Several observational studies have selleck chemicals suggested an associ ation between hemorrhagic stroke and low serum chol esterol. Consistent with this, the Cholesterol Treatment Trialists meta analysis found an excess of hemorrhagic stroke in the meta analysis of more versus less intensive statin regimes, though the excess risk was 50 times less than the beneficial effect on occlusive stroke. No association was found between intensive sta tin therapy and cancer risk. Nonetheless, since data from patients achieving very low levels of LDL C are sparse, additional monitoring by the Data Monitoring Committee will be implemented for those patients reaching LDL C levels of 25 mg dL to further evaluate the safety of very low LDL C levels.

The COMBO trials have used differing lipid entry cri teria depending on whether entrants had a clinical his tory of CVD or were CHD risk equivalent. This reflected that at the time of design, the revised ATPIII then oper ant in the US did not include an unequivocal recom mendation of a target 70 mg dL in all such patients, but left it as a therapeutic option reflecting some de gree of uncertainty. The new 2013 ACC AHA guidelines have moved away from citing lipid targets but instead focus on the intensity of statin therapy being tai lored to CVD risk. Most of the entrants to the COMBO trials would be eligible for intensive therapy under these new guidelines. Regardless of whether physi cians are working to these 2013 ACC AHA guidelines or guidelines that continue to use LDL C targets, the data the COMBO trial will provide on the effi cacy and safety of alirocumab in high risk patients when administered in addition to maximally tolerated statin therapy will be useful since patients warranting intensive statin therapy may not tolerate it.

Overall, the ODYSSEY program comprises 14 studies of more than 23,500 planned subjects across more than 2,000 study centers worldwide. The program will evalu ate multiple patient populations and different treatment op tions. These studies follow a robust approach to in vestigate a new class of drugs with a novel mechanism of action, with efficacy and safety studies ranging from 24 104 weeks duration to provide a greater amount of double blind safety data for building confidence in alirocumab as a potential thera peutic option.

Of note, the ODYSSEY program also in cludes a large cardiovascular outcomes study which will determine the long term impact of alirocumab and lower levels of LDL www.selleckchem.com/products/BAY-73-4506.html C on the occurrence of cardiovascu lar events in 18,000 patients after a recent acute coronary syndrome event, with a randomized treatment period of 64 months. In summary, the COMBO studies are the longest dur ation placebo ezetimibe controlled trials of a PCSK9 inhibitor in high risk patients with poorly controlled LDL C on maximum tolerated standard of care. They will help to guide clinical decision making on the next LLT to use beyond statin therapy.