Originally published March 12.
SAN FRANCISCO – Using a point-of-care genetic test developed by Spartan Bioscience, Canadian researchers have demonstrated that rapid access to genetic test results for cardiac patients who have undergone a stent procedure allows doctors to identify early those at heightened risk of a major cardiac event and then personalize treatment with an antiplatelet drug.
In the so-called Rapid STEMI study, presented at the American College of Cardiology meeting here this week, University of Ottawa Heart Institute's Derek So and colleagues used a research-use point-of-care genetic test developed by Spartan to genotype 102 patients with ST-elevation myocardial infarction after they had had a percutaneous coronary intervention.
Of these participants, 59 were either carriers of the CYP2C19*2 loss-of-function allele or homozygous for ABCB1, which are markers that studies have shown to be associated with reduced response to clopidogrel (marketed by Bristol-Myers Squibb and Sanofi-Aventis as the branded drug Plavix). These 59 participants were then randomized to receive either an alternative antiplatelet drug, prasugrel (Eli Lilly's Effient), 10 mg daily for one month; or 150 mg of clopidogrel daily for a week and then a 75-mg dose for the rest of the study period. The other 43 patients, who didn't harbor an at-risk marker, received standard treatment with clopidogrel.
At the meeting, So concluded that Rapid STEMI, funded by Spartan, serves as a proof of concept that testing for multiple gene variants at the point of care is possible, though he noted that the study wasn't large enough to draw conclusions about whether point-of-care genotyping would lead to improved patient outcomes. The researchers measured platelet reactivity as a surrogate endpoint, in order to assess whether patients were at risk of experiencing a major cardiac event after undergoing a stent procedure, and the extent to which that risk was mitigated following antiplatelet treatment. Platelet reactivity is expressed in terms of PRU, or P2Y12 reactivity units, and measured via another point-of-care test, called VerifyNow P2Y12 from Accumetrics.
While noting that the sample size was small, So said that "quite clearly … those patients [with at-risk variants] that were on prasugrel had a lower PRU" than at-risk patients randomized to clopidogrel.
Rapid STEMI used an RUO point-of-care DNA testing system that is able to concurrently gauge multiple CYP2C19 alleles and ABCB1 genotypes, but Spartan hasn't yet determined whether it wants to commercialize this test. In January, Spartan submitted a 510(k) application to the US Food and Drug Administration for its Spartan Rx CYP2C19 genetic test. That test gauges CYP2C19*2 and *3 alleles associated with poor response to clopidogrel, as well as *17, which is a gain-of-function allele that makes carriers ultra-rapid metabolizers of the drug. Spartan founder Paul Lem said the company is expecting to hear from the FDA this year regarding its filing for the CYP2C19 the point-of-care test system.
The Ottawa group last year published data in the Lancet from another trial, called Rapid Gene. This investigation included 200 acute coronary syndrome or stable angina patients undergoing a percutaneous coronary intervention who were randomized to receive rapid genetic testing or no genetic testing. Those who weren't genotyped received standard treatment with clopidogrel, while those tested with Spartan's assay who were positive for the CYP2C19*2 allele were treated with prasugrel and non-carriers were given standard clopidogrel treatment. The data showed that none of the 23 CYP2C19*2 carriers in the rapid genoytping group had high platelet reactivity after being treated with Effient, but seven patients in the standard treatment arm did.
Similar to Rapid STEMI, the Rapid Gene trial could not come to actual conclusions about whether genotyping impacted patient outcomes, due to the small sample size and the use of surrogate endpoints. But, according to So, that study also suggested that the Spartan test could lead to more effective, safer treatment with antiplatelet drugs.
The FDA in 2010 issued a black box warning for clopidogrel, informing patients and healthcare providers that those with diminished CYP2C19 function are at greater risk of cardiovascular adverse events after an acute coronary syndrome or percutaneous coronary intervention than are normal metabolizers of the drug. Although prasugrel, a newer antiplatelet, doesn't appear to have the pharmacogenetic variability of clopidogrel, the older drug has lost patent protection since FDA's labeling update. As such, researchers have health economic reasons to hone in on PGx strategies that could help doctors cost-effectively determine which patients wouldn't respond to clopidogrel and therefore should receive the pricier prasugrel and which patients are normal metabolizers and can safely receive the cheaper clopidogrel.
