Cover Story | ESC 2017: Understanding Recent Developments in Cardiology

This year’s European Society of Cardiology (ESC) Congress placed a particular emphasis on understanding recent developments in cardiology, said Congress Program Committee Chairperson, Stephan Achenbach, MD, FACC. The ESC Hot Line Late Breaking Clinical Trials sessions marked a historic turning point in cardiology with a host of seminal, practice-changing studies being presented, including key trials of lipid-lowering therapy, anticoagulation therapy and interventional cardiology.

Advances in Lipid Lowering and Cardiovascular Disease Prevention

Lipid-lowering therapy has been the mainstay of cardiovascular disease treatment for decades. “LDL-C is the principal cause of coronary artery disease,” said renowned expert, Eugene Braunwald, MD, MACC. “Over the last few years we have gathered a lot of new information that has not yet been incorporated into guidelines.” Indeed, the congress Hot Line sessions showcased some paradigm shifting studies on lipid lowering and cardiovascular disease prevention. The CANTOS study broke new ground with its practice changing results showing that reducing inflammation, even in the absence of lipid lowering, significantly reduces cardiovascular events and the incidence of cancer.

CANTOS evaluated canakinumab, a monoclonal antibody inhibitor of interleukin 1β (IL-1β) in 10,061 patients with a history of myocardial infarction (MI) and elevated high-sensitivity C-reactive protein (hsCRP). The patients were randomized to subcutaneous canakinumab 50 mg (n = 2,170), canakinumab 150 mg (n = 2,284), canakinumab 300 mg (n = 2,263) or placebo (n = 3,344). After a median follow-up of 3.7 years, the primary endpoint, incidence of cardiovascular death, MI or stroke occurred in 3.86 per 100 person-years in the 150 mg canakinumab group vs. 4.50 per 100 person years in the placebo group (p = 0.02). Canakinumab did not reduce lipid levels from baseline.

"For the first time, we’ve been able to definitively show that lowering inflammation independent of cholesterol reduces cardiovascular risk. This has far-reaching implications. By leveraging an entirely new way to treat patients – targeting inflammation – we may be able to significantly improve outcomes for certain very high risk populations." Paul M. Ridker, MD, MPH, FACC

The patients were also followed for the occurrence of cancer over a median of 3.7 years. Incident lung cancer was significantly less frequent in the canakinumab group than in the placebo group (p = 0.0002). Significantly higher baseline concentrations of hsCRP were found in patients subsequently diagnosed with lung cancer than in those not diagnosed with lung cancer.

“These findings represent the end game of more than two decades of research, stemming from a critical observation that half of heart attacks occur in people who do not have high cholesterol,” said principal investigator Paul M. Ridker, MD, MPH, FACC. “For the first time, we’ve been able to definitively show that lowering inflammation independent of cholesterol reduces cardiovascular risk. This has far-reaching implications. By leveraging an entirely new way to treat patients – targeting inflammation – we may be able to significantly improve outcomes for certain very high risk populations.”

In a related editorial comment in the New England Journal of Medicine, Robert A. Harrington, MD, MACC, wrote “CANTOS has helped move the inflammatory hypothesis of coronary artery disease forward scientifically. However, the modest absolute clinical benefit of canakinumab cannot justify its routine use in patients with myocardial infarction until we understand more about the efficacy and safety trade-offs and unless a price restructuring and formal cost-effectiveness evaluation supports it.”

In an unexpected result, the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib, was superior to placebo at preventing nonfatal adverse cardiac events in the HPS3/TIMI55-REVEAL trial. According to commenter Philippe Gabriel Steg, MD, FACC, “That was a surprise because this is the fourth trial with a CETP inhibitor. The first trial was halted prematurely for increased mortality but we know that there were probably off-target effects with that molecule. There were two negative trials with dalcetrapib and evacetrapib. Then the fourth trial suddenly becomes positive.”

Anacetrapib was evaluated in patients with stable atherosclerosis receiving intensive atorvastatin therapy at baseline. The patients were randomized to additional therapy with anacetrapib (n = 15,225) or placebo. At the trial midpoint, patients in the anacetrapib group had a 43 mg/dL higher mean high density lipoprotein cholesterol (HDL-C) than those in the placebo group. The mean non-HDL cholesterol was lower by 17 mg/dL versus placebo. After a median follow-up of 4.1 years, 10.8 percent of patients treated with anacetrapib had a major coronary event vs. 11.8 percent of patients receiving placebo (p = 0.004). However, there was no improvement in mortality or cardiovascular mortality.

"…this is the fourth trial with a CETP inhibitor. The first trial was halted prematurely for increased mortality but we know that there were probably off-target effects with that molecule. There were two negative trials with dalcetrapib and evacetrapib. Then the fourth trial suddenly becomes positive." Philippe Gabriel Steg, MD, FACC

“The REVEAL trial has shown for the first time that adding anacetrapib to intensive statin therapy reduces the incidence of cardiovascular events in high risk patients,” commented co-principal investigator Martin Landray, PhD.

