Genetic Risk Score Identifies Patients Who Benefit Most From Statin Therapy

March 11, 2015

BOSTON, MA — A genetic risk score devised from 27 genetic single nucleotide polymorphisms (SNPs) not only identified individuals at high risk for first and recurrent coronary heart disease events but also identified individuals who would derive the largest absolute and relative reductions in risk when treated with statin therapy, according to the results of a new study[1].

For primary- and secondary-prevention patients at the highest risk of clinical events based on the genetic risk score, treatment with a statin reduced the risk of coronary heart disease events by 48%. In contrast, for those individuals classified as low and intermediate risk based on the genetic risk score, the risk of coronary heart disease was reduced by 13% and 29%, respectively.

Speaking with heartwire from Medscape, lead investigator Dr Jessica Mega (Brigham and Women's Hospital, Boston, MA) said that after showing the genetic risk score predicted incident and recurrent heart disease, they were interested in determining the absolute and relative risk reductions with statin therapy among patients with different genetic risk scores. As shown, the patients with highest genetic risk had the biggest benefit from statins, including a significantly larger relative reduction in coronary heart disease risk.

"I think the question that will come up in the future is, when we get to a time when genomes are more readily known, what can we do with that information," said Mega. "It's less about saying everybody needs to be tested for these 27 variants and more that these particular variants, if they are known, are helpful in terms of stratifying therapy and who would get the biggest benefit [from statins]. Potentially, this is more relevant in the primary-prevention setting. In the secondary-prevention setting, once someone has a heart attack, the consensus is that these patients should be on statins."

Dr Marc Sabatine (Brigham and Women's Hospital, Boston, MA), senior investigator of the analysis, also said the technology is moving so quickly that it's less about who will be genotyped but rather what to do with the information once it is known. "By having this panel of variants, it's a concept that you can identify individuals at cardiovascular risk and then start thinking about individuals in whom you might start on therapy," he told heartwire . "This [the genetic data] is part of the information you would use to risk-stratify and decide in whom you would start therapy."

The analysis is published March 4, 2015 in the Lancet.

The Genetic Risk Score

The genetic score risk included SNPs that were all previously associated with a significantly increased risk of coronary heart disease in genomewide-association studies. Individually, each SNP increased the risk of coronary heart disease from 7% to as high as 70%. The analysis included participants from the community-based Malmo Diet and Cancer Study, a primary-prevention population, the ASCOT and JUPITER studies, both of which were also primary-prevention studies, and CARE and PROVE-IT TIMI 22, which were secondary-prevention trials. The statins used in the various trials were rosuvastatin (Crestor, AstraZeneca), atorvastatin, and pravastatin.

Compared with individuals with a low genetic risk score, those considered intermediate risk in the primary-prevention studies had a significant 31% increased risk of coronary heart disease events, while the highest-risk patients had a significant 72% increased risk of coronary heart disease. When the researchers analyzed data from CARE and PROVE-IT, the intermediate-risk and high-risk patients had a significant 65% and 81% increased risk of coronary heart disease compared with individuals with a low genetic risk score.

Next, the researchers looked at the reduction in coronary heart disease risk achieved with statin therapy among patients stratified by their genetic risk score. When the primary- and secondary-prevention studies were combined, the risk of coronary disease was reduced 13%, 29%, and 48% in patients at low, intermediate, and high risk for clinical events. In the secondary-prevention studies, the relative risk of events was reduced 34%, 32%, and 50% across the low-, intermediate-, and high-risk patients. In ASCOT and JUPITER, the relative risk of coronary disease was reduced 3%, 28%, and 47% across the three genetic risk scores.

In terms of absolute risk, the researchers also observed a graded increase in risk reduction with statin therapy among patients with low, intermediate, and high genetic risk scores.

In an editorial[2], Dr Heribert Schunkert (Deutsches Herzzentrum München and Technische Universität München, Germany) and Dr Nilesh Samani (University of Leicester, UK) say the differences in relative-risk reduction across the genetic risk scores is intriguing, given that previous data suggest a similar relative reduction in risk with statins (and extent of LDL lowering) across multiple subgroups. The finding suggests the genetic risk score might "display a distinct feature for risk stratification," they write.

For patients considered high risk for coronary heart disease based on their genetic risk score, Mega hypothesized they might have more diffuse atherosclerosis, so treatment might prevent not only a single lesion but others as well. This might explain the larger relative reduction observed among patients with the high genetic risk score, she suggested.

How Many Patients Needed to Treat?

In the primary-prevention trials, the researchers also found a nearly threefold difference between the low and high genetic risk score groups in the number needed to treat (NNT) to prevent one coronary heart disease event. In JUPITER, the NNT to prevent one coronary event in 10 years was 66, 42, and 25 among the low-, intermediate-, and high-risk genetic groups, respectively. In ASCOT, the equivalent NNT was 57, 47, and 20, respectively.

Mega told heartwire that JUPITER was a well-conducted, large-scale clinical trial that showed the benefit of statin therapy in primary prevention. However, there may patient populations where it is important to optimize the NNT, such as in situations where the goal is to reduce the lifetime risk of cardiovascular disease rather than just the 5- or 10-year risk.

"Really, we'd like to prevent those first events," added Sabatine. "That obviously requires a very thoughtful approach. That's why people have started to move away from what's your risk over 5 or 10 years to lifetime risk. Genetics is very helpful for determining lifetime risk."

In their editorial, Schunkert and Samani point out the American and European guidelines base treatment on the predicted 10-year event rate, but the genetic risk score, if validated in other cohorts, would change treatment decisions in many patients. The risk score would need to be tested in the context of other tools used to guide treatment decisions, such as the EuroSCORE and the American College of Cardiology/American Heart Association cardiovascular risk calculator.

"Since both the European Society of Cardiology and the American College of Cardiology/American Heart Association scores are strongly determined by age and sex, to define groups of individuals who specifically benefit by the addition of genetic information will be important to guide decisions about statin treatment," they write.

The study was funded by the National Institutes of Health. Mega has received research grant support through Brigham and Women's Hospital from Bristol-Myers Squibb, Bayer, Janssen, Daiichi Sankyo, and AstraZeneca and personal fees from Janssen, American Genomics, and Boehringer Ingelheim outside the submitted work. Sabatine has received research grant support through Brigham and Women's Hospital from Abbott Laboratories, Accumetrics, Amgen, AstraZeneca, AstraZeneca–Bristol-Myers Squibb Alliance, BRAHMS, Bristol-Myers Squibb–Sanofi Joint Venture, Critical Diagnostics, Daiichi Sankyo, diaDexus, Eisai, Genzyme, GlaxoSmithKline, Intarcia, Merck, Nanosphere, Ortho-Clinical Diagnostics, Roche Diagnostics, Sanofi, Singulex, and Takeda; he has consulted for Aegerion, Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo/Eli Lilly, GlaxoSmithKline, Intarcia, Merck, MyoKardia, Pfizer, Sanofi, Vertex, Zeus, Cubist, and Quest Diagnostics. Disclosures for the coauthors are listed in the article. Schunkert has received a grant from CAD Genomics (Leducq Foundation) and honoraria from AstraZeneca, Servier, Boehringer Ingelheim Pharma, MSD Sharp & Dohme, Berlin-Chemie, and Amgen. Samani reports no relevant financial relationships.

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