Medical Professional Publications

Clinical Decision Support System Uses Pharmacogenomics to Improve Patient Safety

(From the September 2017 issue of Research Now)

Different people have different metabolisms, largely based on their genetic makeup. Genetics also plays a significant role in how the body metabolizes drugs. The safe dosage of many drugs is dependent on how well the body clears the drug.

For example, thiopurine methyltransferase, or TPMT, is one of the key enzymes involved in metabolizing azathioprines – drugs commonly used in the treatment for acute lymphoblastic leukemia (ALL) and some gastroenterological diseases. The gene TPMT codes for the enzyme, and patients with certain variants in the gene produce less enzyme than those without variants. 

“We know that patients who have TPMT variants require a lower starting dose of azathioprines in order to avoid serious side effects,” says Rajeswari Swaminathan, systems programmer in Research Information Solutions and Innovations (RISI) in The Research Institute at Nationwide Children’s Hospital. “This particular drug-genome interaction is one of the few that is well studied and currently used in clinical pediatric practice.”

The effect of TPMT genotype on the metabolism of azathioprine has been so well documented in the pediatric population, that as part of every active protocol that includes azathioprines, the Children’s Oncology Group (COG) has instructions for adjustment of azathioprine dose based on TPMT genotype. However, testing is recommended, not required, in each protocol.

“Despite these guidelines and evidence, physicians within these subspecialties may not be aware of when genotyping is done, where to find the results in the electronic medical record and how to apply the results to each individual patient,” says Swaminathan.  

Additionally, as clinical practice becomes more subspecialized, clinicians who may not routinely prescribe azathioprines, but for whom such a prescription is within the legal scope of practice, may not remember to check for TPMT status prior to prescribing, thus negating the benefit of the cost of genotyping or enzyme measurement, she says.

In an informal survey of pediatric hematologists and oncologists at Nationwide Children’s Hospital, the project team found that the majority surveyed were aware that patients with variant TPMT status required dose adjustment for azathioprines. 

However, outside of the team of physicians and nurse practitioners who routinely care for leukemia patients, the majority of pediatric hematology/oncology physicians were not aware of when such testing was done, how to find the results in the chart or what adjustments would need to be made for a variant status. 

“A system in the electronic medical record that alerts prescribers to this drug-genome interaction is beneficial to both the prescriber and the patient,” says Susan Vear, MD, hematologist at Nationwide Children’s.

Such a clinical decision support (CDS) strategy was implemented to aid physicians in recognizing patients having TPMT variants when prescribing azathioprines. Through the electronic medical record (EMR) within Nationwide Children’s, Best Practice Advisories (BPAs) are a flexible type of CDS that can be disruptive or passive and can be configured using many different types of criteria (i.e. medications, labs, diagnoses, etc.). After careful consideration, BPAs were selected to alert physicians of a patient’s TPMT variant at the time of prescribing.

Nationwide Children’s implemented aggressive alerts for both low and intermediate TPMT metabolizers to ensure that it was not bypassed or ignored. This was accomplished by using a pop-up alert that requires the physician to select one of three acknowledgement reasons before they were able to proceed with signing their order. “Give Full Dose” and “Other” options also require the physician to enter their reason for proceeding without dose modification. The alert is color coded based on patient risk and includes a risk summary and a link to the Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for thiopurines and TPMT. 

“Although alerts can save lives, alerts also cause physician fatigue,” said Simon Lin, MD, MBA, chief research information officer at Nationwide Children’s. “During the design process, we carefully considered how to avoid false positives and over alerting by programming the alert to only fire for patients with lab-confirmed TPMT variants, which helps to reduce alert fatigue.” 

As the CDS is rolled out, the team expects that data collected during the initial months may be used to support the implementation of other drug-genome interaction CDS.

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