While high-risk medications can greatly enhance patient care efforts, if used improperly, these agents have the potential to inflict great harm. Given the nature of these drugs, managing their use requires a more aggressive approach than with most conventional medications. Medication-use guidelines are an essential part of effectively managing high-risk drugs, but guidelines are only one piece of a bigger picture that should include medication-use evaluations (MUEs), education, and employing clinical pharmacists to lead these efforts and work collaboratively with physicians and other medical staff. In the case of recombinant factor VIIa (rFVIIa), the extreme risk, high-cost, and limited clinical research associated with off-label use of this biologic motivated the pharmacy department at The Ohio State University Medical Center (OSUMC) to spearhead efforts to work with physicians to improve the use of this drug in the cardiothoracic surgery service at the Richard M. Ross Heart Hospital, a 150-bed specialty hospital that houses cardiology and cardiothoracic and peripheral vascular surgery. While management efforts proved challenging, our success with improving off-label rFVIIa use spurred us to undertake similar efforts with albumin.

The Value of MUEs
In 1999, the Food and Drug Administration (FDA) approved rFVIIa for the treatment of bleeding in hemophilia A and B patients with acquired coagulation factor inhibitors. Since then, the drug has been used in patients without hemophilia for the control of refractory bleeding in various clinical circumstances, and off-label use of rFVIIa in some clinical areas has continued to gain momentum despite insufficient support from randomized, controlled trials. While the benefits of using rFVIIa for off-label purposes can be significant, so can the harm associated with its use. The worst adverse effect of rFVIIa is the infrequent, but deadly occurrence of thromboembolic complications (TEC). In an effort to guide safe and effective use of off-label rFVIIa, multiple case series and consensus recommendations have been published over the last five years.

In 2005, the first cardiothoracic surgery specialty pharmacy position was approved at OSUMC; the goal of this position was to bring pharmacy oversight to the cardiothoracic surgery service, including decreasing the use of rFVIIa. At the time, treatment of intraoperative and postoperative bleeding was determined solely by the cardiothoracic surgeon and the anesthesiologist, who used rFVIIa frequently. While institutional guidelines recently had been approved—a first attempt at standardizing rFVIIa use—no blood product use guidelines existed. Furthermore, there was no means of enforcing guidelines or better educating staff on the use of this drug. On top of risk, there also were cost issues to consider: rFVIIa is one of the most expensive agents used by this service. The drug costs more than $1000 per mg, and there is no way to bill for non-FDA-labeled uses of rFVIIa—significantly impacting reimbursement. Without an intervention, it was projected that up to $2 million would be spent on rFVIIa annually at OSUMC, with the cardiothoracic surgery service accounting for $750,000 of that amount.

MUEs have been a critical tool for impacting practice change with rFVIIa: several MUEs have been conducted over the past five years to evaluate the effect of rFVIIa on blood product usage at our institution and to identify opportunities to improve practice. Other MUE objectives included assessing the TEC and mortality in patients who received rFVIIa, as well as identifying costs associated with this agent.

The first MUE conducted on rFVIIa evaluated the use of this drug on cardiac surgery patients from June 2003 to December 2005. This evaluation revealed the following issues:

• Use was consistent with OSUMC guidelines in only 1.4% of cases
• Use was consistent with consensus recommendations of 41 to 90 mcg/kg1 36% of the time
• 16% of patients had TEC
• Wide variation in dosing practices was observed

This MUE helped us improve our original guidelines, specifically the need to clearly define bleeding (chest tube output parameters, hemoglobin, and hematocrit) and targeted laboratory parameters (pH, ionized calcium, INR, aPTT, and fibrinogen). Changes to specified dosing and timing, as well as suggested reversal medications, also were made.

The results of this primary MUE were discussed with the cardiothoracic surgery team to create awareness and educate staff on updated guidelines, particularly dosing and risk of TEC. A subsequent MUE again evaluated TEC associated with rFVIIa use throughout the institution. This evaluation uncovered a 17.5% incidence of TEC in patients who received rFVIIa for varying indications. It also was discovered that higher doses correlated with an increased risk for TEC (particularly arterial TEC), similar to that observed in the previous MUE and in outcomes of a recent meta-analysis.2 A multidisciplinary group—including pharmacists, cardiothoracic surgeons, and hematologists—further revised the guidelines in 2008 based on this new data. The dose for each indication was scrutinized, and the dose recommended for the cardiac surgery population was decreased from 90 mcg/kg to 40 mcg/kg based on our MUE data and additional literature supporting a potentially higher risk of TEC with higher doses. Recognizing additional deficits in the previous guidelines, we accounted for newly available vial sizes and added a policy in the pharmacy to round doses of rFVIIa down to the nearest mg dose, as to not waste medication and minimize overexposure.

