CardioSource WorldNews - Page 19

GLAGOV 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, 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 tota l atheroma volume (TABLE). GLAGOV Trial Results Statin Monotherapy Statin + Evolocumab p Value Change in percent atheroma volume (PAV) (1°) 0.5% -0.95% <0.0001 Change in total atheroma volume (2°) -0.9 -5.8 <0.0001 Percent of patients showing regression in PAV 47.3% 64.3% <0.001 Percent of patients showing progression in PAV 52.7% 35.7% <0.001 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] ORION-1 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 inclisirantreated 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.” PIONEER-AF PCI 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, 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. Marijuana use may be linked to temporarily weakened heart muscle Active marijuana use seems to double the risk of stress cardiomyopathy that can mimic MI symptoms. In an analysis of 33,343 patients hospitalized with stress cardiomyopathy in the U.S., 210 were also identified as marijuana users. Despite being younger and with fewer classic risk factors than non-users, during stress cardiomyopathy the marijuana users were significantly more likely to go into cardiac arrest (2.4% vs. 0.8%) and to require an implantable defibrillator (2.4% vs. 0.6%). Sahil Agrawal, MD, co-author of the paper and chief cardiology fellow at St. Luke’s University Health Network in Bethlehem, PA: “This development of stress cardiomyopathy in younger patients who used marijuana suggests a possible link that needs to be further investigated.” CardioSource WorldNews COVER UPDATE 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 mode rate 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.” 17