Personalized medicine coming to cardiovascular, stroke care

Several late-breaking clinical science presentations suggest that personalized medicine could bring the kind of improvement to cardiovascular and stroke outcomes that oncologists have been reporting for more than a decade. The combination of improved biomarkers and highly targeted therapeutic agents can help clinicians identify which patients are more likely to show robust response to specific treatments.

A new sensitivity analysis of the CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) data found that a subset of patients who show a high initial response to treatment also had a significant reduction in cardiovascular mortality and all-cause mortality. Patients with high initial response to canakinumab, which targets the interleukin-1β innate immunity pathway, also showed reduced risk for incident lung cancer and lung cancer mortality. Inflammation is an important element in the pathogenesis of both atherosclerosis and lung cancer.

“There has been growing evidence that reducing inflammation might reduce the risk of cardiovascular disease,” said Paul M. Ridker, MD. “But there has never been proof that atherosclerosis is an inflammatory disease. Now we have seen that reducing inflammation using canakinumab reduces cardiovascular events out to five years. And we have a tool that allows us to predict who is most likely to respond to biologic treatment.”

That tool is an individual patient’s response to an initial dose of canakinumab.

Patients who showed a robust response as measured by hsCRP levels of 2.0 mg/L or lower had a 25 percent reduction in MACE, a 31 percent reduction in cardiovascular mortality, and a 31 percent reduction in all-cause mortality at five years. The primary outcome of CANTOS, presented earlier this year, showed a 15-17 percent reduction in cardiovascular event rates with no change in lipid levels.

“The lipid reduction world has been very successful and showed us that lower is better,” said Ridker, the Eugene Braunwald Professor of Medicine at Harvard Medical School. “CANTOS showed that lower is better in inflammation as well.”

Patients with the most robust anti-inflammatory response — hsCRP levels below 1.2 mg/L — had the most robust reduction in cardiovascular events, a 29-percent drop. Those in the middle tertile with hsCRP between 1.2 and 2.0 mg/L had a 17-percent reduction, while those whose hsCRP remained above 2.0 mg/L had only a 1-percent drop in cardiovascular events. The relationship between elevated anti-inflammatory response and reduced cardiovascular events was consistent at all doses of canakinumab used in the trial.

“This is what our oncology colleagues have been doing for 15 years, using individual biology to target disease,” Ridker said. “It is time for cardiology to follow their lead.”

Data from the Biomarker for Cardiovascular Risk Assessment in Europe consortium suggest that serum metabolites could become the next generation of prognosticators and predictors for coronary heart disease.

Serum Metabolomic Profiles Predict Coronary Heart Disease in the General Population  (BiomarCaRE) is the largest population-based study evaluating the value of metabolites in coronary heart disease. BiomarCaRE combined six European population studies to create a cohort of 10,741 individuals that included 2,166 individuals with coronary heart disease. The full BiomarCaRE population includes more than 300,000 individuals from over 30 cohorts with up to 28 years of follow-up.

“Metabolites are good candidates for biomarkers because they reflect genomic changes in individuals and indicate changes in phenotypes,” said Tanja Zeller, PhD, professor of genomics and systems biology at the University of Hamburg in Germany. “In our cohort of middle-aged, largely healthy individuals, we found four metabolites that are significantly associated with coronary heart disease.”

The four metabolites are phosphatidylcholines, lipoproteins that play important roles in membrane function and signaling. All four metabolites have an inverse relationship with coronary heart disease. Lower metabolite levels increase risk while higher metabolite levels are protective. The predictive strength of metabolite biomarkers is similar to classical risk factors such as lipid levels, hypertension, smoking, obesity and diabetes.

More research and validation is needed before serum metabolites are ready for clinical use, she said. But the BiomarCaRE results demonstrate the value of metabolomics to develop novel biomarkers and improve risk stratification.

A third late-breaking science presentation found that clinicians do not routinely use the one biomarker that is available to predict clinical response to antiplatelet therapy in stroke and cardiovascular care.

An update to the P2Y12 Inhibitor Switching in Response to Routine Notification of CYP2C19 Clopidogrel Metabolizer Status Following Acute Coronary Syndromes (GEMINI-ACS-1) trial found that switching between P2Y12 inhibitors based on the result of pharmacogenomics testing for reduced or enhanced function alleles of CYP2C19 is not common.

Clopidogrel currently carries a black box warning that recommends CYP2C19 testing because patients with reduced function alleles have higher platelet reactivity and a potentially higher risk of ischemic events, especially following PCI. Only 6.5 percent of patients in the trial switched P2Y12 inhibitors, and most of the switches were unrelated to CYP2C19 metabolizer status.

“GEMINI looked at clinical outcomes for rivaroxaban versus aspirin with either clopidogrel or ticagrelor,” said E. Magnus Ohman, MD, professor medicine and member of the Duke Clinical Research Institute in Durham, North Carolina. “This update looks at the impact of mandatory CYP2C19 metabolizer status testing and reporting on switching, especially from clopidogrel to ticagrelor.”

A central lab reported CYP2C19 status for 99 percent of the 3,037 patients in the trial. About 1,700 patients were on ticagrelor and 1,300 were on clopidogrel. The study protocol made no recommendations to investigators with regard to which anti-platelet agent to use or about switching between agents based on CYP2C19 metabolizer status or other factors.

In the total study population, 34.4 percent were ultra metabolizers of clopidogrel, 37.8 percent were extreme metabolizers, 25.5 percent were intermediate metabolizers and 3.2 percent were reduced metabolizers.

Before randomization and CYP2C19 status testing, about half of investigators said they would switch reduced metabolizers from clopidogrel to ticagrelor. But after test results were reported, only 4 percent of clopidogrel patients switched to ticagrelor, Ohman reported. The majority of the switches — 57 percent — were related to bleeding and other adverse events or recurrent ischemic events, not to metabolizer status.

“Our findings do not support the utility of mandatory pharmacogenomics testing for P2Y12 inhibitor use because clinicians do not act on it,” Ohman said.