This year's European Society of Cardiology Congress in Munich, Germany, thankfully lacked the drama of last year's meeting (remember Barcelona?), but instead offered attendees multiple opportunities to fine-tune their practice. In this article, Cardiology: Interventions reviews new imaging data and a host of other topics of interest to interventional cardiologists.

CCTA and FFR-CT

The Late-Breaking Science session dedicated to imaging was dominated by studies on noninvasive cardiac computed tomography angiography (CCTA), and, more specifically, on CCTA combined with CCTA-derived fractional flow reserve (FFR-CT) as a means of noninvasively assessing both anatomy and physiology.

CCTA is increasingly being used as the primary diagnostic strategy for the assessment of chest pain in individuals with suspected coronary artery disease (CAD) based on its high sensitivity to detect the presence of coronary atheroma. However, given its modest specificity when disease is present, there remains concern that the lack of functional information may result in an increased rate of invasive coronary angiography (ICA) showing nonobstructive disease.

"How can this be used to guide revascularization when CT angiography alone does not provide functional information?" asked Timothy A. Fairbairn, MBChB, PhD, at ESC. Fairbairn reported findings from the ADVANCE Registry, designed to test the real-world clinical utility and impact of using FFR-CT (performed by HeartFlow, Redwood City, CA). The results were subsequently published in the European Heart Journal.¹

ADVANCE included 5,083 patients (mean age 66 years) with clinically stable symptoms undergoing CCTA at 38 sites in Europe, North America and Japan for suspected CAD. Individuals with >30 percent diameter stenosis on CCTA were included in this prospective study and FFR-CT was requested in 96.2 percent of patients.

"What we could see is that FFR-CT really did enrich the number of patients going on to an invasive catheterization and safely deferred those individuals who required some form of other testing."

— Timothy A. Fairbairn, MBChB, PhD

The primary endpoint of reclassification between core lab CCTA alone and CCTA plus FFR-CT-based management plans occurred in 66.9 percent of patients. Of the 2,386 (59.7 percent) patients in whom further information was requested after CCTA, FFR-CT reclassified 70.0 percent (n=1,671) to medical treatment. "We know that this was a safe deferral as no events occurred in individuals with a negative FFR-CT," said Fairbairn.

In the positive FFR-CT arm (n=1,529), there were 19 major adverse cardiac events (0.6 percent; hazard ratio [HR], 19.75; p=0.0008), including 14 deaths or myocardial infarctions (MIs).

"What we could see is that FFR-CT really did enrich the number of patients going on to an invasive catheterization and safely deferred those individuals who required some form of other testing," said Fairbairn.

A negative FFR-CT was associated with a significantly lower rate of ICA or revascularization at 90 days. In patients with FFR-CT ≤0.80, ICA showed no stenosis >50 percent in 14.4 percent of patients compared to a rate of 43.8 percent in patients with FFR-CT >0.80 (odds ratio, 0.19; p<0.001). In total, 72.3 percent of patients undergoing ICA with FFR-CT ≤0.80 were revascularized.

"The key message is that FFR-CT when added to a CT coronary angiogram can improve the physician's certainty in terms of diagnostic management of the patient…" Fairbairn concluded.

"A criticism of coronary CT angiography has been that a slightly higher proportion of patients get sent to the cath lab, so the result of your reclassification was that more patients were treated medically. And this is an important statement in a generally stable ischemic population where the value of revascularization is not proven," commented panelist Todd C. Villines, MD, FACC.

A new study out of Aarhus, Denmark, and simultaneously published in the Journal of the American College of Cardiology, showed that FFR-CT is effective in differentiating patients with intermediate range coronary stenoses who do not require further diagnostic testing or intervention (FFR-CT >0.80) from those who may require further testing with ICA.²

The researchers, led by Bjarne L. Norgaard, DO, PhD, retrospectively reviewed CCTA findings for 3,674 consecutive patients evaluated at Aarhus University Hospital. In those with an intermediate stenosis of between 30 and 70 percent, FFR-CT testing was used to guide downstream management.

FFR-CT was available in 677 patients and in 61 percent it was negative (>0.80). In 75 percent of those with a negative FFR-CT, maximum coronary stenosis was ≥50 percent. The primary aim of the study was to assess the incidence of the composite endpoint of all-cause death, MI, hospitalization for unstable angina, and unplanned revascularization in patients with FFR-CT >0.80.