PCSK9 inhibition is a more potent option for lipid lowering. “On the downside, they are quite expensive,” noted Braunwald. “Patients at increased risk whose LDL-C cannot be brought down to below 70 mg/dL should receive PCSK9 inhibition,” he said, adding “this certainly includes patients who have just experienced a heart attack.”

The FOURIER and GLAGOV trials both evaluated the PCSK9 inhibitor evolocumab vs. placebo in patients with elevated LDL-C on statin therapy. LDL-C was reduced to 30 mg/dL in the FOURIER trial and to 36.6 mg/dL in the GLAGOV trial, among patients treated with evolocumab. In the FOURIER trial, patients with established cardiovascular disease treated with evolocumab had a significantly lower incidence of cardiovascular death, MI, stroke, unstable angina or coronary revascularization. In the GLAGOV trial, patients with coronary artery disease (CAD) in the evolocumab group had a significant reduction in percent atheroma volume at 78 weeks vs. those in the placebo group (–0.95 percent vs. 0.05 percent; p < 0.001). According to GLAGOV investigator, Steven E. Nissen, MD, MACC, “A little bit of plaque reduction goes a long way, probably because we’re stabilizing the plaques.”

Anticoagulation Therapy and Thrombosis Prevention

Several trials addressed anticoagulation therapy and thrombosis prevention at this year’s Congress. Of particular interest were new strategies to prevent thrombosis while reducing bleeding from anticoagulation in patients with atrial fibrillation (AFib). Patients with AFib and left ventricular dysfunction had improved outcomes with catheter ablation vs. conventional drug therapy in the CASTLE-AF trial, while the EMANATE trial found that apixaban lowers stroke risk in AFib patients undergoing cardioversion. The COMPASS trial demonstrated the superiority of rivaroxaban added to aspirin in patients with atherosclerosis.

The EORP-AF Long-Term General Registry, organized by the ESC, reported that the use of non-vitamin K antagonist oral anticoagulants (NOACs) has driven an overall rise in the prescription of oral anticoagulant drugs in patients with AFib, according to a late-breaking analysis of more than 11,000 patients. The registry reported that 85 percent of patients with AFib used an oral anticoagulant, with 59 percent of them receiving a vitamin K antagonist (VKA) and 41 percent receiving a NOAC. “The overall use of oral anticoagulants in atrial fibrillation has increased by around 5 percent since the previous survey,” said registry chairman Giuseppe Boriani, MD, PhD.

In the RE-DUAL PCI trial, presented by Christopher P. Cannon, MD, FACC, the risk of bleeding was significantly lower among patients with AFib undergoing PCI who received dual therapy with dabigatran and a P2Y12 inhibitor than among those who received triple therapy with warfarin, a P2Y12 inhibitor and aspirin. Dual therapy was noninferior to triple therapy for occurrence of thromboembolic events.

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 – a major or clinically relevant nonmajor 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).

In an ACC interview, Steg commented, “RE-Dual PCI is the largest ever trial to address this. It’s very clear that using a dabigatran-based strategy versus a warfarin-based strategy reduced bleeding substantially. What’s interesting is that there was no price to pay in terms of ischemic events when you pooled the dabigatran arms. Numerically, a slight increase in thrombosis with the 110 mg dose but greater reduction in bleeding. So that gives clinicians two options to tailor therapy to the risk of each patient.”

Catheter ablation versus conventional therapy significantly reduced the primary endpoint of all-cause mortality and unplanned hospitalization for worsening heart failure (HF) in patients with AFib and left ventricular ejection fraction (LVEF) ≤35 percent in the CASTLE-AF trial, presented by Nassir F. Marrouche, MD. The primary outcome occurred in 28.5 percent of the ablation group vs. 44.6 percent of the conventional therapy group. A risk reduction of 38 percent from baseline to 60 months was observed (p = 0.007).

" (The CASTLE-AF trial) sheds light on the importance of restoring and maintaining regular heart rhythm with ablation and could have a major impact on reducing costs associated with hospitalizations. The take-home message of this trial is that it is time to offer catheter ablation procedures at an early stage in HF patients with AF." Nassir F. Marrouche, MD

Patients were randomized to ablation (n = 179) or conventional drug therapy (n = 184). In addition to rate and rhythm control, the patients received anticoagulation therapy throughout the study. Marrouche noted that despite some limitations, the trial “sheds light on the importance of restoring and maintaining regular heart rhythm with ablation” and could have a “major impact” on reducing costs associated with hospitalizations. “The take-home message of this trial is that it is time to offer catheter ablation procedures at an early stage in HF patients with AF,” he said.

