The European Society of Cardiology (ESC) Congress 2017 was held in Barcelona, Spain from 26–30 August. The highlights of this year's conference were cardiovascular outcomes trial (CVOT) results from Ilaris (canakinumab; NVS, BMY, DRI Capital, REGN, XOMA), Xarelto (rivaroxaban; JNJ, BAYRY), and anacetrapib (MRK). Ilaris became the first drug selectively targeting inflammation to show a cardiovascular (CV) benefit, though efficacy was modest and the drug's prospects may depend on demonstrating a stronger risk:benefit profile in subgroup analysis. A novel finding that the drug also lowered lung cancer deaths has opened a new field of investigation for the mechanism. The anticoagulant Xarelto had strong results with a mortality benefit, though there was some criticism of the trial, and physicians will need to take an increase in major bleeding into account. Anacetrapib's results were disappointingly modest, putting another nail in the coffin for the troubled mechanism of cholesterol ester transfer protein (CETP) inhibition. On the device front, the biggest news was positive data for Medtronic's SPYRAL HTN-OFF MED trial, breathing new life into the renal denervation field, though blood pressure reductions were modest. We highlight these and other presentations below. Atherosclerosis/Cardiovascular Disease

• Ilaris became the first treatment selectively targeting inflammation to demonstrate a cardiovascular (CV) benefit, and in an interesting twist, also showed a benefit in lung cancer.
  • However, the CV benefit was modest in the overall population with borderline statistics, and there was a slight increase in deaths from infection related to its impact on the immune system. Hence, a CV label extension is uncertain, and how the results are viewed by regulators and payers (with pricing lowered from current orphan drug levels) could depend on a subgroup analysis showing stronger efficacy in those with a greater reduction in high-sensitivity C-reactive protein (hsCRP).
    • The findings herald a potential new approach for tackling residual CV risk, though other mechanisms would still need to be proven in a risky CVOT. An ongoing trial evaluating methotrexate is expected to complete 2018/2019.
  • Novartis officials pointed to the number of myocardial infarction patients who are smokers or previous smokers and may be more motivated to be treated due to the lung cancer benefit. They will discuss the benefit with regulators, but the latter are likely to be wary without confirmation.
• Xarelto's COMPASS trial in patients with coronary artery disease (CAD)/peripheral arterial disease (PAD) was stopped early due to superiority of the arm with Xarelto in combination with aspirin over aspirin alone, with a benefit on death likely to outweigh an increase in major bleeding.
  • The trial may have overcome defects seen in ATLAS ACS 2-TIMI 51 that had prevented approval in the acute coronary syndrome (ACS) indication.
  • Some criticized the trial for not emphasizing aggressive use of other secondary prevention therapies, though the investigators noted that results were consistent in those with better blood pressure or cholesterol control.
  • Due to the bleeding risk associated with the combination treatment, it could take some effort to convince physicians to more broadly use the new strategy in this setting, and usage may depend on a patient's bleeding versus thrombotic risk.

Dyslipidemia

• Anacetrapib had disappointing results, with only a modest 9% reduction in the primary endpoint of major coronary events.
  • There was also a slight increase in blood pressure and the percentage of patients with stage 3 or worse renal impairment. While the differences on these safety endpoints were not large, the drug also accumulates in adipose tissue, with unknown longer-term effects.
    • Merck has not decided yet whether to pursue approval, but along with the troublesome history of the class, it seems the drug could well have difficulty being approved, and if approved, unlikely it would see high usage.
  • The 9% reduction was in line with what would be expected from its non-high-density lipoprotein cholesterol (HDL-C) lowering in the trial, with patients starting from a fairly controlled level. This led the investigator to conclude that the large HDL-C increase did not play a role, but the discussant noted it still could have, because the drug produces more atherogenic low-density lipoprotein (LDL) particles.
    • The benefit on the primary outcome was larger in those starting from higher baseline LDL-C, suggesting the drug could be more useful in some subgroups, but that may not be sufficient given the negatives for the drug.

Stroke Prevention in Atrial Fibrillation (SPAF)

• RE-DUAL addressed the perplexing issue of what type of anti-platelet/anticoagulation to use in atrial fibrillation (AF) patients undergoing percutaneous coronary intervention (PCI) and found reduced bleeding with two different doses of Pradaxa (dabigatran; Boehringer) and a P2Y12 inhibitor compared to triple therapy with warfarin, aspirin, and a P2Y12 inhibitor.
  • On thromboembolic events, dual therapy with the 110mg dose had a numerically slightly higher rate than triple therapy, with trends for an increase in various events, whereas the 150mg dual therapy group had a slightly numerically lower rate than triple therapy.
    • Investigators said clinicians could potentially select which regimen to use based on a patient’s risk of bleeding and thromboembolic events.
    • RE-DUAL has some advantage over Xarelto's PIONEER AF-PCI, in that it included doses of Pradaxa approved for SPAF.
  • The study adds further support for initial use of dual therapy, but while it could induce some increase in use of dabigatran, it seems unlikely that it will have a major impact on market position.
• Eliquis's (apixaban; BMY, PFE) EMANATE added further support for use of NOACs in cardioversion, with no signs of efficacy or safety concerns compared to heparin/vitamin K antagonists (VKAs), though like other similar studies it was underpowered to show a difference.
  • Interestingly, similar to Xarelto's X-VeRT and Savaysa's (edoxaban; DSKYF, Daewoong, MRK) ENSURE-AF, Eliquis had numerically lower rates of thrombotic events and major bleeding than the parenteral anticoagulant/VKA comparator.
  • A loading-dose arm for more rapid cardioversion was likewise promising.
  • A European expert felt guideline changes were likely.

