Combining multiple novel therapies for secondary prevention
The combination of icosapent ethyl, ezetimibe and rivaroxaban may lower risk for CV death, MI and stroke well beyond the treatment effect of secondary prevention with background medical therapy for atherosclerotic CVD, a speaker reported.

Thirty percent to 40% of patients with prior myocardial infarction were eligible for three additional drug classes, beyond statins, in a study published in JAMA Cardiology. In addition, these patients who are eligible for multiple simultaneous novel therapies were at higher risk of recurrent cardiovascular events compared with those who were not. Icosapent ethyl, ezetimibe and rivaroxaban are three novel therapies that have been studied in high-quality randomized controlled trials. So, the question becomes should patients with ASCVD be treated with combination therapy, similar to our patients with heart failure with reduced ejection fraction.”

Researchers analyzed outcomes data from the IMPROVE-IT, COMPASS and REDUCE-IT randomized controlled trials to determine the cumulative treatment effect of a comprehensive secondary prevention strategy of ezetimibe 10 mg daily, rivaroxaban 2.5 mg (Xarelto, Janssen/Bayer) twice daily and icosapent ethyl 2 g (Vascepa, Amarin) twice daily in addition to background aspirin and statin therapy. All trials were assessed for the composite endpoint of CV death, nonfatal MI, nonfatal stroke and each component of the composite individually.

According to the presentation, it is unlikely that patients with ASCVD will be on multiple drugs that target similar therapeutic pathways, such as ticagrelor and rivaroxaban. Therefore, these specific therapies were chosen because they each target different biological pathways and had previously undergone rigorous study.

The researchers reported a larger aggregate risk reduction for the composite endpoint with the comprehensive treatment strategy compared with background aspirin and statin therapy alone.

The aggregate risk reduction for each component of the composite endpoint were estimated as follows:

-- 38% reduced risk for CV death (HR = 0.62; 95% CI, 0.46-0.84);
-- 48% reduced risk for nonfatal MI (HR = 0.52; 95% CI, 0.4-0.69); and
-- 65% reduced risk for nonfatal stroke (HR = 0.35; 95% CI, 0.23-0.54).

“There are several limitations to this work,” they said. “First, it is uncertain that the total treatment effect of multiple medications would be additive. Second, the analysis does not address potential safety issues related to combination therapy. Finally, these medications do have significant costs to the patients, which may be a barrier for adoption.”

For a sensitivity analysis, researchers substituted ezetimibe with alirocumab, utilizing data from the ODYSSEY Outcomes trial, and observed similar results.

“The combination of these three novel therapies may be able to reduce CV death, MI and stroke rates by approximately 50% beyond the treatment effect of background medical therapy,” researchers said. “Although these results are exploratory, they demonstrate a significant opportunity to improve secondary prevention of ASCVD. In addition, they may encourage greater utilization these contemporary combination medical therapies. Future clinical studies, however, are required to assess the outcomes of combination therapy in ASCVD.”