Cover Story: The Big Bold Easy | By Debra L. Beck and Rick McGuire

CardioSource WorldNews | After a European meeting with few bold headlines, a return to big - and often positiive - news stories at the 2016 American Heart Association Scientific Sessions in New Orleans.

Doubling Down on Cholesterol Lowering

Now that there are two powerful means of targeting cholesterol, maybe doubling down makes sense (even if economically rough). Adding the PCSK9 inhibitor evolocumab to statin therapy produced more regression of plaque atheroma volume and induced unprecedented plaque regression in a greater percentage of patients than statin therapy alone.

“We did not regress everybody with a statin plus evolocumab but we were able to regress about two-thirds of the patients and we’ve never seen levels of regression of this magnitude in any previously conducted study,” said Steven Nissen, MD, MACC, from the Cleveland Clinic, Ohio.

GLAGOV enrolled 968 patients presenting for coronary angiography, 846 of whom had evaluable intravascular ultrasound (IVUS) imaging at follow-up. Those with angiographic disease (20% to 50% stenosis in a target coronary vessel) were randomly assigned to monthly evolocumab 420 mg subcutaneously or matching placebo injection for 18 months, in addition to a stable, optimized statin dose. The trial was conducted at 197 hospitals on 7 continents.

Mean baseline low-density lipoprotein-cholesterol (LDL-C) was 92.5 mg/dl. After 18 months of treatment, mean achieved LDL-C in the statin plus evolocumab arm was 36.6 mg/dl (-59.8% from baseline) compared to 93.0 mg/dl for statin monotherapy (-3.9% from baseline; p < 0.001).

Almost all patients (99%) were on statins at baseline and about 58% were taking high doses. Nevertheless, compared to placebo, the addition of evolocumab was associated with plaque regression in a greater percentage of patients for both percent atheroma volume and total atheroma volume.

For the primary efficacy measure – the nominal change in PAV through week 78 measured by serial IVUS imaging – there was a significant difference (Table) and – according to previous evidence – likely a meaningful difference. At an AHA press conference, the study’s co-author, Steven J. Nichols, MD, PhD, from the South Australian Health & Medical Research Institute, explained that his research has shown that a 0.5% reduction in PAV is associated with a meaningful reduction in cardiovascular events. So, the 1% reduction in PAV seen in GLAGOV would be expected to translate into clinical benefit, although he stressed that the critical determination of risk and benefit will come from the large outcomes trials underway.

In a post hoc analysis in 144 patients with baseline LDL-C <70 mg/dl, evolocumab add-on treatment was associated with a favorable effect on change in PAV and regression of PAV (p < 0.001 for both), a benefit seen at LDL-C levels as low as 20 mg/dl.

In the paper, published simultaneously, the authors noted: “This is the first clinical trial, to our knowledge, to show incremental effects on regression in patients who had been treated with moderate or intensive statin therapy prior to entry into the study. It is also the first to our knowledge to demonstrate a reduction in atherosclerotic disease progression by IVUS for a nonstatin LDL-C-lowering therapy.”

Nicholls SJ et al. Effect of evolocumab on progression of coronary disease in statin-treated patients. The GLAGOV randomized clinical trial. JAMA 2016 Nov 15. [Epub ahead of print]

Hunting for Another Knockout Drug for LDL

The PCSK9 inhibitors are barely out the door, and there’s already something new that’s come knocking. Inclisiran (ALN-PCSsc) is a long-acting, subcutaneously delivered, synthetic small interfering ribonucleic acid (RNA) molecule that inhibits the production of PCSK9, halting PCSK9 protein synthesis in the liver.

“Targeting intracellular PCSK9 production with inclisiran offers us the potential for bi or tri-annual dosing to significantly reduce LDL cholesterol levels,” Kausik Ray, MD, from the Imperial College London, London, told attending journalists. That’s right: the potential is for maybe twice yearly dosing.

The phase II ORION-1 trial tested inclisiran in 501 patients with atherosclerotic cardiovascular disease (ASCVD) or high ASCVD risk and elevated LDL-C – >70mg/dl with ASCVD or >100mg/dl if at high risk – despite maximally-tolerated statin therapy. About two-thirds of patients had familial hypercholesterolemia and 81% were taking statins at baseline.

Participants were randomly assigned to 1 of 6 doses of inclirisan or matching placebo.

At a 90-day interim analysis, no between-group differences were seen in treatment-related adverse events. Injection site reactions were seen in 3.2% of inclisiran-treated patients.

All doses of inclirisan reduced LDL-C compared to placebo, with a maximal reduction seen at 15 days and sustained to about 90 days.