No difference was noted between those with a CCTA stenosis <30 percent who were not referred for additional testing and those with a negative FFR-CT not referred for additional testing (2.8 and 3.9 percent, respectively; p=0.58). Said Norgaard, "The presence of intermediate range CAD and FFR-CT >0.80 was associated with favorable clinical outcomes similar to the prognosis in patients without or with minimal evidence of CAD who had no planned downstream testing."

In contrast, the composite endpoint rate was higher (vs. those with a CCTA stenosis <30 percent) in those with a positive FFR-CT finding (FFR-CT ≤0.80) who were not referred for angiography (9.4 percent; p=0.04) and trended higher in those with a positive FFR-CT referred for ICA (6.6 percent; p=0.08).

Said the researchers, "…deferral of ICA in patients with lesion-specific ischemia was associated with an increased risk of an unfavorable clinical outcome." Indeed, Norgaard said the group was "a bit surprised" at this finding and said while there was no difference in all-cause death, there was a sixfold greater risk of nonfatal MI in this group, compared with those with a positive FFR-CT referred for ICA.

"In clinical practice, a diagnostic strategy of first-line coronary CTA in patients with suspected CAD, and selective FFR-CT testing in those with moderate disease, is effective in differentiating patients who do not require further diagnostic testing from higher risk patients in whom further testing with invasive cath and possibly intervention may be needed," concluded Norgaard. He noted the observational nature of the study and that multicenter studies with longer follow-up are needed.

The CREDENCE trial was a prospective, multicenter study designed to compare the diagnostic value of an integrated functional vs. integrated anatomic approach for the diagnosis of vessel-specific ischemia. To that end, the trial enrolled 612 patients with signs and symptoms of CAD referred for nonemergent ICA. The researchers completed functional testing with myocardial perfusion imaging (SPECT/PET and CMR) as well as anatomic testing with CCTA, including FFR-CT. Patients were split between a derivation cohort and a validation cohort. ICA with FFR measurement were also completed on all patients and used as the functional reference standard.

The investigators found that the best performing CCTA model integrated multiple measures beyond just stenosis severity, including the number of lesions with stenosis >30 percent, noncalcified plaque volume, an assessment of high-risk plaque and lumen volume. Adding FFR-CT to this model added only slight improvement in specificity (from an area under the curve of 0.88-0.89). Said principal investigator Wijnand J. Stuijfzand, MSc, "The integration of atherosclerosis findings beyond stenosis severity improves diagnosis of vessels that cause ischemia."

For vessel-specific ischemia, the area under the curve for CCTA was significantly higher compared with the myocardial perfusion imaging (MPI) model (0.83 vs. 0.68; p<0.001). "…A comprehensive CCTA interpretation was superior to a comprehensive MPI evaluation for the diagnosis of coronary arteries that cause ischemia," said Stuijfzand.

"But of course we still have to translate this into clinical practice, because now we have, like, six bits of information and in the end we have to translate it into a dichotomous decision. Do we send the patient to the cath lab for an invasive evaluation or do we treat with optimal medical therapy?"

— Wijnand J. Stuijfzand, MSc

In a discussion that included comments on the difficulty and expense of doing FFR-CT he added: "I think the data show that in this population, doing the quantitative and qualitative plaque analysis is as good as FFR-CT, or at least the FFR-CT didn't add to the atherosclerosis findings…But of course we still have to translate this into clinical practice, because now we have, like, six bits of information and in the end we have to translate it into a dichotomous decision. Do we send the patient to the cath lab for an invasive evaluation or do we treat with optimal medical therapy?"

Moving away from FFR-CT, the SCOT-HEART study showed the use of CCTA was associated with a 40 percent reduction in MI compared with standard care alone in patients with stable chest pain referred to a cardiology clinic. The primary endpoint of death from coronary heart disease or nonfatal MI at five years was also significantly reduced with the addition of CCTA (2.3 vs. 3.9 percent for standard care alone; HR, 0.59; p=0.004).

SCOT-HEART was conducted at 12 centers across Scotland and included 4,146 patients (mean age, 57 years). David E. Newby, MD, FACC, the study's lead investigator said the evidence suggested that the benefits of CCTA were attributable to better targeted preventive therapies and coronary revascularization.