In the EMANATE trial, apixaban lowered the risk of stroke significantly more than heparin followed by VKA in anticoagulation-naïve patients with AFib scheduled for cardioversion. The patients were randomized to apixaban 5.0 mg twice daily (n = 753) or to heparin and a VKA (n = 747). No strokes occurred in the apixaban group but there were six in the heparin/VKA group (p = 0.0164). There were no systemic embolic events in either group. Two deaths occurred in the apixaban group and one in the standard care group. Three major bleeds were reported in the apixaban group and six in the standard care group.

“In patients with atrial fibrillation undergoing cardioversion, apixaban with or without a loading dose was safe, resulting in few bleeding events and fewer strokes than conventional anticoagulant therapy. We believe the findings observed in EMANATE support the use of apixaban in this group,” concluded principle investigator Michael D. Ezekowitz, MB, ChB, FACC. According to discussant Jens Cosedis Nielsen, MD, EMANATE is a well-conducted trial that adds to the growing evidence suggesting that NOACs are a viable alternative to heparin/VKA therapy in patients undergoing cardioversion for AFib.

The COMPASS trial showed that patients with stable atherosclerotic disease taking very low dose rivaroxaban plus aspirin have better cardiovascular outcomes, but more major bleeding events than those taking aspirin alone. “This combination was a clear winner,” commented Braunwald in a related editorial in the New England Journal of Medicine.

The investigators randomized 27,395 patients with stable atherosclerotic disease to rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban alone (5 mg twice daily) or aspirin alone (100 mg once daily). The primary outcome was cardiovascular death, stroke or MI. The study was stopped because of the clear superiority of rivaroxaban plus aspirin after a mean follow-up of 23 months.

The primary outcome occurred in 4.1 percent of the rivaroxaban plus aspirin group vs. 5.4 percent of the aspirin alone group (p < 0.0001) and in 4.9 percent of the rivaroxaban alone group but the difference was not statistically significant when compared with aspirin alone (p = 0.12).

"To now have a therapy that reduces major cardiovascular events and major adverse limb events by one-third is going to be a great benefit for these high-risk patients." Sonia Anand, MD, PhD

There were more major bleeding events in the rivaroxaban plus aspirin group vs. the aspirin alone group (3.1 percent vs 1.9 percent; p < 0.0001). However, there was no significant difference in intracranial or fatal bleeding between these two groups. Bleeding events occurred in 2.8 percent of the rivaroxaban alone group.

“There is a highly significant net clinical benefit observed when primary outcome and severe bleeding events are pooled together, with 431 (4.7 percent) of the rivaroxaban plus aspirin group undergoing an event compared with 534 events in the aspirin monotherapy group (p = 0.0005),” said presenter John Eikelboom, MD.

Sonia Anand, MD, PhD, presented results from a subgroup analysis of patients with peripheral arterial disease (PAD) in COMPASS that showed similar benefits with rivaroxaban plus aspirin in this group. She commented, “To now have a therapy that reduces major cardiovascular events and major adverse limb events by one-third is going to be a great benefit for these high-risk patients.”

“This trial represents an important step forward in thrombocardiology and it is likely to change practice guidelines,” concluded Braunwald in his editorial.

Interventional Cardiology

“This year’s Congress marks the 40th anniversary of the first PCI procedure,” noted Achenbach. “In fact,” he added, “this year’s program is particularly rich as far as PCI is concerned.”

In the DIVA trial, no difference was observed in either short-term or long-term outcomes between drug-eluting stents (DES) and bare metal stents (BMS) in patients undergoing saphenous vein graft PCI.

Patients with saphenous vein graft lesions undergoing PCI were randomized to DES (n = 292) vs. BMS (n = 305). The primary outcome was the incidence of target vessel failure, defined as cardiac death, target vessel MI, or target vessel revascularization (TVR) at 12 months. The secondary outcomes were target vessel failure, death and target vessel MI at 2.7 years. The primary outcome occurred in 17 percent of the DES group vs. 19 percent of the BMS group (p = 0.67). There were also no significant differences in the secondary outcomes between the groups.

Relatively small trials have been inconclusive on the comparative effectiveness of DES vs. BMS, while DIVA is one of the largest trials comparing the two types of stents. “The DIVA trial showed no difference in either short- or long-term outcomes between DES and BMS, which has important economic implications and highlights the need for new strategies to treat severe graft lesions,” said principal investigator and study chair, Emmanouil S. Brilakis, MD, PhD, FACC.

A nationwide observational cohort study in patients with type 1 diabetes and multivessel disease, presented by Martin Holzmann, MD, PhD, found that CABG compared with PCI was associated with lower rates and risks of cardiac-specific mortality, MI and repeat revascularization. There were no differences in the rates of all-cause mortality, stroke or HF. Previously, the FREEDOM, BARI and SYNTAX trials reported a survival benefit in patients with diabetes and multivessel disease who underwent CABG compared with PCI. However, these studies did not report on how many patients with type 1 diabetes were included.

