Feature Story | More Clinical Insights from ESC 2017

Here’s a snapshot of some clinical findings from studies selected by the editors for refining your practice. We take a look at atrial fibrillation (AFib) and PCI, comparisons of PCI and CABG including in patients with type 1 diabetes (T1D) and also stroke rates after revascularization, bivalirudin versus heparin in acute coronary syndromes, and aortic stenosis (AS) and transcatheter aortic valve replacement (TAVR).

Atrial Fibrillation and PCI

Dual therapy without aspirin, versus triple therapy with aspirin, was associated with a significantly lower risk of bleeding in patients with nonvalvular AFib undergoing PCI in the RE-DUAL PCI trial. Further, dual therapy was noninferior to triple therapy for occurrence of thromboembolic events. The results were presented by Christopher P. Cannon, MD, FACC, and simultaneously published in the New England Journal of Medicine.

The dual therapy group received dabigatran (110 mg or 150 mg twice daily) plus clopidogrel or ticagrelor, while the triple therapy group received warfarin plus clopidogrel or ticagrelor and aspirin. The primary endpoint – an ISTH major or clinically relevant non-major bleeding event – occurred in 15.4 percent of the 110 mg dual therapy group compared with 26.9 percent in the triple therapy group (p < 0.001 for noninferiority) and in 20.2 percent of the 150 mg dual therapy group compared with 25.7 percent in the corresponding triple therapy group (p < 0.0001 for noninferiority). The mean duration of follow-up was 14 months. Read More >>>

Absolute risk reductions in ISTH major or clinically relevant non-major bleeding was 11.5 percent with the 110 mg dose of dabigatran and 5.5 percent with the 150 mg dose of dabigatran, compared against triple therapy.

When combining the two dabigatran arms, dual therapy was noninferior to triple therapy for the composite of thromboembolic events, death or unplanned revascularization (13.7 percent vs. 13.4 percent; p = 0.005). Notably, stent thrombosis occurred more frequently with the 100 mg dose of dabigatran vs. triple therapy (1.5 percent vs. 0.8 percent; hazard ratio [HR], 1.86; p = 0.15). The rates were similar for the 150 mg dose of dabigatran vs. triple therapy (0.9 percent for both; HR, 0.99; p = 0.98).

As reported at the American Heart Association Scientific Sessions last November, the PIONEER AF-PCI demonstrated that a rivaroxaban-based strategy (at two different doses) was associated with less bleeding compared with a warfarin-based strategy after PCI in AFib patients.

These data appear to suggest that when considering the balance of thrombotic and bleeding risks, physicians have more options to individualize therapy, including dual therapy. In the case of dabigatran, selecting the appropriate dose to balance the risk of stent thrombosis against the risk of bleeding must be considered.

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The improvements in risk stratification for percutaneous revascularization as well as technical and procedural aspects of PCI since the SYNTAX I trial have reaped benefits. The SYNTAX II trial reported that contemporary treatment yielded better clinical outcomes at one year after PCI in patients with de novo triple-vessel disease compared with the SYNTAX I strategy.

The so-called state-of-the-art SYNTAX II strategy employed the new risk stratification tool that incorporates clinical and anatomical variables, second-generation drug-eluting stents (DES), physiology-based revascularization with a hybrid use of instantaneous wave-free ratio and fractional flow reserve, and IVUS-guided PCI. Improved PCI techniques for chronic total occlusion (CTO), developed since the SYNTAX I trial, and guideline-directed medical therapy were also part of the strategy.

The single-arm, open-label, prospective, multicenter trial included 454 patients in the SYNTAX II arm and 315 matched patients from SYNTAX I selected because of equipoise between CABG and PCI for mortality at four years.

SYNTAX II, presented by Javier Escaned, MD, PhD, and published simultaneously in the European Heart Journal, showed that the primary composite outcome of major adverse coronary and cerebrovascular events (MACCE) at one year occurred in 10.6 percent of the SYNTAX II patients and 17.5 percent of the SYNTAX I patients (HR, 0.58; p = 0.006). Also lower in the SYNTAX II vs. SYNTAX I patients were all-cause death (2.0 percent vs. 2.9 percent; HR, 0.69; p = 0.43) and myocardial infarction (MI) 1.4 percent vs. 4.8 percent; HR, 0.27; p = 0.007). Stroke occurred in 0.4 percent and 0.7 percent of the SYNTAX II and SYNTAX I arms (HR, 0.69; p = 0.71). Definite stent thrombosis was lower in SYNTAX II at 0.7 percent vs. 2.7 percent in SYNTAX I (HR, 0.26; p = 0.045).