“A single dose of inclisiran reduced LDL cholesterol by up to 50% at 60 days and maintained levels through to 90 days while a second dose reduced LDL by about 57% at day 180,” said Dr. Ray.

During a press conference, Borge G. Nordestgaard, MD, (University of Copenhagen, Norway) commented on the trial: “Inhibition of PCSK9 synthesis via RNA interference with 50% to 60% reductions in LDL cholesterol over 3 to 6 months with only 2 to 3 injections a year looks really, really encouraging.”

NOACs Plus DAPT for Triple Therapy

Among patients with atrial fibrillation (AF) undergoing primary percutaneous coronary intervention (PCI), rivaroxaban combined with either a thienopyridine or dual antiplatelet therapy (DAPT) does not increase bleeding as compared with triple therapy including the vitamin K antagonist (VKA) warfarin, according to the long-awaited findings of the PIONEER-AF PCI study.

“You only have to treat 11 to 12 people to prevent a clinically significant bleed by using one of these alternate regimens with rivaroxaban and you only need to treat 10 to 15 people to prevent 1 hospitalization,” reported C. Michael Gibson, MD, FACC, Beth Israel Deaconess Medical Center, Boston, MA.

Between 5% and 8% of patients who undergo PCI have AF. For them, the optimal combination and duration of anticoagulation therapy remain uncertain.

In the open-label PIONEER AF-PCI trial, 2,124 patients with AF who had undergone PCI with stenting were randomized to 1 of 3 arms:

  • Group 1: Rivaroxaban 15 mg once daily plus a P2Y12 inhibitor for 12 months
  • Group 2: Rivaroxaban 2.5 mg twice daily plus a P2Y12 inhibitor and aspirin for 1, 6, or 12 months; patients continued on rivaroxaban 15 mg once daily plus aspirin after DAPT discontinuation
  • Group 3: Dose-adjusted warfarin plus DAPT with a P2Y12 inhibitor and aspirin for 1, 6, or 12 months; patients continued on warfarin and aspirin after DAPT discontinuation

The P2Y12 inhibitor prescribed to subjects in all 3 groups was primarily clopidogrel, but was ticagrelor or prasugrel in ≤15% of patients.

Patients in groups 1 or 2 had significantly lower rates of clinically significant bleeding compared to group 3, but similar rates of cardiovascular death, myocardial infarction, and stroke, although the confidence intervals were broad in the case of stroke.

The composite of all-cause mortality or recurrent hospitalization was significantly lower for both rivaroxaban arms compared to triple therapy (hazard ratio [HR]: 0.79; p = 0.008 for group 1 vs. group 3 and HR: 0.75; p = 0.002 for group 2 vs. group 3).

In an editorial commenting on the trial, Deepak Bhatt, MD, MPH, FACC, (Brigham and Women’s Hospital, Harvard Medical School, Boston, MA), suggested it may be time to “abandon the strategy of full-dose triple therapy.” And while this trial was not powered for efficacy, ongoing trials such as AUGUSTUS and RE-DUAL PCI will further clarify that point.

Wrote Dr. Bhatt: “For the time being, in patients not in clinical trials, full-dose oral triple therapy with dual antiplatelet agents and full dose anticoagulation should be avoided as a routine practice.” Circulation 2016 Nov 14. [Epub ahead of print]

“This study provides an important and robust contribution to the evidence base in this area and given that we have had nothing in this area to date, this piece of evidence may very well change practice,” said Philippe Gabriel Steg, MD, FACC, (Hôpital Bichat, Paris, France).

Looking for Solid Iron Evidence

Symptomatic patients with heart failure (HF) and iron deficiency had significantly improved peak Vo2 at 24 weeks after treatment with intravenous (IV) ferric carboxymaltose, compared to those who received standard care, at least according to the EFFECT-HF trial. On the other hand, IRONOUT HF, a randomized, double-blind study, showed that high-dose oral iron had little effect in replacing iron stores and did not improve peak exercise capacity in anemic heart failure patients with reduced left ventricular ejection fraction.

Iron deficiency is seen in about half of patients with chronic heart failure with reduced ejection fraction (HFrEF). It is associated with impaired functional capacity, poor quality of life, and increased morbidity and mortality, irrespective of the presence of anemia.

In the open-label EFFECT-HF trial, 174 patients with stable HFrEF with reduced exercise capacity and iron deficiency received either IV injections of ferric carboxymaltose on day 0, week 6, and week 12 (mean treatment dose: 1,204 mg) or usual optimal care for 24 weeks.

Peak Vo2 was significantly improved compared with usual care at 24 weeks (mean difference: 1.32 ml/kg/min in the per protocol analysis; p = 0.01 for between-group difference). This benefit was seen both in patients with and without baseline anemia.

