New lipid guidelines from the American Heart Association (AHA) and American College of Cardiology (ACC) released late last year were viewed as controversial by some clinicians, with many thinking the revised cardiovascular risk assessment and the lack of LDL targets would result in overprescribing of statins. New data suggest that these guidelines actually better match statin use to patients’ total plaque burden than previous guidelines, while only modestly increasing overall statin usage.
Meanwhile, at the 2014 European Society of Cardiology (ESC) Congress, positive lipid-lowering results were presented for alirocumab, an investigational monoclonal antibody with a novel mechanism of action. Post-hoc data from one trial even suggested a potential benefit for cardiovascular outcomes. According to its developers, Sanofi and Regeneron Pharmaceuticals, these data from the Phase III ODYSSEY trials have alirocumab on track for a regulatory submission by the end of this year.
A large retrospective study in the Journal of the American College of Cardiology, using coronary plaque burden as a marker of cardiac risk, found that the AHA/ACC new lipid guidelines more accurately assigned statin usage to the highest-risk patients compared with the 2001 National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines.
Kevin Johnson, MD, Associate Professor of Diagnostic Radiology at Yale University School of Medicine, and David Dowe, MD, Medical Director of Atlantic Medical Imaging, conducted a single-center, retrospective study to determine the accuracy of statin assignment using the 2013 AHA/ACC cholesterol guidelines compared with the 2001 NCEP ATP III guidelines in patients with features of coronary imaging known to have predictive value for cardiovascular events. A key difference between the two sets of guidelines is that while both select patients for statin therapy on the basis of an assessment of cardiovascular risk, the AHA/ACC new guidelines no longer apply LDL thresholds to guide therapy.
A total of 3,076 patients (65% male, mean age 56 y) underwent computed tomography (CT) angiography. The probability that each patient would be prescribed statin therapy was calculated using both the newer assessment of cardiovascular risk and the older ATP III recommendations. This probability was then matched to each patient’s actual burden of coronary atherosclerosis, as assessed by CT angiography.
The investigators reported that under the 2001 guidelines, 59% of patients with ≥50% stenosis of the left main coronary artery and 40% of patients with ≥50% stenosis of other branches would not have been treated. Under the new 2013 guidelines, however, these numbers decreased to only 19% and 10%, respectively. The investigators also reported that under the new guidelines, fewer patients with no plaque burden would be assigned to statin therapy compared with the ATP III (36% vs. 41%).
“Although many have expressed concerns that the new guidelines would result in excessive statin use, our data found that the proportion of patients assigned to statin therapy was only 15% higher under the new guidelines,” Johnson told Pharmacy Today. “However, the exact percentage will depend on the mixture of patients in the population under consideration.”
Johnson said the use of LDL targets seriously degraded the accuracy of the old guidelines to assign statins. “Generally speaking, the two sets of guidelines partition patients into risk groups in a similar manner, but the old method then applies LDL targets to decide who gets statin therapy,” Johnson told Today. “This substantially reduces the accuracy of statin assignment. This is not surprising in retrospect because the data also show a lack of correlation between plaque burden and LDL cholesterol. The AHA/ACC guidelines cite the lack of evidence for LDL targets from randomized controlled trials as a major reason for their abandonment.
When asked about the clinical implications of the data, Johnson highlighted a few key takeaway points from the study: “Our data show that a high proportion of patients with no plaque are still being prescribed statin therapy under both sets of guidelines. This is concerning, as long-term statin use is not without the potential for adverse events or increased costs. Both sets of guidelines calculate risks based on epidemiologic analyses, and the accuracy of these types of models to determine risks in individual patients is limited. The simple absence of calcification on coronary imaging may aid in determining if statin therapy is warranted in asymptomatic patients.”
He added that better methods are needed to identify low-risk patients who could safely forgo statin therapy, because once patients are on statins, they are generally on them for life. “If you are willing to consider coronary plaque burden as a surrogate for risk, then our data clearly show that the new guidelines assign statins to patients more accurately than the old ones,” he concluded.
