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American College of Cardiology 2015
Nearly 14,000 health professionals (total attendance, 19,200) attended the 64th American College of Cardiology (ACC) Annual Scientific Session and Expo in San Diego from March 14 to 16, 2015. We review one key session on a new agent administered to lower cholesterol, and four other sessions on agents given in the milieu of acute coronary syndromes: cangrelor, bivalirudin, unfractionated heparin, ticagrelor, and Bendavia.
Effect of the PCSK9 Inhibitor Evolocumab on Cardiovascular Outcomes
Evolocumab’s robust 61% reduction of low-density lipoprotein-cholesterol (LDL-C) at 12 weeks plus significantly reduced cardiovascular outcomes in the OSLER 1 and 2 trials support the potential value of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition in patients with hypercholesterolemia, Dr. Sabatine said.
Evolocumab, a fully human monoclonal antibody against PCSK9, has demonstrated safety and large reductions in LDL-C in prior phase 2 and 3 studies. However, its impact on cardiovascular outcomes had previously remained undefined.
Because of questions about the safety and outcome effects of new agents capable of lowering LDL-C dramatically, current guidelines emphasize statin therapy rather than absolute LDL-C–lowering capacity, ACC discussant Eric Peterson, MD, commented at an ACC press conference. “I think this study is a start down the roads of actually trying to answer those two questions.”
Dr. Sabatine presented results from an extension of the OSLER trials including 4,465 patients (74% of the original cohort) who were randomized 2:1 to evolocumab plus standard of care (n = 2,976) or standard of care alone (n = 1,489). Patients in the evolocumab group received open-label, subcutaneous injections (140 mg every two weeks or 420 mg every month). Their mean age was 58 years; 51% were male.
In the parent OSLER trial, baseline LDL-C was 120 mg/dL. After 12 weeks of treatment, median LDL-C was reduced 61% compared with standard of care alone to 48 mg/dL (95% confidence interval [CI], 59–63%), a 73 mg/dL absolute reduction (95% CI, 71–86%). The reduction was maintained through 48 weeks. In the evolocumab group, 90.2% of patients met the goal of LDL-C lower than 100 mg/dL and 73.6% met the goal of LDL-C lower than 70 mg/dL, compared with 26.0 and 3.8%, respectively, in the standard-of-care alone group (P < 0.001).
At one year, the combined cardiovascular outcome rate (including death, myocardial infarction [MI], unstable angina leading to hospitalization, coronary revascularization, stroke, transient ischemic attack, or congestive heart failure hospitalization) was 2.18% for standard of care and 0.95% for evolocumab (hazard ratio [HR], 0.47; 95% CI, 0.28–0.78; P = 0.003), a 53% reduction. The evolocumab benefit was apparent across all components of the combined endpoint. Analysis of subgroups (age, sex, LDL-C levels, statin use, National Cholesterol Education Program class, known vascular disease) revealed no significant heterogeneity.
Overall adverse event rates were 69.2% for evolocumab and 64.8% for standard of care (P not specified). Neurocognitive deficits, however, were more common in the evolocumab group (0.9% versus 0.3%). An analysis of adverse events according to achieved LDL-C levels showed no correlations, including among patients with very low LDL-C (less than 25 mg/dL).
“These data support PCSK9 inhibition as a safe and effective means to reduce major adverse cardiovascular outcomes through particularly robust LDL cholesterol-lowering,” Dr. Sabatine concluded.
The FOURIER study, which will assess evolocumab versus placebo, will include 27,500 patients with cardiovascular disease and at least one other high-risk feature.
Cangrelor in Elderly Patients Undergoing PCI: Findings From CHAMPION-PHOENIX
Patients 75 years of age or older in the CHAMPION-PHOENIX trial benefited as much from cangrelor versus clopidogrel during percutaneous coronary interventions (PCIs) as the general population (N = 11,145). Patients at least 75 years of age (n = 2,101) were at higher risk in this trial, Dr. Cavender reported in a poster presentation, because they were more likely to be female, to weigh more than 60 kg, and to have experienced prior PCI/coronary artery bypass grafts (CABGs) or prior stroke. They were also more likely to undergo multivessel PCI.
