Genetic testing is now part of routine practice in at least some U.S. centers for managing a short list of cardiovascular disease scenarios.
Although it remains well shy of ubiquitous for cardiovascular practice, for at least four important settings genetic testing has begun to play a key role: diagnosis of inherited cardiac conditions such as cardiomyopathies and channelopathies, diagnosis of homozygous and heterozygous familial hypercholesterolemia, treatment of stented coronary-disease patients with clopidogrel, and use when starting patients on warfarin.
Cardiomyopathies and channelopathies
Genetic testing of patients with any of the several inherited diseases that fall into these categories, including hypertrophic cardiomyopathy, dilated cardiomyopathy, long QT syndrome, and Brugada, received official recommendation from the Heart Rhythm Society and European Heart Rhythm Society in 2011 ( Europace 2011;813:1077-109 ), and genetic testing for patients with hypertrophic cardiomyopathy and their first-degree relatives received a class I level B rating in guidelines for this specific cardiomyopathy released last year from the European Society of Cardiology ( Eur. Heart J. 2014;35:2733-79 ).
Those endorsements put these cardiac diseases on the firmest ground for categorization as routine practice, a status that grew firmer still when researchers announced in January 2015 new evidence that better clarified the genetic underpinnings of dilated cardiomyopathy, the most common inherited cardiac condition.
“Genetic testing clearly contributes to risk assessment” of cardiomyopathies and channelopathies, Dr. Ray E. Hershberger said during a talk last November at the American Heart Association scientific sessions in Chicago. “Finding a plausible genetic cause for a condition lays the foundation for more durable intervention,” said Dr. Hershberger, professor and director of human genetics at Ohio State University in Columbus.
“Genetic testing for dilated cardiomyopathy is becoming increasingly important in clinical practice. Genetic testing is available, affordable, and efficient,” Dr. Luisa Mestroni , director of the Adult Medical Genetics Program of the University of Colorado, Denver, said during a separate talk at the AHA meeting. She cited three commercially available genetic tests for dilated cardiomyopathy that use next-generation sequencing and screen dozens of implicated genes. The genetic findings are available within about 10 weeks and cost in the range of several thousand dollars. Similar panels also exist for the other cardiomyopathies and channelopathies. Perhaps the most significant limitation on genetic testing for these patients is that it be done within the context of genetic counseling, said both Dr. Mestroni and Dr. Hershberger.
Genetic testing for dilated cardiomyopathy has been hindered by the disorder’s genetic heterogeneity, but understanding of the genetic picture grew much clearer in January with publication of genetic findings from 5,267 people representing the full spectrum of cardiac status, including fully-assessed healthy controls; 3,603 unselected community dwellers taken from the Framingham and Jackson Heart Studies; 374 unselected, ambulatory patients with dilated cardiomyopathy; and 155 patients with severe, end-stage dilated cardiomyopathy. The large, multicenter team of mostly British and U.S. researchers validated the findings in 163 additional patients with familial dilated cardiomyopathy (Sci. Transl. Med. 2015;7:[ doi: 10.1126/scitranslmed.3010134 ].
The findings showed that mutations that produce truncated forms of titin, the body’s largest protein and a critical part of cardiac muscle, appear in about 2% of the general population, about 13% of ambulatory patients with dilated cardiomyopathy, and about 20% of patients with end-stage DCM. In addition, the truncations that occur in people who lack clinical disease tended to affect minor titin isoforms and produce mild functional changes, while the titin truncation mutations in people with severe disease were in the most commonly used isoforms and at sites that severely impaired function.
Until now, in the United Kingdom, “it would not have been standard of care to do gene testing [for patients with suspected dilated cardiomyopathy] unless there was a clear family history or some phenotypic indicator, but going forward we believe the yield from titin truncations [as well as from other, less common known mutations] is sufficient to include genetic testing in a patient’s work-up,” Dr. James S. Ware , a coauthor of the new report and a cardiologist at Imperial College, London, said during a press conference in January.
“The American College of Cardiology and American Heart Association guidelines for managing cardiomyopathy say that it is critical to perform longitudinal clinical follow-up on all first-degree relatives of patients with cardiomyopathy. The cost for longitudinal clinical screening is huge and also poses inconvenience for the family members screened. Genetic testing can now identify which family members really need clinical follow-up and which ones don’t need it,” said Dr. Cristine E. Seidman , a coauthor of the new titin-genetics report, professor of genetics and medicine at Harvard Medical School, and director of the Cardiovascular Genetics Center at Brigham and Women’s Hospital, Boston.
Familial hypercholesterolemia
Routine screening for familial hypercholesterolemia (FH) is not as widely endorsed, but it does have backers, and evidence shows that the approach is cost effective. In part, that’s because both heterozygous and homozygous FH are substantially more common than had been believed until recently. Recent study results documented prevalence rates roughly threefold more common than previously calculated.
For example, a study published last year of more than 104,000 residents of the Netherlands documented a homozygous FH prevalence of 1 in 300,000 ( Eur. Heart J. 2014 [doi.org/10.1093/eurheartj/ehu058] ). Results from a 2012 study of more than 69,000 Danish residents demonstrated a prevalence of 1 in 137 for people with heterozygous FH ( J. Clin. Endocrinol. Metab. 2012;97:3956-64 ).