At the start of Rapid STEMI, So et al. tested participants' platelet reactivity at baseline and noted that those patients with CYP2C19*2 alleles or the ABCB1 3435 TT genotype had PRU of 183.5±90.6 compared with PRU of 147.3±84.7 in non-carriers. After participants were on treatment for a month, the researchers compared the number of participants with at-risk variants on prasugrel who had high platelet reactivity (defined by PRU greater than 234) against those on clopidogrel.
So and his colleagues reported that among those Spartan's test identified as carrying a risk marker, no Effient-treated patients had high platelet reactivity after a month, while seven at-risk patients in the Plavix arm did. The study data also showed that patients with at-risk variants who were randomized to receive Effient for 30 days had significantly lower platelet reactivity than those at-risk patients who received clopidogrel (PRU of 53.8±60.3 vs. 157.1±94.7).
Patients without at-risk variants had 147.3±84.7 PRU at baseline and 110.4±85.1 PRU after 30 days of standard clopidogrel treatment. Two patients in this arm experienced high platelet reactivity at one month.
"Point-of-care genetic testing at the clinical bedside is capable of concurrently identifying multiple genetic variants associated with high-platelet reactivity and enabled a pharmacogenomic approach to antiplatelet therapy in patients with STEMI undergoing percutaneous coronary intervention," So concluded at the meeting. "Treatment of CYP2C19*2 and ABCB1 TT carriers with [Effient] resulted in a significant reduction in high platelet reactivity after one month of treatment compared to those receiving a high dose [of] clopidogrel."
Since Rapid STEMI was designed, studies have shown that the poor response to clopidogrel seen in cardiac patients who are carriers of CYP2C19 loss-of-function alleles may be overcome with very high doses of the drug. So hypothesized at the ACC meeting that CYP2C19 heterozygous patients may have responded to a clopidogrel dose of 225 mg daily.
Furthermore, in Rapid STEMI researchers also tested patients for the CYP2C19 *17 gain-of-function allele, and 33 percent of patients in the study had this marker. "At present, we have not specifically looked at the influence of PRU on *17, but that will be a secondary analysis," So told PGx Reporter.
At the meeting, So described Spartan's point-of-care test as being the "size of a toaster." He highlighted that nurses with no previous experience with genetics can operate the test after 30 minutes of training. The PCR-based test analyzes buccal swab samples and yields a result in 45 minutes.
In the Lancet paper on the Rapid Gene study, researchers reported that Spartan's test had incorrectly identified one patient as a CYP2C19*2 carrier. So and his colleagues are currently confirming potential misclassifications in Rapid STEMI. "The risk of a misclassified patient is low [with Spartan's test], but it is there," So told PGx Reporter. "The goal is to optimize the specificity and sensitivity with subsequent versions of the test."
In Rapid Gene, Spartan's CYP2C19 point-of-care test had a sensitivity of 100 percent and a specificity of 99.3 percent. If a test misidentifies a patient as harboring a marker associated with lower response to clopidogrel, then he or she could receive a more potent agent that could increase their risk of bleeding, So noted. However, the patient in Rapid Gene did not have a bleeding complication.
"For any potential miscall, we do several wet-lab genotyping tests to ascertain the miscall," So said. "We think our numbers will be similar to Rapid Gene for Rapid STEMI in terms of miscalls."
The aim of Rapid STEMI was not just to study the possibility of accurately administering point-of-care genetic testing, but to serve as a proof-of-concept study for the rapid testing of multiple genes at the patient's bedside. CYP2C19 mutations are carried by approximately 30 percent of the population. By testing for CYP2C19 alleles and ABCB1 genotypes, researchers were hoping to identify a larger subset of cardiac patients who are unlikely to derive benefit from clopidogrel.
A study published in 2010 in the Lancet by Jessica Mega and colleagues at Brigham and Women's Hospital and Harvard Medical School reported that acute coronary syndrome patients undergoing a stent procedure who had the ABCB1 3435 TT genotype experienced reduced platelet inhibition and were at greater risk of cardiovascular death, myocardial infarction, or stroke when treated with clopidogrel compared to those with ABCB1 3435 CC or CT genotypes. In particular, the researchers concluded in the paper that for patients with acute coronary syndromes who have undergone a stent procedure, when tested for ABCB1 and CYP2C19 variants, nearly 50 percent had a genotype that would put them at heightened risk of experiencing a major adverse cardiovascular events while on standard doses of clopidogrel.