In an exploratory analysis comparing the SYNTAX II patients with 334 CABG patients from SYNTAX I selected based on equipoise, the investigators showed noninferiority for the contemporary PCI strategy for MACCE (10.6 percent vs. 11.2 percent; HR, 0.91; p < 0.001 for noninferiority). Read More >>>

Other overall findings include significantly fewer lesions being treated with PCI using the contemporary vs. older strategy and significantly higher success rates for CTO revascularization with the SYNTAX II strategy. Using the SYNTAX II risk stratification for PCI treatment led to similar outcomes at one year in patients with high anatomical risk (SYNTAX score >22) as those with low anatomical risk (SYNTAX score ≤22).

Another study in the PCI and CABG arena – in patients with T1D and multivessel disease – found that CABG was associated with a lower risk of coronary heart disease mortality, MI and repeat revascularization compared with PCI.

Published in the Journal of the American College of Cardiology simultaneously with its presentation at ESC, these results extend the finding that CABG is better than PCI in previous studies including BARI, FREEDOM and SYNTAX from type 2 diabetes to T1D.

This registry study conducted in Sweden by Martin Holzmann, MD, PhD, et al., included 2,546 patients with T1D who had a first multivessel revascularization (73 percent with PCI) during the study period. From 1995 to 1999, most patients received CABG (62 percent), but thereafter the rates of CABG declined and by 2010 to 2013 PCI was the treatment in 98 percent of patients.

For the primary outcome of all-cause mortality, over the mean follow-up of 10.6 years, there was no significant difference between the strategies after adjustment (HR, 1.14). The annual mortality rate was 4.3 percent with CABG and 6.1 percent with PCI.

The rate of cardiovascular mortality was lower with CABG than PCI (2.1 percent vs. 2.9 percent), translating to a 45 percent higher risk with PCI after adjustment. For MI, these rates were 2.7 percent and 4.6 percent, respectively, with a 47 percent higher adjusted risk with PCI.

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The risk of repeat revascularization was five-fold higher with PCI (1.9 percent with CABG vs. 20.1 percent with PCI). While the 30-day stroke rate was higher with CABG than PCI (1.9 percent vs. 0.8 percent) there was no difference in the long-term risk. Similarly, there was no difference between strategies for the long-term risk of heart failure.

The issue of stroke after revascularization continues to be a concern, yet individual studies are underpowered to detect significant differences between CABG and PCI. Data from a patient-level pooled analysis of 11 randomized trials reported by Stuart J. Head, MD, PhD, et al., found a higher rate of stroke with CABG than PCI over the follow-up in the studies and in a landmark analysis in the first 30 days.

Among the 11,518 patients, 293 strokes occurred. Over the five-year follow-up, the stroke rate was 3.2 percent post CABG and 2.6 percent post PCI (HR, 0.77; p = 0.027). Of the 5,753 patients who had a PCI, 1,518 received a bare-metal stent, 2,156 a first-generation DES and 1,978 a second-generation DES.

The stroke rates in the landmark analysis for 30 days and 31-1,825 days are shown in Table 1. As expected, mortality was higher in patients who had a stroke than those who did not with both strategies (31 percent vs. 8.6 percent with CABG; 28.1 percent vs. 10.8 percent with PCI; p < 0.001 for both). Notably, for both strategies, five-year mortality was higher in patients who had a stroke within the first 30 days (Table 2).

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Acute Coronary Syndromes

The VALIDATE-SWEDEHEART trial demonstrated no benefit with bivalirudin over heparin for STEMI or NSTEMI patients undergoing PCI. For the composite primary outcome of death, MI or major bleeding, there was no significant difference at 180 days between the two groups.

The study, the results of which were also published in the New England Journal of Medicine, compared bivalirudin with heparin monotherapy among 6,006 STEMI and NTEMI patients in Sweden who had PCI, predominantly with the radial approach. The majority of patients were receiving treatment with high-intensity platelet inhibitors. Read More >>>

A primary endpoint event occurred in 12.3 percent of patients in the bivalirudin group (369 of 3,004 patients), compared with 12.8 percent in the heparin group (383 of 3,002 patients) (p = 0.54). These results were consistent across patients with STEMI and NSTEMI, as well as other major subgroups.

Broken down by event, MI occurred in 2.0 percent and 2.4 percent of the bivalirudin and heparin groups (p = 0.33); definite stent thrombosis occurred in 0.4 percent and 0.7 percent, respectively (p = 0.09); and death in 2.9 percent and 2.8 percent. Major bleeding occurred in 8.6 percent of patients in both groups (p = 0.98).

In this investigator-initiated, registry-based, randomized clinical trial, “we enrolled patients with acute coronary syndromes who were undergoing PCI and receiving treatment with aspirin and potent P2Y12 inhibitors, without the planned use of glycoprotein IIb/IIIa inhibitors,” wrote David Erlinge, MD, PhD, FACC, et al. “The low rates of ischemic events overall and the absence of a significant between-group difference in event rates may have been influenced by the robust antithrombotic regimen used in the trial.”

