PCSK9 at ACC Sessions Joins Washington, DC, Acronym Alphabet Soup

March 14, 2017

WASHINGTON, DC — This is a city of acronyms and abbreviations, from familiar ones such as FEMA and FBI to the more obscure, like SAMHSA or MARCORSYSCOM. But taking center stage in Washington this week at the American College of Cardiology (ACC) 2017 Scientific Sessions is proprotein convertase subtilisin kexin type 9 (PCSK9), the LDL-regulating enzyme targeted by a drug class still waiting to catch fire with clinicians 2 years after it came into their hands.

Although the yearly cost of PCSK9 inhibitors such as evolocumab (Repatha, Amgen) and alirocumab (Praluent, Sanofi/Regeneron) is a widely cited reason for the drugs' tepid reception, a shortage of solid clinical outcomes data is another. That could be changing with the lead presentation at the first of the meeting's series of late-breaking clinical trials (LBCTs), primary results from the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial.

Amgen let the world peek at the trial's results last month with a cursory announcement that FOURIER showed a significant drop in risk of cardiovascular events in secondary-prevention patients who received evolocumab on top of statin therapy.

Excitement at the news was typically tempered by caution as the world awaited more details from the trial at its ACC presentation. But offerings in the meeting's tightly packed 3 days will also include more offbeat agents aimed at managing dyslipidemia and treatments with the direct oral anticoagulants (DOACs) in ACS and atrial fibrillation (AF); transcatheter aortic-valve replacement (TAVR), especially in intermediate-risk patients; and PCI guided by measures of vascular function and myocardial ischemia. Here are selected highlights of the meeting's LBCTs and featured research sessions:

Friday March 17, 9:00-10:00 am: Joint ACC/JACC LBCTs
  • FOURIER: The >27,000-patient trial "met its primary composite end point" of CV death, nonfatal MI or stroke, or hospitalization for unstable angina or coronary revascularization, Amgen previously announced, without disclosing the magnitude of the observed evolocumab benefit.

  • The SURTAVI safety and efficacy trial with a planned 2500 intermediate-risk patients compared TAVR with the CoreValve (Medtronic) and surgical aortic-valve replacement (SAVR) and is following them for all-cause mortality or stroke at 2 years. The sessions promise "first results."

Friday March 17, 12:15-1:45 pm: Featured Clinical Research 1
  • RESET-HCM is a randomized test of a moderate-intensity exercise program in a projected 128 patients with hypertrophic cardiomyopathy (HCM). It follows growing evidence that exercise per se doesn't necessarily raise the risk of sudden death in this population.

  • MR-INFORM randomized a planned 915 patients with suspected coronary artery disease to management guided by either magnetic-resonance stress perfusion imaging or angiography with fractional flow reserve (FFR) measurement.

  • The ORION 1 trial explored an alternative way to suppress PCSK9 for reduction of LDL cholesterol: inhibit its synthesis in the first place. That's what occurs, at least for 90 days, with injections of the long-acting RNA interference agent inclisiran (ALN-PCSsc, Alnylam Pharmaceuticals/the Medicines Company), as evidenced by the study's interim results reported late last year. The ACC sessions will feature the study's primary outcomes.

Saturday March 18, 8:00-9:15 am: Joint ACC/JAMA LBCTs
  • The EINSTEIN CHOICE trial, the latest in the EINSTEIN series looking at the DOAC rivaroxaban (Xarelto, Bayer) for treatment or prevention of peripheral-vessel thrombosis, entered nearly 3400 patients managed with anticoagulation for 6 to 12 months after symptomatic deep-venous thrombosis (DVT) or pulmonary embolism (PE). They were then randomized to either 10-mg/day or 20-mg/day rivaroxaban vs aspirin 100 mg/day and were followed for a year for bleeding or recurrent thromboembolism.

  • The GEMINI-ACS-1 trial transposes a similar comparison to the post-ACS arena. It randomized >3000 patients to four parallel groups that compare not only rivaroxaban and aspirin but one accompanying P2Y12-inhibiting antiplatelet agent with another, clopidogrel vs ticagrelor (Brilinta/Brilique, AstraZeneca).

  • In the CARAT study, about 300 patients received 10 sequential infusions of CER-001 (Cerenis Therapeutics), a bioengineered HDL-mimicking agent designed to enhance reverse cholesterol transport. The novel agent showed mixed success in prior limited phase 2 studies in ACS and in patients with inherited dyslipidemias. CARAT's enrolled patients had ACS with significant coronary plaque volume by angiography.

  • Along with Albert Einstein and physicist-mathematician Jean-Baptiste Joseph Fourier, the memory-research pioneer Hermann Ebbinghaus has earned a role at the ACC sessions. The eponymous EBBINGHAUS trial explored the effects of evolocumab added to statins on cognitive function in a cohort of >1900 patients enrolled in the FOURIER trial. Amgen's top-line results announcement for the broader trial had also disclosed that evolocumab was noninferior to placebo for effects on cognition.

Saturday March 18, 10:45 am-12:00 pm: Interventional LBCTs
  • With advances in technology and technique, the question of complete vs culprit-vessel-only revascularization appears never to be answered clearly or for long. With an enrollment target of >800 patients with acute ST-segment-elevation MI (STEMI), COMPARE-ACUTE is a randomized comparison of FFR-guided complete revascularization vs ischemia-driven staged PCI.