Although Rapid STEMI didn't conduct cost-effectiveness analysis, industry observers have opined that PGx testing can save healthcare dollars when tests gauge multiple markers at once and doctors have genotype information readily available in patients' medical records when it's time to make a treatment decision.
"A major obstacle" to CYP2C19 genetic testing adoption "is the cost for testing in Canada," So said. "We have a universal healthcare system, so we cannot charge patients for tests. Hospitals will take a loss to do these tests if there is no reimbursement from the government. An outcomes-based study along with endorsement by guidelines will be required before restrictions are lifted."
Based on currently available data, "clinical guidelines would only suggest use of platelet function or genetic testing in high-risk patients," So reflected. "An outcomes-based trial with a positive result will change guidelines and permit physicians to adopt this more widely."
In an effort to garner the types of evidence that payors and other healthcare decision-makers in the US and in other countries will require to use and pay for point-of-care CYP2C19 testing, Spartan launched a large outcomes study with the Mayo Clinic in December last year. The so called TAILOR-PCI trial will evaluate whether genotyping cardiac stent patients at the time of angioplasty can help doctors personalize treatment decisions with either AstraZeneca's Brilinta (ticagrelor) or clopidogrel, and improve patient outcomes (PCR Insider 12/20/2012).
Investigators in the trial, sponsored by the Center for Individualized Medicine at the Mayo Clinic, are currently getting ready to enroll the nearly 6,000 patients that they aim to study. "It is a landmark clinical trial that is looking at hard clinical outcomes instead of surrogate endpoints such as platelet reactivity," Spartan's Lem said. "If it is successful, it will demonstrate that point-of-care CYP2C19 testing and personalized antiplatelet therapy is superior to one-size-fits-all treatment."
Another issue barring adoption has been the turnaround times of available tests. In 2010, when the FDA issued the black box warning for clopidogrel, it took a week or longer to return test results, by which time doctors had already made treatment decisions for acute cardiac patients, rendering the genotyping results useless.
Since then, the FDA has cleared two CYP2C19 genotyping tests, one from Naonsphere last year and another from AutoGenomics in 2010. These tests are indicated for use in guiding treatment strategy with drugs that are metabolized by the CYP2C19 gene product. Nanosphere's test, with a turnaround time of two and a half hours, might be a potential competitor to Spartan's test, which yields results in about an hour.
Spartan garnered CE self certification for its RX CYP2C19 rapid DNA testing system in the European Union in late 2010 and since then has launched the test commercially in various markets. The point-of-care testing platform is available for research use ahead of regulatory clearance in the US. During his presentation, So also noted that Spartan's point-of-care test is currently only being used as part of research studies in Canada, as it doesn't yet have the approval of regulatory authorities.
As part of its 510(k) application for the point-of-care CYP2C19 test, Spartan compared its test against bidirectional Sanger sequencing, which the FDA deems as the gold standard method, Lem noted. For 510(k) clearance, Autogenomics' Infiniti CYP2C19 test will serve as the predicate device for Spartan's point of care CYP2C19 test. Lem added that Spartan will submit for approval of its test in Canada after it receives approval in the US.
Spartan is also planning to launch cost-effectiveness studies involving its test in Europe. Meanwhile, there have already been some cost-effectiveness studies that have shown that genotyping certain cardiac patients undergoing a percutaneous coronary intervention can avoid adverse events and save money.
In 2012, researchers at the University of Maryland published a paper in Pharmacotherapy in which they investigated in a simulated cohort the cost-effectiveness of genotype-guided administration of antiplatelet therapy compared to giving patients Effient regardless of genotype and Plavix regardless of genotype. While the genotype-guided strategy saved money compared to giving Effient to all patients, the "cost savings were not evident" when generic clopidogrel was given with the aid of genotyping or without genotyping to all patients.
Lem pointed out that in this study the authors also found that one cardiovascular event was avoided for every 30 patients genotyped, saving a total of $27,000, or $900 per patient, after factoring in the cost of a $300 genetic test.