Failure of Another Trial Testing Guided Antiplatelet Therapy Prompts Debate 4

Updated, Saturday, April 7

Yet another trial has failed to prove the hypothesis that guided antiplatelet therapy with platelet function testing or genetic testing improves outcomes. Although there has been no public announcement so far, the TARGET-PCI (Thrombocyte Activity Reassessment and GEnoTyping for PCI) was suspended last October, according to the TARGET-PCI page on ClinicalTrials.Gov.

TARGET-PCI was a large study in which 1,500 PCI patients were randomized to guided antiplatelet therapy with genotyping and platelet function tests or standard antiplatelet therapy. The primary endpoint was major adverse cardiovascular events at 6 months. The principal investigator was Paul Gurbel of Sinai Hospital of Baltimore, where the study was performed.

Here is what one cardiologist who wished to remain anonymous commented about the trial:

It was an ambitious study that was probably underpowered to look at efficacy outcomes. The positive predictive value of the CYP2C19*2 allele is reported as being < 20%. My guess is that the study was halted due to futility, and they discovered that it would be unlikely that any difference in outcome would be apparent with either personalized guided therapy or with routine care, even if the study was carried to completion.

This mirrors what we saw with the TRIGGER-PCI study and GRAVITAS, with the addition of the genetic testing by the Verigene assay.   It seems that both the Verify-now and Verigene assays are solutions still looking for problems to solve.

Sanjay Kaul offered the following comment:

The prognostic utility for genotype testing is not substantial or consistent. The outcome most strongly associated with CYP2C19 loss of function genotype is stent thrombosis (hazard ratio of 3 to 4), a rare but potentially life-threatening event. However, given the rare occurrence of stent thrombosis, the positive predictive value of genotype is only 3-4%, too small to be clinically directive. A randomized controlled trial to definitively address the role of genotype is currently lacking. Given the paucity of thrombotic events, a trial with a sample size of 20,000-30,000 would be required to adjudicate the clinical utility of genotype testing, a number that might be understandably viewed as being prohibitive. With a sample size of around 1500 and a follow-up up to 6 months, the TARGET-PCI is woefully underpowered to address this. Not surprisingly, and given the null results of GRAVITAS and premature stopping of TRIGGER-PCI for futility, the decision to suspend TARGET-PCI does not seem unwarranted.

Based on the totality of evidence, personalized antiplatelet therapy using genotype testing cannot be routinely recommended at the present time. The CYP2C19 polymorphisms affecting clopidogrel metabolism offers a cautionary tale about the unlimited power of genetic technology to generate ‘bountiful’ information on one hand, and our limited ability to properly analyze, reliably interpret, and judiciously translate it into clinical practice on the other hand. The CYP2C19 polymorphisms were heralded with much fanfare to catapult genomics to prominence in personalized cardiovascular medicine. However, the cold hard facts are that not only is the use of genetic testing to improve risk stratification premature, but whether the power of genomics can be harnessed to improve decision making and clinical outcomes also remains to be defined. The unbridled (and uncritical) enthusiasm for genomics revolutionizing personalized medicine has often blurred the distinction between hope, hype and reality. While the progress in DNA sequencing technology and bioinformatics is undeniably breathtaking, the translation of this knowledge to clinical practice has lagged behind. Genomics will eventually get there, but it cannot be expected to move faster than the speed of science.

Eric Topol offered this response to Kaul’s statement:

With at least 30% of individuals carrying DNA loss-of-function sequence variants for metabolizing clopidogrel, it should be standard of care to genotype individuals who are undergoing coronary stenting. The recent RAPID GENE publication in the Lancet (from last week), the first randomized trial of rapid, point of care genotyping , demonstrated unequivocal and marked improvement in platelet suppression using genotype-guided information as compared with no DNA data. The resistance to use genomic data to improve patient care is indefensible, and does not require “a trial with a sample size of 20,000-30,000 would be required to adjudicate the clinical utility of genotype testing.” That trial will never be done, is not even warranted, and while the debate for its need ensues, too many patients will experience stent thrombosis unnecessarily. And the stakes are high, since most stent thrombosis results in MI or death. In next week’s JAMA correspondence, there will be important perspectives published on this matter.

Update, Saturday, April 7:  Sanjay Kaul provided the following response to Topol’s statement. CardioBrief has invited Topol to respond:

The message I take away from the RAPID GENE trial is that point-of-care genetic testing is clinically feasible and might facilitate rapid personalization of anti-platelet therapy. However, genomic data is best utilized to “improve patient care”, not to “improve platelet suppression” – a surrogate marker of unclear clinical relevance. Although the trial was not powered to address clinical outcomes, bleeding episodes occurred in 5/91 of the rapid genotyping patients compared with 2/96 of standard therapy patients.

Individualizing antiplatelet therapy should ideally be based on a biomarker that precisely measures drug responsiveness, accurately characterizes low and high risk patients, is readily available and affordable, and reliably guides treatment decisions to optimize outcomes in a cost-effective manner. Unfortunately the quest for such a biomarker remains elusive as none of the currently available genetic tests (or platelet function tests) exhibits these desirable attributes.

Despite the inordinate attention being given to genomic and personalized medicine, the body of evidence continues to be insufficient to justify the clarion calls for “standard of care” use of genotype testing in the care of patients undergoing coronary stenting.

CardioBrief will be happy to provide a forum for additional discussion and debate about this topic.

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Proof-of-Concept for Bedside Rapid Genotyping Test of CYP2C19 1

A new point-of-care test can rapidly identify people with a common genetic variant associated with impaired clopidogrel function. The authors claim that this is the first study to demonstrate the feasibility of delivering a genetic test at bedside.

In an article published online in the Lancet, Jason Roberts and colleagues report on a new point-of-care test that can identify people who have a common variant of the CYP2c19 gene associated with reduced clopidogrel effectiveness. In their “proof-of-concept” study, 200 patients undergoing PCI were randomized to standard therapy with clopidogrel or to the new test. Patients found to have the CYP2C19*2 allele received prasugrel instead of clopidogrel.

Each group had 23 patients who carried at least one CYP2C19*2 allele. Among these patients, no patients in the test group, and 7 patients (30%) in the control group, were found to have high on-treatment platelet reactivity (PRU) after 1 week of treatment. At 7 and 30 days, there were no ischemic events in either group and no significant differences in major or minor bleeding.

The investigators write that their study “confirms the potential clinical benefits associated with a personalised approach to antiplatelet treatment with selective use of P2Y12 inhibitors in patients at increased risk of adverse events with clopidogrel,” but they also noted that the “major limitation” of their study “was use of a surrogate endpoint to assess clinical efficacy.”

In an accompanying comment, Amber L Beitelshees notes that “.”many clinicians do not know what action to take, if any” until the completion of large trials that are in progress. Earlier studies testing the platelet hypothesis may have failed, she says, because new evidence suggests that benefits of genotyping or platelet function tests may be confined to the PCI population. The new rapid genotyping test will make it easier “for incorporation into clinical care in the catheterisation laboratory.”
Click here to read the Lancet press release…