Fractional Flow Reserve

Two trials, FUTURE and FAME 2, offered clinicians important information on FFR as a guide for treatment choice. In FUTURE, Gilles Rioufol, MD, explored whether FFR could help guide treatment decisions for complex patients with multivessel disease.

The trial was conducted at 31 French centers and randomly assigned 937 eligible patients to either FFR-guided or angiography-guided intervention. The treatment decision was less likely to be PCI in the FFR arm (71 vs. 79 percent for controls; p=0.002). Twelve percent of each arm was sent for CABG after angiography, and 17 percent (compared with only 9 percent of controls) of FFR-studied patients were recommended to medical treatment only.

"…with FFR we can double the number of patients that could be treated with just medical treatment and they get well."

— Gilles Rioufol, MD

The trial was halted early based on an excess in all-cause death at one year in the FFR arm (p=0.038). In the final analysis, Rioufol concluded that decisions based on FFR in an all-comer multivessel-disease patient population did not increase the risk of the primary endpoint of death, MI, revascularization or stroke at one year (p=NS), but did increase the risk of death (3.7 vs. 1.5 percent; p=0.036).

"Our main feeling is that those patients oriented to PCI due to FFR may have been treated better treated by CABG," said Rioufol. "The second message is good news, which is that with FFR we can double the number of patients that could be treated with just medical treatment and they get well."

A FAME 2 post hoc analysis showed that PCI reduces five-year death or MI in patients with silent ischemia and stable CAD vs. medical therapy. But since the analysis was limited to just 45 patients, the findings were received as "interesting" but preliminary.

Valvular Interventions

On the valvular heart disease front, some attendees might have been surprised by the findings of the MITRA-FR trial, which showed a lack of benefit for medical therapy plus percutaneous mitral regurgitation (MR) repair over medical therapy alone in patients with chronic heart failure and secondary MR.³

The trial enrolled 307 patients with severe secondary MR and used the MitraClip device (Abbott Vascular). While the device showed good safety and was effective in reducing MR, there was no difference seen for the primary efficacy outcome of a composite of all-cause death or unplanned hospitalization for heart failure (54.6 percent for the intervention group and 51.3 percent for medical therapy only; odds ratio, 1.16; p=0.53).

While MR was reduced in the intervention arm, no differences were seen for the primary endpoint of 12-month mortality across any of the prespecified subgroups. In his presentation of the findings, Jean-Francois Obadia, MD, PhD, noted a lack of power to determine subgroup differences and suggested that further study is warranted to see if any specific groups of patients are more likely to benefit from repair of secondary MR.

"Most probably, the cause of the disease is the underlying cardiomyopathy and the regurgitation is probably just a signal or marker of the disease, and not the real cause," said Obadia in a press conference. (Editor's Note: The COAPT study of TMVR showed benefit for hospitalization and all-cause mortality in heart failure patients. Read more on page 26 in the TCT 2018 News Roundup.)

At the late-breaking science session devoted to interventional cardiology, Sung-Han Yoon, MD, presented outcomes from the 40-center strong TMVR (Transcatheter Mitral Valve Replacement) registry on patients with degenerative bioprostheses, failed annuloplasty rings and severe mitral annular calcification (MAC) treated by valve-in-valve (ViV), valve-in-ring (ViR), and valve-in-MAC, respectively. TMVR is an emerging alternative treatment for these populations, but limited data exist regarding its procedural and clinical outcomes.

"Most probably, the cause of the disease is the underlying cardiomyopathy and the regurgitation is probably just a signal or marker of the disease, and not the real cause."

— Jean-Francois Obadia, MD, PhD

A total of 521 patients were assessed, 322 had ViV, 141 had ViR and 58 had ViMAC. Mean age overall was 73 years and mean STS score was 9.0 percent and did not differ between the three groups of patients.

The ViV group saw high technical success (94.4 percent), low 30-day mortality (6.2 percent) and low one-year all-cause mortality (14.0 percent), despite being at high surgical risk. However, despite similar surgical risk scores, ViR and ViMAC patients had significantly higher 30-day and one-year mortality (30.6 percent and 62.8 percent at one year for ViR and ViMAC, respectively; p<0.001 vs. ViV).