“Serum ferritin levels were 60 at baseline but went up to almost 300 in the active group whereas they were hardly changed in the control group so we had very pronounced effects from IV iron administration over 24 weeks,” reported Dirk J. Van Veldhuisen, MD, University Medical Center, Groningen, The Netherlands, at an AHA press conference.

Those who received ferric carboxymaltose injections also had significantly improved New York Heart Association (NYHA) class and self-reported patient global assessment scores. Ferric carboxymaltose was well tolerated in this patient population.

Of course, regular administration of IV iron poses logistical challenges and is expensive. The utility of inexpensive, readily available oral iron supplementation in HF was unknown, until a team of Duke investigators reported that after 16 weeks of oral iron supplementation, they saw no change in peak Vo2, 6-minute walk distance, or ventilator efficiency in patients with HFrEF and iron deficiency in the IRONOUT-HF study.

“High-dose oral iron minimally repleted iron stores and did not improve peak Vo2 in patients with iron deficiency and heart failure with reduced ejection fraction, so results do not support oral iron supplementation in this patient population,” said Gregory Lewis, MD, from the Massachusetts General Hospital, Boston, MA.

Dr. Lewis noted that IV iron is expensive and complicated to provide to patients, increasing the appeal of oral supplementation, should it be found effective and safe.

The multicenter IRONOUT HF study randomly assigned 225 patients with NYHA class II-IV HFrEF and iron deficiency to daily oral iron polysaccharide or matching placebo.

Iron stores were only modestly repleted following treatment.

“It’s very simple. Oral iron does not work in patients with chronic heart failure—that is the take-home message,” said Stefan Anker, MD, PhD, Humboldt-University, Berlin, Germany, the scheduled discussant on the study.

The IRONOUT-HF investigators, however, could offer key mechanistic insight into the refractoriness of HF patients to the commonly used strategy of oral iron supplementation. They found that hepcidin levels were predictive of responsiveness to oral iron.

“Those that had higher hepcidin levels were completely refractory to increases in transferase saturation, for example,” said Dr. Lewis.

Hepcidin is a peptide hormone produced primarily by the liver. It regulates systemic iron metabolism by interacting with its receptor, ferroportin, and degrading it.

According to Adrian F. Hernandez, MD, MHS, Duke Clinical Research Institute Faculty Associate Director and Professor of Medicine, “Our study found that oral iron supplementation had its limitations. Additional studies will be needed, in a larger population, to determine whether a different oral formulation might be effective, or whether IV iron is needed to improve anemia and the ability of these patients to exercise.”

Victory Lap for REDUCE LAP-HF?

The implantation of a novel transcatheter interatrial shunt device appears to be safe and offers meaningful clinical and hemodynamic benefits in patients with heart failure with preserved ejection fraction (HFpEF), according to the REDUCE LAP-HF trial.

“At 1 year, we were pleased to see an excellent safety profile and no device-related complications requiring removal, and we also showed maintenance of improved symptomatic status as demonstrated on several efficacy measures,” reported principal investigator David Kaye, MD, PhD, FACC, from Alfred Hospital, Melbourne, Australia.

“Randomized trials are required and ongoing to determine the value of this novel strategy for the management of heart failure with preserved ejection fraction,” he added.

Almost all patients with HFpEF have elevated left atrial pressure (LAP), particularly during exercise. Preliminary studies show that the interatrial shunt device (IASD) made by Corvia Medical might reduce LAP and high pulmonary capillary wedge pressure (PCWP), reducing symptoms and improving functional capacity, quality of life, and, possibly long-term clinical outcomes.

The stent-like IASD is deployed into a small hole made in the atrial septum and allows the left atrium to decompress at rest and during physical activity.

The open-label REDUCE LAP-HF trial tested the IASD in 64 patients with NYHA class II to IV HF, LVEF ≥ 40%, and elevated PCWP (≥ 15 mm Hg at rest or ≥ 25 mm Hg during supine bicycle exercise).

Previously reported 6-month outcomes showed good initial safety and an indication of efficacy, with 52% of patients having a reduction in PCWP at rest, 58% a reducing during exertion, and 39% showing both. Mean exercise PCWP was lower at 6 months than at baseline, even though mean exercise duration was increased (p = 0.03).

Building on these promising 6-month findings, the 12-month data showed sustained clinical efficacy. At 1-year post-procedure, median NYHA class had improved from III to II (p < 0.001), and there was a 15-point improvement seen in the Minnesota Living with Heart Failure score (p < 0.001). Additionally, the 30-meter improvement in 6-minute walk distance seen at 6 months was increased to 33 meters at 1 year.