Cangrelor is an intravenous adenosine diphosphate (ADP)-receptor antagonist. “Many of the PCI drugs, like clopidogrel or ticagrelor, are prodrugs and have to be metabolized, whereas cangrelor is an intravenous drug and is basically 100% bioavailable. Also, it is reversible, and within two hours of ending the infusion, platelets are restored to normal function. It is quick onset and quick offset—which is very appealing to an interventional cardiologist,” Dr. Cavender said in an interview.
In a double-blind study, CHAMPION-PHOENIX investigators randomized patients undergoing PCIs after the end of a two-hour infusion of cangrelor to either cangrelor followed by clopidogrel 600 mg or to 300 or 600 mg of clopidogrel.
In the overall population, the primary endpoint of combined death, MI, ischemia-driven revascularization, or stent thrombosis was reduced in the cangrelor group (odds ratio [OR], 0.78; 95% CI, 0.66–0.93). In patients 75 years of age or older, the benefit was directionally similar: 5.4% for cangrelor versus 7.4% for clopidogrel (OR, 0.72; 95% CI, 0.51–1.03) and just shy of statistically significant (P = 0.07). Among patients younger than 75 years old, the rates were 4.5% and 5.6%, respectively.
In patients younger than 75 years, GUSTO (Global Utilization of Streptokinase and tPA for Occluded Arteries) severe bleeding (non-CABG) was reported at a rate of 0.1% for cangrelor and 0.0002% for clopidogrel. In the older-than-75 population, rates were 0.3% and 0.5%, respectively (interaction P = 0.053).
With regard to either the primary efficacy endpoint (P = 0.55) or a net clinical endpoint that combined the primary safety and efficacy endpoints (P = 0.48), Dr. Cavender concluded that in CHAMPION-PHOENIX there was no evidence that age modified the effects of cangrelor. The essential message, Dr. Cavender said, “is that this is a drug that’s safe in the elderly.”
PEGASUS-TIMI 54 Prevention of CV Events in Patients With Prior Heart Attack Using Ticagrelor
Current PCI guidelines recommend adding a P2Y12 receptor antagonist to aspirin only for the first year after an acute coronary syndrome (ACS). Evidence from nearly three years of follow-up in the PEGASUS-TIMI 54 trial, however, showed that adding ticagrelor to low-dose aspirin reduced the long-term risk of cardiovascular death, MI, or stroke in stable patients with a history of MI. Ticagrelor did increase TIMI major bleeding, noted Dr. Sabatine, the lead investigator.
PEGASUS-TIMI 54 enrolled 21,162 patients at 1,144 sites in 31 countries, randomly assigning them 1:1:1 to a twice-daily regimen of ticagrelor at either 90 mg or 60 mg or matching placebo. The primary efficacy endpoint was combined cardiovascular death, MI, or stroke. TIMI major bleeding was the primary safety outcome. All patients had experienced an MI in the previous one to three years, and each had at least one more risk factor, such as advanced age or diabetes, for a second MI.
The PEGASUS-TIMI 54 hypothesis was that adding ticagrelor to standard therapy (including low-dose aspirin [75–150 mg per day]) would reduce major adverse cardiovascular events in this patient population during long-term follow-up.
The primary endpoint rates for ticagrelor 90 mg, ticagrelor 60 mg, and placebo after a median follow-up of 33 months were 7.8% (HR, 0.85; 95% CI, 0.75–0.96; P = 0.008), 7.8% (HR, 0.84; 95% CI, 0.74–0.95; P = 0.004), and 9.0%, respectively. The ticagrelor benefit was apparent across all endpoint components, including coronary death (ticagrelor 90 mg, 1.5% [HR, 0.73, P = 0.02]; ticagrelor 60 mg, 1.7% [HR, 0.80; P = 0.09]).
“We followed patients for an average of just under three years, and our event curves continue to spread out over time, suggesting that the benefit continues to accrue over time,” Dr. Sabatine noted.