“Genetic testing improves the care of individual patients with FH because with genetic testing you can catch patients with FH presymptomatically and you can then treat them and change their long-term prognosis,” Dr. Anne Tybjaerg-Hansen , professor of clinical biochemistry and chief physician at Copenhagen University Hospital, said in a talk at the AHA meeting last November. She cited a report last year from Australia on a model demonstrating the cost effectiveness of testing first-degree relatives of index patients diagnosed with FH, an approach known as cascade screening ( J. Clin. Lipidology 2014;8:390-400 ).
Last year, a consensus panel of the European Atherosclerosis Society recommended that genetic testing “should be considered” for both the diagnostic work-up of index cases with suspected FH and for cascade screening of first-degree relatives of confirmed cases ( Eur. Heart J. 2014;35:2146-57 ). The European panel noted that genetic testing was potentially useful not only to confirm a clinical diagnosis but also to better distinguish patients with heterozygous and homozygous FH. The panel’s report last year endorsed the updated understanding that heterozygous FH occurs in roughly 1 in every 200 people, while homozygous FH has a prevalence of 1 case in every 160,000-300,000 people.
Despite these relatively high prevalence rates, FH is woefully underdiagnosed. A 2013 report from the European Atherosclerosis Society cited recent data documenting that less than 1% of U.S. residents with FH are currently identified ( Eur. Heart J. 2013;34:3478-90 ). The same report noted that less than half of all FH patients have been identified in every country worldwide with reported statistics – aside from the Netherlands, which topped the world with an estimated identification rate of 71% of patients with either form of FH.
Clopidogrel responsiveness
It’s now been several years since researchers determined that roughly 30% of people fail to adequately metabolize the antiplatelet drug clopidogrel into its active form, a finding that in 2010 led the Food and Drug Administration to mandate a boxed warning on clopidogrel’s labeling. The cytochrome P450 (CYP) 2C19 gene codes for the enzyme that activates clopidogrel, and the warning states that people in this significant minority carry alleles of the CYP2C19 gene that make them poor clopidogrel metabolizers and hence clinicians should consider using “alternative treatment strategies.” Usually this means treatment with prasugrel (Effient) or ticagrelor (Brilinta), two thienopyridines that match clopidogrel’s efficacy but do not require metabolic conversion and so are effective even in poor-metabolizing patients.
But years after this well documented and well publicized problem with blind clopidogrel dosing first became apparent, many clinicians remain uncertain how to deal with the issue and how to use genetic testing to clarify the risk faced by individual patients ( Circulation 2012;122:445-8 ).
“The evidence for CYP2C19 is really strong, but because prospective, randomized clinical trials of genotype-directed antiplatelet testing have not been performed, there is a lot of resistance to adoption of genotype-directed treatment,” Dr. Alan R. Shuldiner said in a talk at the November AHA meeting. An editorial published in late 2011 called the boxed warning on clopidogrel “irrational exuberance” ( JAMA 2011;306:2727-8 ). Dr. Shuldiner and others contend that overall evidence today supports a need to screen the CYP2C19 gene before starting clopidogrel, although he conceded that the optimal clinical algorithm for using testing has not yet been devised and that paying for screening remains problematic.
Despite these limitations, Dr. Shuldiner and several colleagues from around the United States issued recommendations in 2013 for the implementation of CYP2C19 genetic testing in patients ( Clin. Pharmacol. Ther. 2013;94:317-23 ) on behalf of the Clinical Pharmacogenetics Implementation Consortium . And in February 2013, clinicians at the University of Maryland in Baltimore began to implement those recommendations as one of eight U.S. sites participating in the PGRN Translational Pharmacogenetics Program.
“It took us 18 months to figure out how to implement pharmacogenetics in the cath lab,” said Dr. Shuldiner, former director of the program for personalized and genomic medicine at the University of Maryland, and now vice president of translation genomics at Regeneron in Tarrytown, N.Y.
From February 2013 through August 2014, the University of Maryland program screened on a routine basis 557 patients undergoing percutaneous coronary intervention (PCI) – with a 5-hour turnaround time on the results – enrolled 446 into the program, found 67 patients with an “actionable” genotype, and actually prescribed an alternative therapy because of the genotype in 37 patients. Patients usually did not receive the genomic-guided treatment because of a contraindication, Dr. Shuldiner said. He concluded that the Maryland experience shows routine screening is doable, and with its strong evidence base warrants use in all catheterization labs.
PCI patients at the University of Florida in Gainesville also now routinely undergo genomic assessment,said during a separate session at the AHA meeting. “Physicians recently began starting their acute coronary syndrome (ACS) patients on ticagrelor, and then when they get the genotype if the patient has an allele associated with good metabolism and can’t afford ticagrelor and needs to change to clopidogrel we know it will be okay. That’s the way we deal with the delay” in getting the genomic results. “At least you know that the patient is protected [with ticagrelor] during the really hot period,” said Dr. Cavallari, director of the center for pharmacogenomics of the University of Florida.
