Complexities of Off-label Prescribing in CV Pediatrics

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Off-label usage in cardiovascular (CV) pediatric patients is prevalent, but the lack of data makes it difficult to determine if this practice is harmful, requiring rectification. While not illegal, off-label prescribing has the potential to lead to wasteful or even injurious care in some instances, yet it can be advantageous in others. Most experts agree about the value of tracking these practices. Health IT solutions and larger studies may provide some answers.

Off-label prescribing, the use of drugs for indications that have not received regulatory approval, occurs with up to 21 percent of prescribed drugs among U.S. office-based physicians (Arch Intern Med 2006;166[9]:1021-1026). Yet, the problem isn’t unique to the ambulatory setting, and it seems to be particularly prevalent in the pediatric population.

One study found that 78.7 percent of 355,409 children discharged from 31 tertiary care pediatric hospitals were taking at least one off-label medication (Arch Pediatr Adolesc Med 2007;161[3]:282-290). Moreover, off-label use accounted for approximately $270.28 million of the total dollars spent on these medications. The study used an administrative database, which the authors acknowledged “cannot determine which of these treatments are unsafe or ineffective and which treatments result in substantial benefit to the patient.”

Specific to pediatric cardiology, one study that examined 31,432 patients in the Pediatric Health Information System database found that 78 percent received at least one cardiovascular (CV) medication off-label, and 31 percent received at least three CV medications off-label (Circ Cardiovasc Quality and Outcomes 2008;1:74-83). Paquali et al found that the most commonly used CV medications were furosemide, epinephrine, dopamine, lidocaine and milrinone. The latter three (prescribed in 69 percent of patients) were used off-label in all cases. Also, an analysis revealed that heart transplant recipients were most likely to receive a greater number of off-label CV medications.

The study’s senior author, Samir S. Shah, MD, of Cincinnati Children’s Hospital Medical Center, speaks to why off-label prescribing practices are common in the pediatric population. “Children have always been considered a vulnerable population, causing researchers to be hesitant to study the side effects of certain medications with them.” However, he points out that without definitive proof and a lack of alternate therapies, physicians still may be using these drugs in children—either appropriately or not.  

The bigger question may lie in understanding why and how that physician makes a clinical decision. “Traditionally, when physicians have written prescriptions, they do not have to write down an indication,” explains Surrey Walton, PhD, of the University of Illinois at Chicago. “Indications are typically coded for billing purposes with ICD-9 codes tending to be broad, and therefore, they aren’t very helpful for assessing clinical diagnostics or when trying to ascertain why a physician used one drug over another.”

For improved prescribing, Tewodros Eguale, MD, MSc, of McGill University in Montreal, says that physicians need to be made aware of three things at the time of decision-making: whether the drug is approved; whether there is strong evidence to use a particular drug for a particular indication; and whether there is any report of adverse drug reactions and the severity of that reaction.

Frequency Distribution of Patients Receiving Cardiovascular (CV) Medications Off-label

Frequency Distribution of Patients Receiving Cardiovascular (CV) Medications Off-label - 26.78 Kb
Source: Pasquali S K et al. Circ Cardiovasc Qual Outcomes 2008;1:74-83


Data collection is critical

“Off-label prescribing is not bad in and of itself, because there are many situations where a mountain of evidence supports the use of a particular drug for a particular condition or population, even when the FDA has not granted approval for that particular indication,” explains Shah, who adds that this is why continual data collection, especially in the pediatric population, is necessary.

The consensus on the need for improved data in this area might be best summarized by a recent editorial by Randall S. Stafford, MD, PhD, of the Stanford University School of Medicine in Stanford, Calif. “Objective, comprehensive and comparative syntheses of data relating to off-label use of drugs would be valuable to prescribers, patients and healthcare payers,” he wrote (Nature 2012;91[5]920-925). “Data from EHRs relating to drug prescriptions could provide an early alert if off-label use of a particular drug is increasing. In addition, data mining of claims data from multiple healthcare payers could help identify potential safety issues associated with off-label use.”