Echocardiography showed no change in ejection fraction, but a small decrease in the left ventricular end-diastolic volume index (p < 0.001) and a small increase in the right ventricular end-diastolic volume index (p < 0.001). Invasive hemodynamic studies demonstrated a sustained reduction in the workload indexed PCWP (p < 0.01).

At 1 year, there were 3 deaths (4.7%) and one fatal stroke (1.5%), with sustained evidence of left-to-right shunt flow in all patients, and no device-related complications. Device patency was confirmed by echocardiography or oximetry in 54 subjects.

“This is an important trial because no pharmacological trial to date has demonstrated any significant reduction in mortality in this disease,” said the scheduled discussant Nancy K. Sweitzer, MD, PhD, FACC, University of Arizona, Tucson. If benefits are confirmed in larger randomized trials, the IASD could have “an enormous impact” on the treatment of HFpEF, she said.

One hurdle: confirm that the improvements seen are not a placebo effect. “Anyone enrolled in a heart failure trial tends to get better,” she noted.

In March 2016, Corvia Medical received an investigational device exemption approval from the U.S. Food and Drug Administration for a multicenter study of the IASD. In May they gained CE Mark approval.

Kaye DM, et al. Circ Heart Fail 2016 Nov 16. [Epub ahead of print]

HeartMate LVAD Maintains MOMENTUM

In a multicenter head-to-head comparison of the HeartMate II and the HeartMate 3 (and yes, they have mixed Roman and English numerals), the newest left ventricular assist device (LVAD) system performed well, reducing clotting-related complications and improving patient outcomes. Results from MOMENTUM 3 demonstrated that patients receiving the HeartMate 3 had an 86.2% survival rate with freedom from disabling stroke and reoperation to repair or replace the device.

“This trial showed marked improvement in outcomes that were driven by a reduction in a need for reoperation for pump malfunction or replacement of the HeartMate 3 pump compared to the currently available HeartMate 2 device,” reported Mandeep R. Mehra, MD, FACC, from Brigham and Women’s Hospital, Boston, MA.

The HeartMate II (HMII) is a mechanical bearing axial continuous-flow pump and still the only device approved in the U.S. for both bridge-to-transplant (BTT) and destination therapy (DT) patients. Its use, however, has been limited by reports of major bleeding complications, along with issues of pump malfunction, principally due to pump thrombosis.

The investigational HeartMate 3 (HM3) is a continuous-flow, fully magnetically levitated (often referred to as “maglev”) blood pump designed with wide blood flow passages to reduce shear stress. The device is also frictionless due to the absence of mechanical bearings, and its fully magnetically levitated centrifugal flow incorporates rapid changes in rotor speed to create an artificial pulse.

The MOMENTUM 3 trial enrolled patients with New York Heart Association class IIIB and IV heart failure who were candidates for LVAD implantation, either as BTT or DT. A total of 294 patients were randomly assigned to receive either an HMII or HM3 LVAS.

At an AHA press conference, Dr. Mehra reported interim, pre-specified 6-month findings, which were simultaneously published in the New England Journal of Medicine (Mehra MR, et al. A fully magnetically levitated circulatory pump for advanced heart failure. New Engl J Med. 2016 Nov 16. [Epub ahead of print])

Survival at 6 months free of disabling stroke or reoperation to replace or remove the pump other than for myocardial recovery did not differ between the HeartMate 3 and the HeartMate II (86% for HM3 and 77% for HMII; absolute difference, 9.4% favoring HM3; superiority analysis: hazard ratio, 0.55; p = 0.037).

Reoperations were required in 1% of HM3 recipient, compared with 18% of HMII recipients (p = 0.002). There were no reports of suspected or confirmed pump thrombosis in the HM3 recipients, compared to 10% (14 events) in the HMII recipients (p < 0.0001).

There were no differences in rates of death at 180 days or disabling stroke, nor in rates of gastrointestinal bleeding, or hemorrhagic, ischemic, or all-type stroke.

“We saw similar functional improvement in quality of life in patients treated with either the HeartMate 2 or the HeartMate 3 pump with no difference whatsoever in other adverse effects,” said Dr. Mehra.

MOMENTUM 3 will enroll a total of 1,028 patients and follow them for 2 years. The HeartMate 3 is CE Mark approved and limited to investigational use in the United States.

Read the full December issue of CardioSource WorldNews at

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Acute Heart Failure

Keywords: CardioSource WorldNews, American Heart Association, Antibodies, Monoclonal, Atrial Fibrillation, Cholesterol, Double-Blind Method, Ferric Compounds, Heart Failure, Hemorrhage, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Iron, Liver, Percutaneous Coronary Intervention, Plaque, Atherosclerotic, Stroke Volume

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