TIMI bleeding rates were significantly higher (P < 0.001) in the ticagrelor groups, with TIMI major bleeding at 2.6% for ticagrelor 90 mg (HR, 2.69; 95% CI, 1.96–3.70) and 2.3% for ticagrelor 60 mg (HR, 2.32; 95% CI, 1.68–3.21) versus 1.1% for placebo. TIMI minor bleeding rates were 1.3%, 1.2%, and 0.4%, respectively. Differences in fatal bleeding and intracranial hemorrhage rates were not significant. Dyspnea was also more frequent for the ticagrelor groups (18.9% and 15.8% versus 6.4% for placebo, P < 0.001). Assignment to ticagrelor led more often (P < 0.001) to study-drug discontinuation (6.5% and 4.6% versus 0.8% for placebo).
Overall efficacy was about the same for the two ticagrelor doses, Dr. Sabatine said, but bleeding and other side effects tended to be less frequent with the 60-mg twice-daily dose. He concluded, “Long-term dual antiplatelet therapy with low-dose aspirin and ticagrelor should be considered in appropriate patients with myocardial infarction.”
The EMBRACE STEMI Study: A Phase 2a, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Safety, Tolerability and Efficacy of Intravenous Bendavia on Reperfusion Injury in Patients Treated With Standard Therapy Including Primary PCI and Stenting for ST-Segment Elevation Myocardial Infarction
Reperfusion injury may occur when blood flowing back into the ischemic myocardium after revascularization for MI stimulates inflammatory processes. In the EMBRACE trial, a drug designed to reduce reperfusion injury among patients undergoing angioplasty for MI failed to significantly reduce infarct size. Benefits among the subset of patients in EMBRACE who were hypertensive, however, were significant, according to Dr. Gibson’s presentation at an ACC press conference. Bendavia is a cell-permeable peptide that targets cardiolipin, a phospholipid found exclusively in the inner mitochondrial membrane. Also, Bendavia cuts inflammatory reactive oxygen species generation and positively affects the integrity, electron transport, and bioenergetics of mitochondria. In animal studies, Dr. Gibson said, it reduced infarct size by 10% to 40%.
In EMBRACE, investigators enrolled 297 patients with a first anterior ST-segment elevation myocardial infarction (STEMI) at 24 hospitals in Poland, Hungary, Germany, and the U.S. Half were randomized to placebo and half received intravenous Bendavia (0.05 mg/kg per hour) starting at least 15 minutes before the angioplasty procedure and lasting for 60 minutes afterward. The primary endpoint was area under the curve (AUC) for creatine kinase-MB (CK-MB) over the initial 72 hours post-procedure.
Patients meeting various exclusion criteria reduced the evaluable population to 118, which, Dr. Gibson said, was unfortunate and left the trial “grossly underpowered.” In this diminished group, there was a significant (P = 0.02) and consequential imbalance in the incidence of hypertension, which was found in 60% of patients in the placebo group and in 37.9% of patients in the Bendavia group. “Patients with hypertension,” Dr. Gibson explained, “have thicker hearts with more muscle at risk.”
Serum CK-MB at six hours was 266.6 ± 37.7 ng/mL for placebo and 217.4 ± 41.1 ng/mL for Bendavia with a geometric mean of CK-MB AUC (0–72 hours) of 5,785 ng•h/mL for placebo and 5,570 ng•h/mL for Bendavia. While the 10% to 20% reduction is in keeping with the animal studies, Dr. Gibson said, “to detect a difference we would have needed 800 to 1,000 patients.”
Cardiac MRI at three to five days and at 23 to 37 days post-PCI showed similar infarct volumes but trends toward reduced total left ventricular mass with Bendavia (P = 0.08 and P = 0.17, respectively). Noting that 75% of new-onset heart failure events occurred in the first 24 hours post-procedure, Dr. Gibson said that such events were reduced in the first eight hours with Bendavia (18.3% for placebo, 8.6% for Bendavia; P = 0.18). Analysis of the clinical composite endpoint (death, new-onset heart failure more than 24 hours post-procedure, heart failure rehospitalization) at one and six months also revealed no Bendavia benefit.
EMBRACE investigators conducted an unplanned exploratory analysis of hypertensive patients that revealed reduced infarct volume (P = 0.03) and reduced edema volume (P = 0.053) in patients receiving Bendavia. In a further exploratory analysis, Bendavia was associated with a significantly lower change in creatinine over the first 12 hours (1.0 versus 3.7 mcmol/L, P = 0.03). The agent was safe and well tolerated.