"The DIVA trial showed no difference in either short- or long-term outcomes between DES and BMS, which has important economic implications and highlights the need for new strategies to treat severe graft lesions." Emmanouil S. Brilakis, MD, PhD, FACC

The study included all patients with T1D who underwent a first multivessel revascularization with PCI or isolated CABG from 1995 to 2013 in Sweden. During the mean follow-up of 10.6 years, the yearly mortality rate was 4.3 percent in the CABG group vs. 6.1 percent in the PCI group. The adjusted risk of death was similar with CABG vs. PCI. After adjustment, patients in the PCI group had a 45 percent higher risk of cardiac-specific mortality, 47 percent higher risk of MI and 5-fold higher risk of repeat revascularization. The 30-day rate of stroke was higher with CABG (1.9 percent) vs. PCI (0.8 percent). The authors concluded that CABG should be the preferred strategy in patients with type 1 diabetes.

A patient-level pooled analysis of 11 randomized trials comparing CABG against PCI in patients with multivessel disease found that the rates of stroke at 30 days and 5 years were significantly higher after CABG than after PCI. However, the rate of stroke occurring between 31 days and 5 years was comparable between the CABG and PCI groups. Five-year mortality was significantly higher among patients suffering from stroke within 30 days after CABG and PCI compared with those who did not have a stroke (p < 0.001 for both).

Aortic Stenosis and TAVR

According to data from the British Society of Cardiovascular Magnetic Resonance (BSCMR), myocardial scar is a key predictor of outcomes, which doubles mortality in patients with severe aortic stenosis (AS), and is the strongest independent predictor of all-cause and cardiovascular mortality. In 703 patients with severe AS, myocardial scar was present in 51 percent. Patients with myocardial scar 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 transaortic valve replacement (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.

"Early diagnosis of leaflet thrombosis may be crucial for planning appropriate management and optimizing clinical outcomes for patients. " Ankur Kalra, MBBS, FACC

A Manufacturer and User Facility Device Experience (MAUDE) registry study, presented by Ankur Kalra, MBBS, FACC, found that leaflet thrombosis is a serious adverse event following TAVR that is associated with stroke, cardiogenic stroke and death. Data from 5,691 TAVR-related adverse events were found in the database. Of these, 156 adverse events of structural valve dysfunction (SVD) due to leaflet restriction or malcoaptation were retrieved and documented in 30 cases. Sixty percent occurred in the first year following TAVR and 40 percent occurred within 13 to 60 months. SVD presented as aortic stenosis 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.

“Early diagnosis of leaflet thrombosis may be crucial for planning appropriate management and optimizing clinical outcomes for patients,” Kalra concluded. Achenbach commented, “This was a database of patients with clinical problems, not a database of patients with leaflet thrombosis that was used for this analysis. Hence, one cannot conclude from this data how often leaflet thrombosis results in severe consequences…Many imaging trials published in the last year showed that leaflet thrombosis is not infrequent, usually resolves spontaneously or with anticoagulation, and that clinical relevant consequences are seldom seen.”

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Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Valvular Heart Disease, Anticoagulation Management and Atrial Fibrillation, EP Basic Science, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Cardiac Surgery and VHD, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Interventions and Coronary Artery Disease, Interventions and Structural Heart Disease, Interventions and Vascular Medicine

Keywords: ACC Publications, Cardiology Magazine, Adenosine, Angina, Unstable, Antibodies, Monoclonal, Anticoagulants, Aortic Valve, Aortic Valve Stenosis, Aspirin, Atherosclerosis, Atrial Fibrillation, Blood Coagulation, Cardiovascular Diseases, Catheter Ablation, Cholesterol, Cholesterol Ester Transfer Proteins, Cholesterol, HDL, Cicatrix, Coronary Artery Disease, Cost-Benefit Analysis, C-Reactive Protein, Cytarabine, Antithrombins, Diabetes Mellitus, Type 1, Drug-Eluting Stents, Early Diagnosis, Electric Countershock, Heart Failure, Heparin, Hospitalization, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Incidence, Inflammation, Interleukin-1, Ischemic Attack, Transient, Lung Neoplasms, Magnetic Resonance Spectroscopy, Myocardial Infarction, Oxazolidinones, Peripheral Arterial Disease, Plaque, Atherosclerotic, Pyrazoles, Registries, Research Personnel, Risk Factors, Risk Reduction Behavior, Saphenous Vein, Stroke, Stroke Volume, Sulfhydryl Compounds, Thromboembolism, Thrombosis, Purinergic P2Y Receptor Antagonists, Ticlopidine, Transcatheter Aortic Valve Replacement, Ventricular Dysfunction, Left, Vitamin K, Warfarin


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