In an accompanying editorial, Gregg W. Stone, MD, FACC, highlights several limitations to the study that make it difficult to definitively answer the question of whether to use bivalirudin or heparin during PCI. He notes the principal investigators from each of the large-scale randomized trials comparing bivalirudin and heparin for MI, including VALIDATE-SWEDEHEART, have agreed to combine individual patient data from their respective studies into a single database, which “should provide robust evidence to guide decisions.”

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Aortic Stenosis and TAVR

Myocardial scar is a key predictor of outcomes in patients with severe AS, as shown by data from the British Society of Cardiovascular Magnetic Resonance (BSCMR) group. Myocardial scar was associated with a doubling in mortality and was the strongest predictor of all-cause and cardiovascular mortality in their analysis.

In 703 patients with severe AS, myocardial scar was present in 51 percent. Patients with myocardial scar vs. those without had significantly higher rates of all-cause mortality (28.7 percent vs. 14.5 percent; p < 0.001) and cardiovascular mortality (16.6 percent vs. 6.4 percent; p < 0.001). The risk of all-cause mortality was higher regardless of whether patients were treated with TAVR or surgical aortic valve replacement (SAVR). Presenter Thomas Treibel, MD, concluded that timing valve intervention to pre-empt scar development or progression warrants further investigation. Read More >>>

In the post TAVR setting, leaflet thrombosis was shown to be a serious adverse event associated with stroke, cardiogenic stroke and death. The Manufacturer and User Facility Device Experience (MAUDE) registry study, presented by Ankur Kalra, MBBS, FACC, interrogated the database for the period of January 2012 to October 2015.

A total of 5,691 TAVR-related adverse events were identified. Of these, 156 were adverse events related to structural valve dysfunction (SVD) due to leaflet restriction or malcoaptation; SVD was documented in 30 cases. Sixty percent of adverse events occurred in the first year following TAVR and 40 percent occurred within 13 to 60 months. SVD presented as AS in 53.3 percent of patients, regurgitation in 23.3 percent or both in 13.3 percent of patients. Three of the 30 patients had a stroke or transient ischemic attack.

The registry study also found that AS occurred within 15.5 ± 12.2 months and regurgitation occurred within 10.1 ± 10.9 months of TAVR.

Leaflet thrombosis was treated with escalation of antiplatelet or anticoagulant therapy in 26.7 percent, valve-in-valve TAVR in 10.0 percent or surgery in 46.7 percent of patients. Other interventions included diuretics (n = 1), balloon aortic valvuloplasty (n = 2) and no intervention (n = 2). Outcomes after leaflet thrombosis were stroke or TIA (10.0 percent), cardiogenic shock (6.7 percent) and death (30.0 percent).

“As indications for TAVR expand to include patients at intermediate and perhaps low risk for perioperative mortality following surgery, an early diagnosis of leaflet thrombosis may be crucial for planning appropriate management and optimizing clinical outcome of this patient subset,” write the investigators in the article that was simultaneously published in Structural Heart.

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New Expert Roundtable on the Hottest Trials From ESC Congress 2017

Watch the new “ACC Cardiology Hour,” an expert roundtable discussion of the hottest trials from ESC Congress 2017. Valentin Fuster, MD, PhD, MACC, hosts Barbara Casadei, MD, DPhil; Deepak L. Bhatt, MD, MPH, FACC; Borja Ibáñez, MD, PhD; and Adnan Kastrati, MD, in a lively discussion on CANTOS, COMPASS, RE-DUAL PCI, SPYRAL HTN-OFF MED, and more. Watch ACC Cardiology Hour >>>

To view the full coverage of trial summaries, ACC news stories, journal scans, videos and more, visit ACC.org/ESC2017 and ACC’s YouTube Channel.

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Keywords: ACC Publications, Cardiology Interventions, Acute Coronary Syndrome, Adenosine, American Heart Association, Anticoagulants, Aortic Valve, Aortic Valve Stenosis, Aspirin, Atrial Fibrillation, Antithrombins, Cicatrix, Coronary Artery Disease, Antithrombins, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Diuretics, Drug-Eluting Stents, Early Diagnosis, Heart Failure, Hemorrhage, Heparin, Hirudins, Ischemic Attack, Transient, Magnetic Resonance Spectroscopy, Metals, Myocardial Infarction, Peptide Fragments, Numbers Needed To Treat, Platelet Aggregation Inhibitors, Platelet Glycoprotein GPIIb-IIIa Complex, Prospective Studies, Registries, Shock, Cardiogenic, Stents, Stroke, Thromboembolism, Thrombosis, Ticlopidine, Transcatheter Aortic Valve Replacement, Warfarin

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