Left ventricular outflow tract (LVOT) obstruction was 2.2 percent in the ViV group, compared with 5 percent for ViR and 39.7 percent for ViMAC (p<0.001). As well, the need for a second valve was higher (p<0.001), as was conversion to surgery (p=0.004). Post-procedure MR (moderate or greater) was seen in 5.6, 18.4 and 13.8 percent of VIV, ViR and ViMAC patients, respectively (p<0.001).

"TMVR provided excellent outcomes for patients with degenerated bioprosthetic valves despite high surgical risk. However, procedural outcomes with ViR and ViMAC were suboptimal with higher rates of second valve implantation, LVOT obstruction and post-procedural MR," said Yoon. "Optimal patient selection and advanced device technology promises to improve the outcomes in TMVR, particular in ViR and ViMAC procedures."

A report by Jean-Philippe Collet, MD, PhD, from the FRANCE-TAVI registry focused on whether antithrombotic therapy at discharge influences long-term mortality and early bioprosthetic valve dysfunction (BVD) after transcatheter aortic valve intervention (TAVI).⁴ Dual antiplatelet therapy (DAPT) is recommended after TAVI, but single antiplatelet therapy or oral anticoagulation (OAC) is frequently used based on the patient profile.

The use of oral anticoagulation, prescribed mainly because of atrial fibrillation (AFib), was independently associated with a higher risk of death at three years and a lower risk of BVD. However, gender, renal failure and AFib itself more strongly impacted mortality, leading Collet to note the nonrandomized nature of the data and the need to wait for stronger data from ongoing randomized trials. "But these data are very important because it is a no-man's land and, so far, the recommendations we have are not evidence based. But I would say they are expert driven because of the lack of data."

The registry enrolled 12,804 patients between January 2013 and December 2015; 11,469 of whom were alive at discharge with known antithrombotic treatment. From these, 2,555 had at least two echocardiographic evaluations for the assessment of BVD.

Cath Lab Strategies

Transradial access racked up another win in the one-year, final results of the MATRIX trial, presented by Marco Valgimigli, MD, PhD. "The radial access reduced the one-year [net adverse event rates] owing to a durable effect on cardiovascular death and bleeding complications," he reported.

The trial previously reported a 30-day benefit in favor of the radial approach, driven by reductions in all-cause and cardiovascular mortality and bleeding. However, no other study has so far reported outcomes for radial compared with femoral access beyond 30 days.

MATRIX enrolled 8,404 patients across the whole spectrum of acute coronary syndromes (ACS) undergoing invasive management and also tested the use of bivalirudin vs. unfractionated heparin (UFH) with optional glycoprotein IIb/IIIa inhibitors. At one-year, major adverse cardiovascular event and net adverse clinical event rates did not differ between those assigned bivalirudin or UFH.

"Radial access should become the default approach in ACS patients undergoing invasive management," wrote the MATRIX investigators in the Lancet.⁵

"The radial access reduced the one-year [net adverse event rates] owing to a durable effect on cardiovascular death and bleeding complications."

— Marco Valgimigli, MD, PhD

One-year data from CULPRIT-SHOCK showed a still lower rate of the primary composite outcome of all-cause mortality or renal replacement therapy for patients with acute MI complicated by cardiogenic shock undergoing PCI who have culprit-lesion-only revascularization vs. immediate multivessel revascularization (52.0 vs. 59.5 percent; relative risk, 0.87; p=0.048).⁶ This followed on 30-day findings presented earlier that showed primary composite endpoint rates of 45.9 and 55.4 percent, respectively (p=0.01), with the difference primarily driven by an absolute 8.2 percent reduction in 30-day mortality (43.3 vs. 51.5 percent; HR, 0.84; p=0.03).

As expected, one-year repeat revascularization rates were higher in the culprit-lesion arm (32.3 vs. 9.4 percent for multivessel revascularization; p<0.001), but there were no differences seen in the occurrence of stroke, major bleeding or any bleeding between arms. Staged revascularization was performed in 17.7 percent of patients in the culprit lesion-only PCI group.

"The one-year results of CULPRIT-SHOCK support the recent change in the 2018 ESC/EACTS Guidelines On Myocardial Revascularization," said principal investigator Holger Thiele, MD. The 30-day findings from this trial prompted the guideline writers to recommend a strategy of culprit-lesion only PCI with the possibility of staged revascularization over a multivessel PCI strategy.

