With the help of CardioDx's molecular diagnostic Corus CAD, six cardiologists taking part in a study decided to reduce the level of diagnostic testing they had planned for more than half of participating women, resulting in no adverse cardiac outcomes after six months.
The study focused on 57 women enrolled in the 83-patient IMPACT trial, which included patients who had presented with chest pain but had no history of CAD. Researchers led by Vanderbilt University's John McPherson found that after cardiologists learned their patients' scores from CardioDx's multi-gene expression blood test, they changed their treatment plan for 60 percent, or 34 women. For 31 of these women, doctors decided to reduce the diagnostic workup they had planned, while they determined to increase diagnostic evaluations for three women.
Corus CAD gauges the expression level of 23 genes in peripheral blood that change depending on the amount of plaque on the walls of coronary arteries. The algorithm underlying the test factors in the expression of these genes, patients' age, and sex to yield a score between 1 and 40 that is associated with their risk of obstructive CAD. The higher a patient's Corus CAD score, the greater the risk that his or her chest pain is due to a blockage in the arteries of the heart. Corus CAD is specifically indicated for non-diabetic patients who have symptoms that suggest they may have obstructive CAD, but who have not been diagnosed with a heart attack or had invasive procedures to open a blocked artery.
Since it tends to be more challenging for doctors to diagnose CAD in women than in men, CardioDx is hoping to market Corus CAD as a tool that cardiologists can use to identify low-risk women and rule out the need for more invasive testing.
"The standard of care [for diagnosing CAD] is the same for men and women," McPherson told PGx Reporter. "However, women tend to be lower-risk when referred for testing. We contend that traditional testing is less accurate in lower-risk patients. Thus, I believe that with its very high negative predictive value, Corus is particularly well-suited for women."
At a symposium hosted by CardioDx at the American College of Cardiology annual meeting in San Francisco earlier this month, Alexandra Lansky, director of interventional cardiovascular research at Yale University School of Medicine, noted that although women experience 20 percent more angina than men do, the rate of obstructive CAD is lower in women compared to men. Additionally, the symptoms for angina in women can be "atypical" and "vague," with some symptoms that may appear to not even be associated with chest pain, such as weakness and shortness of breath.
"Symptoms in the female population are clearly not as predictive as what we see in the male patients," Lansky said at the symposium, adding that a blood-based molecular diagnostic for assessing the risk of CAD could potentially have a lot of clinical utility in the female population.
"I believe this is where the money is," she said.
In the gender-specific analysis of IMPACT, of the 31 women who had their diagnostic testing reduced, 29 had low Corus CAD scores, while all three women whose testing increased had high scores by gene expression testing. "The test was integrated into the sum of clinical information taken into consideration by the cardiologist; thus other factors must have led to a change in testing when the results were discordant. However, this was the exception in only two patients," McPherson said.
Researchers followed patients for six months to track their outcomes. "We know that no adverse outcomes were observed in the patients at six months despite a marked reduction in testing," McPherson said.
Based on these findings, McPherson and colleagues concluded in the abstract presented during the ACC meeting that the Corus CAD gene expression score "showed feasibility of use in discriminating which women patients should be recommended for additional testing. Specifically, the [test score] was associated with an overall relevant reduction in diagnostic test utilization among women with low [scores]."
Convincing Docs, Payors
Under provisions of healthcare reform, payors are increasingly under pressure to curtail unnecessary treatment. In the US, there are more than six million evaluations of acute chest pain each year, and it costs more than $3 billion to conduct this initial evaluation. Doctors can use computed tomography angiograms and stress tests to rule out whether certain types of chest pain are due to CAD or other heart conditions, but these tests expose patients to radiation. Additionally, a March 2010 New England Journal of Medicine article reported that 62 percent of nearly 400,000 patients undergoing elective invasive angiographic procedures had no obstructive CAD.
"Medicare and other payors are reducing their reimbursement for testing and have made it difficult to order tests by instituting administrative processes such as prior authorization," Pamela Douglas, director of the imaging program at Duke Clinical Research Institute, said during the symposium at ACC. Since the negative predictive value of Corus CAD is around 96 percent, CardioDx is hoping that payors will recognize the benefit of adding a blood-based molecular diagnostic to a cardiologist's armamentarium to rule out the need for conducting additional expensive imaging tests or invasive procedures in non-diabetic patients who are at low risk of obstructive CAD.
Last year, Medicare contractor Palmetto GBA established coverage for Corus CAD for patients who had typical and atypical symptoms of CAD. CardioDx hasn't revealed how much its reimbursement is from Medicare, but the company has stated in the past that Corus CAD carries a list price tag of around $1,200.
"Certain private insurance plans currently pay for the test on a patient-by-patient basis, and CardioDx has contracts in place with some smaller plans," a CardioDx spokesperson told PGx Reporter. "The company is also in discussion with multiple commercial payors, including many of the large payors."
New technologies entering a complex treatment paradigm always have an uphill battle in terms of adoption. It usually takes data from multiple, large studies comparing the new technology against standard procedures to convince doctors to change their practices and sway payors to broadly cover the test. Also, there are economic tensions at play that can hinder adoption of novel technologies to replace older methods.