Specifically with pediatric patients, it’s important to find out if a particular drug or dose works as efficaciously and safely as it does with adults.

To this end, researchers recently examined aprotinin (Trasylol, Bayer), which was used frequently in children undergoing congenital heart operations with the aim of reducing bleeding, until it was taken off the market after adult studies reported increased renal failure and death.

“It’s possible that children would positively benefit from this drug, but one of the challenges was that we had no idea whether children suffered the same adverse events,” explains Shah, who was also the senior author on this study.

Using the Pediatric Health Information Systems Database, this study included 30,372 patients at a median age of seven months, of whom 44 percent received aprotinin (Ann Thorac Surg 2010;90:14-21). The researchers found no difference in postoperative mortality, dialysis or length of stay between aprotinin recipients and non-recipients.

While there was no difference in mortality or dialysis in patients undergoing reoperation, Shah et al found that aprotinin recipients in the reoperation subgroup had significantly reduced length of stay. Reoperation is common among pediatric patients undergoing repair of a congenital heart defect, so a reduced length of stay could mean better patient outcomes and fewer costs.

The researchers concluded that further evaluation of aprotinin in this population could be undertaken without undue risk. However, since the drug is no longer on the market, it’s not possible to conduct a clinical trial to see if the same side effects observed in adults bears out in children. “Unfortunately, some of the safety decisions about drugs, which could be used in children, are often based on the results of adult studies,” he says.

While registries are somewhat informative, they don’t contain data on how patients who didn’t receive the drug fare, according to Shah.

“If it turns out that 30 percent of children who did not receive a drug experience a particular complication while 10 percent of those who did receive a drug experience the same complication, then we can start to say that maybe this drug is preventing the complication,” he says. “Not having comparable data metrics makes it difficult to assess a drug’s true safety and efficacy.”

Health IT may provide a solution

Many administrators and physicians are beginning to recognize the value of various health IT systems, such as EHRs, e-prescribing, computerized physician order entry (CPOE) and clinical decision support (CDS) as a means to track, collate data and potentially prevent widespread use of the more harmful practices.

The solution may be as simple as color coding on-label and off-label status in the CDS, or another technological or visual method of informing the physician of a potential error, suggests Eguale.

“Linking a prescribed drug with an indication could be a meaningful use objective, and vendors could easily incorporate this feature into EHR systems,” Eguale et al recently wrote in a study (Arch Intern Med 2012;172[10]:781-788). “EHRs can be used to document treatment indication at the time of prescribing.”

However, Shah sees flaws in using technology solutions, such as CDS alert systems, to simply discourage physicians from using a particular drug, “which may be completely appropriate.” Rather, he suggests using the strengths of IT infrastructure to actually facilitate data collection to examine drug benefits, complications or adverse effects.

As with many quality improvement initiatives, progress may come on a case-by-case basis. For instance, Eguale says that Canada’s MOXXI EHR system is tracking drug indications during treatment, as well as what happens with treatment down the line.

Therefore, if a physician stops administering or changes the dose of a particular medication, the EHR system has a mandatory requirement to input a reason (e.g. adverse drug reaction, ineffectiveness)—a novel method of generating data for CDS and pharmacosurveillance.

“With the treatment indication and treatment discontinuation features of the EHR, we have created a longitudinal record of ‘drug-treatment indication-reason for drug discontinuation,’” Eguale says.

Also, these data then could be filtered to the physicians or drug regulatory bodies as CDS or comparative safety/effectiveness profiles of drugs, respectively.

The primary goal in attaining these metrics, according to Stafford, is to ensure patient safety by reducing the risk that somebody has an adverse effect of a medication and to improve cost-efficiencies by using cheaper drugs, “if those drugs do pretty much the same thing as a more expensive drug.”   

“Ultimately, the benefits reaped from IT systems will always come down to the physicians’ willingness to input the appropriate information about their decision making,” Walton says.  

Particularly with pediatric CV patients, it seems like the status quo of off-label prescriptions will continue without more comprehensive data on how these medications directly impact this population. Without this information, physicians will be left to base their decisions on personal clinical knowledge and experience to treat these at-risk children.