Four studies presented at ESC, which evaluated the novel lipid-lowering agent alirocumab, found the drug to result in dramatic reductions in LDL cholesterol among patients on maximally tolerated doses of statins and/or ezetimibe (Vytorin—Merck). Alirocumab is a monoclonal antibody that is dosed once every 2 weeks (75 mg or 150 mg) and self-injected by patients. It targets PCSK9 (proprotein convertase subtillisin/kexin type 9) and blocks the binding of PCSK9 to the LDL receptor, thereby interrupting the resultant internalization and degradation of the LDL receptor. The four studies, known as the ODYSSEY trials, are part of a large Phase III program encompassing more than 5,000 patients studied in double-blind trials for durations lasting from 24 to 104 weeks.
ODYSSEY LONG TERM. This ongoing double-blind trial with 2,341 patients evaluated the long-term safety and efficacy of alirocumab, given as 150 mg once every 2 weeks, versus placebo in combination with maximally tolerated lipid-lowering therapy, including statins, in patients with hypercholesterolemia who were at high cardiovascular risk. Data from a prespecified analysis conducted when all patients reached 1 year were presented at ESC and showed dramatic LDL reductions. At 24 weeks, a 61% reduction from baseline in LDL levels was observed in the alirocumab group compared with a 1% increase in the placebo group (P < 0.0001). The results were maintained through 1 year, with a 57% reduction from baseline in LDL levels observed in the alirocumab group compared with a 4% increase in the placebo group (P < 0.0001). The safety profile of alirocumab showed the most common adverse reactions to be nasopharyngitis, upper respiratory tract infection, and injection site reactions.
A post-hoc analysis from this trial caught the attention of many. In the alirocumab group (1.4%), results suggested a lower rate of adjudicated major cardiovascular events, defined as cardiac death, myocardial infarction, stroke, and unstable angina requiring hospitalization compared with the placebo group (3%). This potential benefit on cardiac outcomes is currently being assessed as part of the ongoing 18,000-patient ODYSSEY OUTCOMES trial.
ODYSSEY COMBO II. This 720-patient, double-blind trial evaluated the long-term safety and efficacy of alirocumab versus ezetimibe in combination with a maximally tolerated statin dose in patients with hypercholesterolemia at high cardiovascular risk. Alirocumab was given as an initial dose of 75 mg once every 2 weeks, increasing to 150 mg if needed to reach prespecified LDL levels. At 24 weeks, a 51% reduction from baseline in LDL levels was observed in the alirocumab group compared with a 21% reduction in the ezetimibe group (P < 0.0001). As with ODYSSEY LONG TERM, the results were maintained through 1 year, with a 52% reduction from baseline in LDL levels observed in the alirocumab group compared with a 21% reduction in the ezetimibe group (P < 0.0001). Upper respiratory tract infection, accidental overdose, dizziness, and myalgia were the most common adverse events reported in this trial.
ODYSSEY FH I and FH II. These trials involved a total of 738 patients with heterozygous familial hypercholesterolemia and compared alirocumab with placebo in combination with maximally tolerated lipid-lowering therapy, including statins. The dosing of alirocumab was similar to that of the ODYSSEY COMBO II trial. Again, results observed in this trial were consistent with the two presented above, with LDL reductions at 24 weeks being 49% in the alirocumab group compared with a 3% to 9% increase in the placebo group. “Across these four trials, alirocumab showed significant and sustained reductions in LDL cholesterol over 1 year on top of standard-of-care statin therapy across different patient types,” said Jennifer Robinson, MD, MPH, Professor in the Departments of Epidemiology and Medicine at the University of Iowa College of Public Health, in a news release on Sanofi’s website. “We are also encouraged by the consistent safety profile across the trials, including in ODYSSEY LONG TERM, the largest [Phase III] trial of a PCSK9 inhibitor, with the longest follow-up period reported to date.”
Recent data suggest that the new AHA/ACC guidelines may better match statin use to patients who are at higher risk for cardiovascular events and that a novel self-injected lipid-lowering agent dosed once every 2 weeks may be a future treatment option for patients with elevated LDL levels despite maximal doses of other drugs. Appropriate lipid management in patients at risk for cardiovascular events can have a substantial impact on improving cardiovascular morbidity and mortality.