For example, XDx markets a multi-gene expression, blood-based molecular diagnostic called AlloMap that gauges whether a heart transplant patient is at high or low risk of rejecting a new heart two to six months after the procedure. AlloMap carries a list price of more than $3,000 in the US. In comparison, cardiac biopsies can range from between $4,000 and $10,000. Given that heart transplant patients often undergo 12 biopsies in the first year following transplantation, XDx is marketing AlloMap as a tool that can help doctors reduce the number of expensive and invasive biopsies a transplant patient receives.
However, XDx in the past has bemoaned the slower-than-expected uptake of AlloMap, claiming that doctors aren't using the molecular diagnostic since it reduces the number of biopsies they conduct and subsequently cuts into the reimbursement they get from these procedures (PGx Reporter 4/13/2011). Of course, at the time XDx made these comments, the clinical evidence backing the use of AlloMap in clinical practice was still evolving.
CardioDx is similarly betting that Corus CAD will reduce the need to conduct more invasive and costly procedures, but like AlloMap, Corus CAD is also entering a complex marketplace that can challenge its uptake. "Any new product that involves changing a provider's usual care pattern has hurdles to adoption, and Corus CAD is no exception," the CardioDx spokesperson said over email. "Some of those hurdles may be driven by patient flow in certain care settings (e.g., primary care vs. cardiology), or they may be intrinsic to the way certain procedures are reimbursed within the usual care (e.g., cardiac imaging)." While physicians would not be reimbursed for performing Corus CAD, they would receive payment for conducting cardiac imaging tests.
However, as CardioDx gathers evidence backing the utility of Corus CAD, the company is confident that these hurdles will become less of an issue. "We are seeing this happen today for Corus CAD subsequent to our Medicare coverage decision and as our post-market clinical evidence continues to be presented and published in peer-reviewed forums," the company spokesperson said.
Growing Evidence
So far, Corus CAD has been clinically validated in two prospective, multicenter US trials, PREDICT and COMPASS. In 2010, the PREDICT trial was published in the Annals of Internal Medicine. Led by Steven Rosenberg, chief scientific officer of CardioDx, the researchers found that the Corus CAD gene expression score "modestly increases classification accuracy … compared with clinical factors." Specifically, in PREDICT, the Corus CAD score improved the accuracy of assessing CAD by 20 percent compared to using just the Diamond-Forrester score and by 16 percent compared to using an expanded clinical model.
In an accompanying editorial in AIM, Donna Arnett, an epidemiologist at the University of Alabama, Birmingham, characterized the PREDICT trial as a "first step in what may prove to be a long but hopefully rewarding journey." In PREDICT, Corus CAD misidentified as "intermediate risk" two-thirds of patients who were deemed low risk by the Diamond-Forrester model. Additionally, 15 percent of patients classified as low risk by Diamond-Forrester were incorrectly judged by Corus CAD to be high risk. "Thus, it might have led to more low-risk patients undergoing invasive testing than warranted," Arnett wrote in her editorial.
Since then, in February, the COMPASS trial data were published in Circulation: Cardiovascular Genetics. In this 431-patient trial, Corus CAD had a negative predictive value of 96 percent and a sensitivity of 89 percent for assessing obstructive CAD in patients referred for stress testing by myocardial perfusion imaging. Non-diabetic patients with typical or atypical CAD symptoms enrolled in the trial were tested by Corus CAD before receiving myocardial perfusion imaging, and then got either invasive coronary angiography or coronary CT angiography.
The study showed that Corus CAD had better sensitivity than myocardial perfusion imaging (89 percent vs. 27 percent) and a better negative predictive value (96 percent vs. 88 percent). The Corus CAD score "has high sensitivity and negative predictive value for obstructive CAD," concluded the authors, led by Gregory Thomas of Long Beach Memorial Medical Center. "In this population clinically referred for myocardial perfusion imaging, the [gene expression score] outperformed clinical factors and myocardial perfusion imaging."
With regard to the sex-specific analysis of IMPACT, Arnett pointed to some weaknesses, such as the study's observational design and the small cohort. The researchers "did not randomize subjects to [Corus CAD testing]," she told PGx Reporter via email. "This is a before and after, simple observational study of change of behavior with the test, rather than a test of differences in screening rates with [the gene expression test].
"While I understand that [CardioDx] might want to market to women, this is a subgroup analysis of an observational cohort with a small number of women, and a very small number (three) who ended up with more testing," added Arnett, who is currently the president of the American Heart Association.
CardioDx is studying Corus CAD as part of a large randomized study comparing the effectiveness of anatomic imaging versus non-invasive diagnostic tests, such as exercise electrocardiogram, stress echocardiography, or myocardial perfusion imaging. As part of the study, researchers will also collect genomic samples from between 2,500 and 3,000 patients. CardioDx will analyze these samples with Corus CAD and analyze whether the test can predict whether patients will experience major cardiovascular events.