While Bendavia did not reduce the EMBRACE primary endpoint of infarct size by CK-MB AUC, the promising evidence with respect to heart failure and kidney injury led ACC discussant Eric Peterson, MD, to comment: “I think this drug is going to be an interesting one.”
Bivalirudin Infusion Compared to Unfractionated Heparin in Patients With Acute Coronary Syndromes Undergoing Invasive Management: Results From the Minimizing Adverse Hemorrhagic Events by Transradial Access Site And Systemic Implementation of Angiox Program
In the MATRIX trial (Minimizing Adverse Hemorrhagic Events by Transradial Access Site and Systemic Implementation of Angiox Program), the primary composite endpoints of 30-day major adverse coronary events (MACE) and net adverse coronary events (NACE) were similar for unfractionated heparin (UFH) and for bivalirudin in a largely unselected acute coronary syndrome (ACS) population. All-cause mortality and cardiovascular mortality, however, were lower in the bivalirudin group, according to Dr. Valgimigli. Patients in MATRIX were also allocated to either radial- or femoral-access PCIs; results for this aspect of randomization were presented separately.
UFH with and without glycoprotein IIb/IIIa inhibitors (GPIs) and bivalirudin with GPI use limited to bailout conditions are the most common antithrombotic regimens in current practice, Dr. Valgimigli said. Ischemic and bleeding outcomes have been inconsistent in prior studies comparing these options in ACS patients.
The MATRIX trial’s primary objective was to assess these two treatment strategies with respect to MACE (death, MI, and stroke) and NACE (death, MI, stroke, and major bleeding [Bleeding Academic Research Consortium (BARC) 3 or 5]) in a broadly inclusive ACS population. Investigators randomized about 3,600 patients to each treatment arm in 78 hospitals in four European countries. Patients’ mean age was approximately 65 years; approximately 76% were male.
Thirty-day MACE was reported at a rate of 10.9% in the UFH arm and 10.3% in the bivalirudin arm (relative risk [RR], 0.94; 95% CI, 0.81–1.10; P = 0.45). NACE rates were 12.4% for UFH and 11.2% for bivalirudin (RR, 0.89; 95% CI, 0.78–1.103; P = 0.122).
Offering a potential explanation for the nonsignificant findings, Dr. Valgimigli noted the high MI rates in both groups (8.6% for bivalirudin, 8.5% for UFH), and pointed out that while most of these were clinically harmless periprocedural events, they diluted the mortality and bleeding benefits in the endpoint calculation. Evaluated individually, the bivalirudin all-cause mortality rate of 1.7% compared with 2.3% for UFH was significantly lower (P = 0.042), as was the bivalirudin rate for cardiovascular death (1.6% versus 2.3%; P = 0.037). Stroke rates were comparable at 0.4% for bivalirudin and 0.5% for UFH (P = 0.57).
Similarly, BARC 3 or 5 bleeding was reduced with bivalirudin at 1.4% versus 2.5% for UFH (P = 0.001). Bleeding was reduced with bivalirudin across all scales, Dr. Valgimigli noted, including fatal events and non–access-site events. BARC 3 signifies bleeding that requires intervention. Stent thrombosis rates were low but higher in the bivalirudin group (1% versus 0.6%, P = 0.048).
“We have a 70% reduction in fatal bleeding with bivalirudin and corresponding reductions in cardiovascular mortality, as well,” commented David Kandzari, MD, Director of Interventional Cardiology and Chief Scientific Officer of Piedmont Heart Institute in Atlanta, Georgia, the ACC discussant at the press conference. “There was a higher stent thrombosis rate early with bivalirudin which did not translate to mortality differences. The significant reduction in bleeding for bivalirudin is consonant with earlier trials, but here the reduction of bleeding leading to an improvement in survival is particularly clear.” He called MATRIX “a high-impact trial.”
Sanjit Jolly, MD, of McMaster University in Ontario, Canada, was also on the ACC press conference panel. “MATRIX gives bivalirudin a second wind,” he said.