CRT that results in muscle twitching, hiccups, or shortness of breath.

The MORE-CRT study was conducted in in 63 centers in 13 countries with patients randomized to either a bipolar lead (controls; n = 348) or a quadripolar lead (n = 720). At 6 months, compared to controls, patients with quadripolar leads were significantly more likely to be free from a composite endpoint of both intra- and post-operative LV lead-related complications (85.97% vs 76.86%; p = 0.0001)—a relative risk reduction of 40.8%. According to Giuseppe Boriani, MD, PhD, Institute of Cardiology, University of Bologna, Italy, "For every 11 patients treated with a quadripolar lead instead of a conventional bipolar lead, we avoid an event related to placement of the left ventricular lead. And intraoperative events were also markedly reduced by more than half by use of the quadripolar lead (5.98% vs 13.73%; p < 0.0001)."

(EDITOR'S NOTE: Medtronic received US Food and Drug Administration approval for its Attain Performa quadripolar lead and Viva Quad XT and Viva Quad S CRT-defibrillators and these were expected to be broadly available in the US as of mid-September.)


  1. Sun X, Lindsay J, Monsein LH, Hill PC, Corso PJ. J Am Coll Cardiol. 2012;60:791-7.

Keywords: CardioSource WorldNews Interventions

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