GLOBAL LEADERS was possibly one of the most important negative trials presented this year, showing that long-term antiplatelet monotherapy is safe but does not improve outcomes compared with standard DAPT.⁷

The investigators, led by Patrick W. Serruys, MD, PhD, FACC, hypothesized that ticagrelor might be appropriately used as monotherapy in at-risk patients beyond the initial period of high stent thrombosis risk. The trial enrolled 15,968 patients with stable CAD or ACS undergoing PCI (with a drug-eluting stent and periprocedural bivalirudin) and randomly assigned them to 75-100 mg aspirin daily plus 90 mg ticagrelor twice daily for one month and followed by 23 months of ticagrelor monotherapy, or to standard DAPT with 75-100 mg aspirin daily plus either 75 mg clopidogrel daily (for patients with stable CAD) or 90 mg ticagrelor twice daily (for patients with ACS) for 12 months and followed by aspirin monotherapy for 12 months.

For the primary endpoint at two years – a composite of all-cause mortality or nonfatal new Q-wave MI – the rates did not differ between arms (3.8 percent for the experimental group and 4.4 percent for the control group; p=0.073). Similarly, no differences were seen in the individual endpoints of all-cause mortality or new Q-wave MI, nor was a differential effect noted in the subgroups of patients with ACS or stable CAD. On the plus side, moderate or severe bleeding also did not differ, at about 2 percent in each arm (p=0.77).

Serruys suggested that a lack of adherence might have "compromised the assessment of superiority." Had the trial been stopped after one year, he said, the findings would have likely been positive. Indeed, the general consensus from those commenting on the study was that it was an unfortunate "near miss," which, as Deepak L. Bhatt, MD, MPH, FACC, noted in an accompanying editorial does not negate the idea that "aspirin monotherapy cannot be improved upon."⁸

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References

1. Fairbairn TA, Nieman K, Akasaka T, et al. Eur Heart J 2018;Aug 25:[Epub ahead of print].
2. Norgaard BL, Terkelsen CJ, Mathiassen ON, et al. J Am Coll Cardiol 2018;Aug 25:[Epub ahead of print].
3. Obadia J-F, Messika-Zeitoun D, Leurent G, et al. N Engl J Med 2018;Aug 27:[Epub ahead of print].
4. Overtchouk P, Guedeney P, Rouanet S, et al. J Am Coll Cardiol 2018;Aug 25:[Epub ahead of print].
5. Valgimigli M, Frigoli E, Leonardi S, et al. Lancet 2018;Aug 25:[Epub ahead of print].
6. Thiele H, Akin I, Sandri M, et al. N Engl J Med 2018; Aug 25:[Epub ahead of print].
7. Vranckx P, Valgimigli M, Juni P, et al. Lancet 2018; Aug 27:[Epub ahead of print].
8. Bhatt DL. Lancet 2018; Aug 27:[Epub ahead of print].

Keywords: ACC Publications, Cardiology Interventions, ESC Congress, ESC18, Acute Coronary Syndrome, Adenosine, Angina, Unstable, Angiography, Coronary Angiography, Aortic Valve, Aspirin, Atherosclerosis, Atrial Fibrillation, Bioprosthesis, Antithrombins, Cardiomyopathies, Catheterization, Chest Pain, Constriction, Pathologic, Control Groups, Coronary Artery Disease, Coronary Disease, Coronary Stenosis, Coronary Vessels, Drug-Eluting Stents, Echocardiography, Fibrinolytic Agents, Follow-Up Studies, Heart Failure, Heart Valve Diseases, Heart Valve Prosthesis, Heparin, Hirudins, Hospitalization, Mitral Valve, Mitral Valve Insufficiency, Myocardial Infarction, Myocardial Perfusion Imaging, Myocardial Revascularization, Patient Discharge, Patient Selection, Peptide Fragments, Percutaneous Coronary Intervention, Plaque, Atherosclerotic, Prognosis, Prospective Studies, Registries, Renal Insufficiency, Renal Replacement Therapy, Research Personnel, Retrospective Studies, Risk, Shock, Cardiogenic, Stroke, Thrombosis, Ticlopidine, Tomography, Emission-Computed, Single-Photon, Tomography, X-Ray Computed

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