DEVICES Renal Denervation and Baroreceptor Implants for Hypertension

• In Medtronic's renewed effort at studying renal denervation after the failed SYMPLICITY HTN-3 pivotal study, SPYRAL HTN-OFF MED, a Phase II trial in patients off medications, showed significant, albeit modest, reductions compared to placebo in systolic and diastolic blood pressure, spurring Medtronic to announce it would move ahead with another pivotal study.
  • Despite procedural improvements, there was still a large variability in response, with blood pressure increasing in 10/38 patients who underwent the procedure. It could hence still be a challenge to predict who will respond.
  • The modest blood pressure reduction suggests a number of patients would still need antihypertensive drugs, and the study excluded patients with isolated systolic hypertension, who are more difficult to treat.
  • While testing patients off medication helped reduce confounders, data in treated patients from SPYRAL HTN-ON MED are still pending. That segment will be more important from a commercial standpoint, as clinicians would be reluctant to use the procedure in newly diagnosed patients or those who want to come off their medications.
• Encouraging preliminary blood pressure reduction results were seen for endovascular baroreflex amplification with MobiusHD (Vascular Dynamics/Rainbow Medical), but without a control, it is difficult to draw conclusions, given the experience with other devices in the indication.
  • On safety, however, there were two transient ischemic attacks, though it is not clear if these were related to very high blood pressures during the procedures, use of an autoinjector for contrast, or various complications. More study is needed to determine the risk and whether it can be prevented, as well as potential consequences from reshaping the carotid.

Catheter Ablation Devices for Dysrhythmia

• The CAPTAF trial found improved quality of life (QOL) for catheter ablation (using either Medtronic's Arctic Front Catheter or irrigated radiofrequency catheter ablation) compared to drug therapy, without a significantly greater reduction in AF burden (though ablation had a numerically greater reduction).
  • This was the first such trial with QOL as its primary endpoint.
  • The investigator believed the benefit was due to side effects of antiarrhythmic drugs, although that has not yet been shown in the trial.

Cardiac Arrhythmia Monitors

• Not surprisingly, patients monitoring their hearts with AliveCor's Kardia Mobile device identified more episodes of AF than routine care in the REHEARSE AF trial.
  • Patients were at least 65-years old with stroke risk-factors who were not taking anticoagulant drugs and did not have a prior diagnosis of AF.
  • The increase in AF diagnosis suggests that the device has the potential to reduce stroke.
    • Interestingly, control patients reported being slightly more anxious about their risk of heart rhythm abnormalities and stroke, and frequently said they would have preferred to have been enrolled in the regular monitoring group.

Coronary Stents

• Orsiro's (BIOTRONIK) Pivotal IDE trial for US PMA submission demonstrated non-inferiority to Abbott's Xience on 12-month target lesion failure (using a Bayesian analysis incorporating other trials), actually showing significantly lower rates on this measure, as well as target vessel myocardial infarction (MI).
  • Rates of any ARC or definite/probable stent thrombosis were numerically lower for Orsiro, helping relieve concerns raised by the BIOSCIENCE trial.

This report also has data on Victoza (liraglutide; NVO: LEADER CVOT – subgroup analysis for prior MI/stroke), inclisiran (MDCO, ALNY: Phase II ORION-1 updated results), Praluent (alirocumab; REGN, SNY: ODYSSEY APPRISE – patients with high CV risk in "real-life" setting), Repatha (evolocumab; AMGN, Astellas: FOURIER – achieving very low LDL-C levels and subgroup with history of stroke, GLAGOV virtual histology sub-study), Xarelto (PIONEER AF-PCI – effect of procedure and lesion characteristics), Savaysa (ENGAGE AF-TIMI 48 subgroup analysis by stroke risk scores), Brinavess (vernakalant; CRME: retrospective analysis), Brilinta (ticagrelor; AZN, MDCO: PEGASUS-TIMI 54 – subgroup analysis according to European Medicines Agency [EMA] label), ralinepag (ARNA: preclinical results), and Reveal XT Insertable Cardiac Monitor (MDT: REVEAL-AF – AF detection rates and presenting symptomatology). Like our report? Have any questions or feedback? Please let us know at askanalyst@sagientresearch.com.

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