Recent publications on Residual Risk

Presentation of top-line results from ODYSSEY Outcomes, showed that treatment with the PCSK9 inhibitor alirocumab improved major adverse cardiovascular events and also had a benefit on all-cause mortality in patients with a recent acute coronary syndrome (ACS). ODYSSEY Outcomes randomized 18,924 ACS patients (median age 58 years, 25% female, 19% with a prior myocardial infarction (MI), 29% with diabetes, mean baseline low-density lipoprotein cholesterol [LDL-C] 87 mg/dl); 9,462 patients each received alirocumab or placebo. The majority of patients (89%) were on intensive statin therapy at entry to the study. The primary study endpoint of major adverse cardiovascular events (MACE) was a composite of first coronary heart disease (CHD) death, nonfatal MI, ischaemic stroke or unstable angina requiring hospitalization.
 
After a median follow-up of 2.8 years, treatment with alirocumab substantially lowered LDL-C levels and this was associated with a significant 15% relative reduction in the primary endpoint (hazard ratio 0.85, 95% CI 0.78-0.93, p=0.0003). There were also significant beneficial effects on secondary outcomes including a 15% reduction in all-cause death. A post hoc analysis showed that patients with higher LDL-C levels at baseline derived greater clinical benefit from alirocumab treatment. Importantly, the study also provided reassuring safety data for this therapeutic strategy.
 
Full publication of the results is still awaited; the study will be discussed as a Landmark Trial when published.
 
For the presentation slides: https://accscientificsession.acc.org/features/2018/03/video-sanofi-regeneron
 
CANTOS: canakinumab did not affect rates of incident diabetes in people with prediabetes
 
This pre-specified analysis follows the primary CANTOS (Canakinumab Antiinflammatory Thrombosis Outcome Study) publication last year.1 The investigators hypothesized that since type 2 diabetes mellitus is thought to be related to inflammatory processes, treatment with canakinumab may slow or prevent the progression from prediabetes to diabetes.
 
This analysis2 focused on 4,960 patients with prediabetes at the start of the study. Despite large reductions in high-sensitivity C-reactive protein (hsCRP) and interleukin-6, canakinumab did not reduce the incidence of new onset diabetes over a median period of 3.7 years (rates per 100-person years in the placebo, 50mg, 150mg, and 300mg canakinumab groups were 4.2, 4.2, 4.4, and 4.1, respectively). The hazard ratio for incident diabetes comparing all canakinumab doses to placebo was 1.02 (95% CI 0.87-1.19, p=0.82). While canakinumab reduced HbA1c during the first 6-9 months of treatment there was no consistent long-term benefits on HbA1c or fasting plasma glucose. While there was no effect on diabetes progression, patients with prediabetes derived the same benefits from canakinumab in terms of cardiovascular outcomes.
 
ANCHOR: Icosapent ethyl in patients with elevated triglycerides and inflammatory markers
 
The 12-week ANCHOR study randomized 702 statin-treated patients at increased cardiovascular risk with triglycerides (TGs) 200-499 mg/dL despite statin treatment. This post hoc subanalysis3 of the ANCHOR Study focused on 246 patients with elevated TGs and hsCRP ?2.0 mg/L; 126 were allocated to icosapent ethyl 4 g/day and 120 to placebo.
 
Treatment with icosapent ethyl 4 g/day to statin therapy significantly reduced TGs by 20% without increasing levels of low-density lipoprotein cholesterol (LDL-C). Notably, there was also an 18% reduction of hsCRP versus placebo over 12 weeks (p=0.02).
 
Real-World Data: elevated triglycerides increase cardiovascular risk and healthcare costs
 
This retrospective, longitudinal administrative claims analysis4 evaluated data from the Optum Research Database which included patients aged ?45 years with diabetes and/or atherosclerotic cardiovascular disease who had a statin prescription filled in 2010, continuous medical/pharmacy coverage, and had data from 6 months pre-index and ?6 months from index date (or less if due to death) up to March 2016. The analysis focused on patients with TGs ?150 mg/dL (median 197 mg/dl, n=23,181) and a propensity-matched comparator cohort (median TGs 98 mg/dl). Patients with elevated TGs had a 26% (95% CI 16-34%) increase in risk for major adverse cardiovascular events (p<0.001). This increase in risk was driven by a 32% (95% CI 1.20-1.45) increase in risk of non-fatal MI (p<0.001) and a 46% (95% CI 1.33-1.61) increase in risk of coronary revascularization (p<0.001). From the payer’s perspective, this increased cardiovascular risk associated with elevated TGs led to a 12% higher average total healthcare cost (95% CI 1.08-1.16), as well as 13% higher rate of occurrence of initial inpatient hospital stay (95% CI 1.10-1.17).
 
References
 
1. Ridker PM, Everett BM, Thuren T et al. Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease. N Engl J Med 2017;377:1119-1131.
2. Everett BM, Donath MY, Pradhan AD et al. Anti-Inflammatory Therapy with Canakinumab for the Prevention and Management of Diabetes. J Am Coll Cardiol 2018; doi: 10.1016/j.jacc.2018.03.002. [Epub ahead of print]
3. Miller M, Ballantyne CM, Bays HE et al. Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) Reduces Potentially Atherogenic Lipid, Lipoprotein, Apolipoprotein, and Inflammatory Parameters in High-Risk, Statin-Treated Patients With Persistent Elevated Triglycerides and High-Sensitivity C-reactive Protein: A Post hoc Subanalysis of the ANCHOR Study,” Poster presentation. 1287-251. http://www.abstractsonline.com/pp8/#!/4496/presentation/38983
4. Toth P, Granowitz C, Hull M et al. Triglycerides ? 150 mg/dL Associated With Greater Risk of Cardiovascular Events, Costs, and Resource Utilization in High-Risk Statin-Treated Patients With Controlled Low-Density Lipoprotein Cholesterol: A Real-World Analysis. Poster presentation. 1290-303. http://www.abstractsonline.com/pp8/#!/4496/presentation/39282