  • Next on the schedule are two randomized comparisons of FFR-guided PCI vs interventions guided by a novel technique for evaluating coronary-lesion functional impact that doesn't require hyperemia-inducing adenosine infusions. The upstart in both the DEFINE-FLAIR (estimated enrollment, 2500 patients) and iFR-SWEDEHEART (with 2037 patients) is a measurement of translesional pressure by a proprietary algorithm for the instantaneous wave-free ratio (iFR), taken in a moment during diastole.

  • DECISION-CTO hopes to address a longstanding question on the strengths of a prospective, randomized trial and contemporary drug-eluting stents: how valuable is PCI recanalization on top of optimal meds in patients with chronic total occlusions? With an estimated enrollment approaching 1300, the trial started in 2010 and is slated to be completed for the primary composite clinical end point in 2023, so the presentation seems likely to include results at baseline or somewhat later in at least the earliest participants.

  • Will the 2-year outcomes report from ABSORB III, which pitted a bioresorbable scaffold (Absorb, Abbott Vascular) against a popular everolimus-eluting metal stent (Xience, Abbot Vascular) make the novel device look like more of a step forward than was seen in the trial's 1-year results? At that point, the Absorb's performance was noninferior (P=0.007) and showed no advantage in a superiority analysis (P=0.16) for the primary end point of target-lesion failure and was similar in secondary clinical and angiographic end points.

Saturday March 18, 12:30-1:45 pm: Featured Clinical Research 2
  • A Society of Thoracic Surgeons/ACC TVT Registry analysis will compare early and 1-year outcomes of patients undergoing TAVR for a failed bioprosthetic valve vs those getting standard TAVR.

  • RAD Matrix is a study ancillary to the randomized MATRIX comparisons of PCI access sites and anticoagulants in patients with ACS. In it, selected operators from the larger trial measured their radiation exposure during procedures. The primary end point of the analysis that compared radial-artery vs femoral-artery access is thoracic radiation absorbed dose, although exposure to wrists and eyes were also recorded.

Sunday March 19, 8:00–9:15 am: Joint ACC/NEJM LBCTs
  • LEVO-CTS is exploring whether a 24-hour infusion of the calcium-sensitizing agent levosimendan (Simdax, Orion) will improve outcomes in patients with depressed LV function who undergo cardiac surgery with cardiopulmonary bypass support. The agent, which has both vasodilator and inotropic properties, has shown mixed results in acute heart failure and septic shock in trials for more than a decade. The current trial's 30-day primary end points encompass mortality, need for a mechanical assist device, or perioperative MI.

  • The Neuroprotection in Patients Undergoing Aortic-Valve Replacement trial comparing two catheter-based embolic-protection devices during SAVR is following an estimated 535 patients for evidence of cerebral infarction within 10 days of surgery. The devices include the EMBOL-X (Edwards Life Sciences) and the Embolic Protection Cannula (CardioGard Medical).

  • The joint RESOLVE and SAVORY analysis of subclinical leaflet thrombosis looks at the possibly worrisome event in the ongoing registries, estimated ultimately to include 1000 and 75 patients, respectively, who underwent either TAVR or SAVR. Patients in the RESOLVE registry who show abnormalities of prosthetic-valve function by imaging are receiving warfarin.

  • A decade ago the massive VISION prospective cohort study started enrolling patients aged 45 or older undergoing noncardiac surgery and has been following them for 30-day vascular events, including MI and stroke. The current analysis will focus on the 30-day mortality prognostic impact of early troponin-T measurements using a high-sensitivity assay.

Sunday March 19, 10:45 am-12:00 pm: LBCTs
  • In the RE-CIRCUIT trial, close to 700 patients with paroxysmal or persistent atrial fibrillation slated for catheter ablation were randomized to an uninterrupted oral anticoagulation regimen with either the DOAC dabigatran (Pradaxa, Boehringer Ingelheim) at the 150-mg twice-daily dosage or warfarin. The primary end point is major bleeding during the procedure and out to 2 months.

  • The GIFT of Warfarin study has randomized 1598 patients already on warfarin therapy for DVT prophylaxis after hip or knee arthroplasty to one of four warfarin INR-targeting arms: dosing guided by pharmacogenetics to a target INR of 2.5 vs 1.8 and clinically guided dosing to a target INR of 2.5 vs 1.8. The former pharmacogenetic approach in patients relies on their presence and prevalence of the CYP2C9, VKORC1, and CYP4F2 variants in conjunction with clinical cues. The group is followed for primary end points that include death, nonfatal venous thromboembolism (VTE) or major hemorrhage, and INR>4.0.

Sunday March 19, 2:00-3:30 pm: Featured Clinical Research 3
  • With potential cognitive effects a contemporary concern for patients on statins and PCSK9 inhibitors, an analysis based on the STOMP trial, which once showed little adverse effect of atorvastatin on muscle strength or physical performance, will look at the drug's possible effects on neuron activity and cognition. The trial had randomized 420 primarily healthy statin-naïve patients aged 20 or older to atorvastatin 80 mg/day vs placebo and followed them for anthropometrics and with exercise-based tests at baseline and at 6 months.

  • A presentation based on the CVD-REAL study, an international cohort study of adults with type 2 diabetes and new prescriptions for a either a sodium-glucose cotransporter 2 (SGLT-2) inhibitor, such as empagliflozin (Jardiance, Lilly/Boehringer Ingelheim), or "other glucose-lowering drugs," is billed as showing "lower rates of hospitalization for heart failure" on the former vs the latter in >360,000 patients, using multivariate analyses. The study is in tune with a controversial new wave of thinking in cardiology that views some primarily antidiabetic drugs, such as SGLT inhibitors and glucagonlike peptide 1 (GLP-1) receptor agonists like liraglutide (Victoza, Novo Nordisk), as cardiovascular treatments.

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