“For ACS patients if you treat with prasugrel or ticagrelor then you’ve pretty much overcome the roadblock, but for patients on clopidogrel I think it is very reasonable to use genetic testing or platelet-reactivity testing, especially for patients with a stented left main coronary,” Dr. Jessica L. Mega said during a panel discussion with Dr. Cavallari at the meeting. “We have pretty good data to suggest that at least in the peri-PCI patients who are homozygous for the *2 allele [the worst clopidogrel metabolizers] should not be on a standard clopidogrel dosage.”
Dr. Mega agreed with other genetic-testing proponents who see a double standard surrounding these tests. “I think there is a little genetic exceptionalism going on, and people feel differently about using genomics compared with other biomarkers. We have good data, and we just need to act on it,” said Dr. Mega, a cardiologist at Brigham and Women’s Hospital in Boston. “If you had an ACS event and received a stent in your left anterior descending coronary and were known to have a *2 allele or had high on-treatment platelet activity would you want to go home on 75 mg a day of clopidogrel?” Dr. Mega asked during a talk at the meeting.
Warfarin dosing
Evidence has implicated polymorphisms in two genes, CYP2C9 and VKORC1, as playing key roles in warfarin metabolism and suggested that determination of a patient’s allele profile for these two genes could assist in more quickly finding the best warfarin dose for a patients requiring oral antithrombotic therapy to reach their target International Normalized Ratio (INR).
In late 2013, researchers reported results from two major prospective trials designed to test the efficacy of genetic analysis of these two genes. The results were split. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial with 455 patients in the United Kingdom and Sweden showed that genotype-based dosing at the start of warfarin therapy increased the time in the therapeutic range, the primary outcome, by 7 percentage points and reduced the incidence of excessive anticoagulation, the time required to reach a therapeutic INR, the time required to reach a stable dose, and the number of adjustments in the dose of warfarin (N. Engl. J. Med. 2013;369:2294-303). But results from the Clarification of Optimal Anticoagulation through Genetics (COAG) trial, which included 1,015 patients at 18 U.S. centers, showed that after 4 weeks genotyping-based warfarin dosing produced no significant between-group difference in the mean percentage of time in the therapeutic range (N. Engl. J. Med. 2013;369:2283-93).These inconsistent results, and especially the COAG study’s inability to show a benefit from genetic analysis in improving warfarin-dose selection, “called into question the clinical utility” of genetic testing, Dr. Cavallari wrote in a comment she coauthored last July (Clin. Pharmacol. Ther. 2014;96:22-4).
But recent data from Dr. Cavallari’s research group suggests that the value of genetic testing in patients starting warfarin may have been masked by the high proportion of African Americans in the COAG study, 27% of enrolled patients, and the finding that these patients did poorly because the alleles they carry most frequently were not covered by the genetic-test panel used in the study.
Before she moved to Gainesville, Dr. Cavallari worked at the University of Illinois in Chicago and she and her associates there began in August 2012 to routinely genotype patients prior to the start of warfarin treatment, using the information to guide initial dosing levels. The analyses they performed included several alleles commonly seen in African Americans – roughly two-thirds of the 389 patients they screened under this program were African American.
Expanding the testing panel had a major impact on efficacy. Results reported by her group at the AHA meeting last November showed that immediately following the start of warfarin treatment the percentage of INR levels that fell out of the therapeutic range was 42%, a statistically significant improvement over the 65% rate seen in 308 historic controls drawn from the year immediately preceding the start of routine genotyping (Circulation 2014;130A:16119). The results showed that the average number of days for patients to reach their first INR measurement in the therapeutic range fell from 11 days prior to genotyping to 4 days, and the average number of days needed on treatment with low-molecular-weight heparin, a bridging strategy until a therapeutic INR is achieved, fell from 10 days among the historic controls to an average of 2 days. The between-group differences for all three of these metrics reached statistical significance in analyses that adjusted for multiple variables, and that used propensity scoring, Dr. Cavallari said.But although genotyping prior to starting warfarin “is available and reasonable to use, until Medicare starts paying for it, doing this will be hard to implement,” Dr. Cavallari conceded during a November talk. Although warfarin-oriented genetic testing may be performed routinely at the University of Illinois, a lot of clinicians elsewhere are holding back, in part because of reimbursement issues and in part because “they want to see proof of better patient outcomes,” said Pharm.D., a cardiovascular pharmacology researcher at the University of Connecticut in Storrs. Like many who look at the evidence for routine genetic testing in cardiovcascular medicine, they “want to see differences in hard clinical outcomes before incorporating it into their practices,” Dr. Baker said.
Dr. Hershberger, Dr. Mestroni, Dr. Ware, Dr. Seidman, Dr. Tybjaerg-Hansen, and Dr. Cavallari had no disclosures. Dr. Shuldiner is an employee of Regeneron. Dr. Mega has been a consultant to Janssen, Boehinger Ingelheim, American Genomics, Bayer, and Portola, and has received research grants from eight companies. Dr. Baker received a research grant from Gilead.
mzoler@frontlinemedcom.com On Twitter @mitchelzoler