The most recent MUE was performed from September 2008 through August 2009 to assess guideline compliance and TEC incidence with smaller doses. Data revealed that the TEC rate was further reduced to 13.2% and that less aggressive dosing was being adhered to (now 35.1 mcg/kg versus 87.9 mcg/kg previously).

Despite our success, how to best manage rFVIIa use between the hours of 6 pm and 2 am has been an ongoing challenge. According to data from the primary MUE, this is when approximately 50% of the rFVIIa doses are ordered. During this time period, the attending cardiac surgeon is not always available in-house to assess the need for surgical intervention versus rFVIIa use and the available night staff may not have the knowledge or expertise to determine an appropriate course of action. In addition, the clinical specialty pharmacist for this area also may not be available. Therefore, a step-wise approach to treat bleeding has been introduced for review. 

Making Progress with Albumin
Similar to rFVIIa, resources expended on albumin also have been a challenge to contain. While the risks and cost of this biologic are not as significant as rFVIIa, there was still a need to better manage albumin in the cardiothoracic surgery department. MUE criteria have been developed for use; however, lack of clinical data to support or refute albumin’s use in cardiac surgery as a resuscitative fluid has made changing established practices and perceptions difficult. In 2008, we spent nearly $1.1 million on albumin, of which approximately 25% was used in cardiothoracic surgery.

Many albumin MUEs have been conducted at OSUMC, and, in 2006, a trend was noted regarding excessive albumin use in the cardiothoracic surgery service. At the time, post-operative orders included albumin to be administered based on specific hemodynamic parameters. These parameters were largely derived from physician preferences and lacked substantial literature support. From this MUE, the following were identified:

• During March 2006, more than $15,390 was spent on albumin through the cardiothoracic surgery service; the estimated annualized cost was $184,600
• 88% of albumin was administered per order set parameters
• An estimated $14,800 would be lost annually due to waste because of the vial sizes in our automated dispensing cabinets (5% 500 mL vials). Albumin 5% 250 mL vials should be made available to the nursing unit for the cardiac surgery service to prevent waste.

Following this MUE, there was an albumin shortage, and with physician approval, it was removed from post-operative order sets. The next year, despite albumin price increases, we were able to show a cost avoidance of approximately $130,000 among all services in OSUMC’s Richard M. Ross Heart Hospital. However, the cardiac surgery unit remained the only unit able to override the automated dispensing cabinets for emergent access to albumin.

By 2009, trends in institutional spending on albumin were noted to be rising again, beyond that expected from inflation. Albumin expenditures at our entire facility were estimated to be $865,000 annually. An institution-wide MUE was conducted between January and March 2010, evaluating albumin use in the operating room (23%) and the cardiac surgery service (23%). Together, these two areas accounted for almost half of annual institutional albumin use. In order to assess reasons for use in these areas, the automated dispensing cabinets were programmed to require indication for use when removing albumin. The most common indications were low blood pressure (50%), low cardiac index (40%), and post-operative fluid resuscitation (10%). Also, 72% of albumin used was removed using the override function in the cabinets; after the override, orders were then placed in the computerized order entry system. Cultural habits in this unit facilitated the perception that orders to give fluid meant giving albumin. Concerns over abuse of the override status of albumin in the automated dispensing cabinets led to physician-supported removal of this function, leaving crystalloid fluids as the only resuscitative fluid available on override.

While we have clearly made strides changing perceptions and habits, managing albumin use in cardiac surgery is still an ongoing struggle. By bringing the scope of cost and actual benefit versus the perceived benefit and patterns of use to the attention of the patient care team, progress has been made. Recent educational efforts have reinforced that if fluid resuscitation is indicated, more cost-effective crystalloid agents should be used initially, reserving colloids as second-line therapies. In cardiac surgery the verdict is still undetermined regarding the optimal colloid of choice, but as with all pharmacotherapy, cost and benefit must be justifiable.

Securing Physician Buy-in
Working closely with physicians was critical to successfully advancing management efforts with both rFVIIa and albumin. This process involved educating physicians on current applicable literature and comparing this data to practices in place. Additionally, involving key physicians in the MUE process—particularly physicians that are the largest users of that product—and sharing the data with the whole patient care team is vital. Rationale for use is not always the only issue identified through these evaluations; often, process improvements, product availability issues, and clinical decision support matters are discovered as well. We also involved key physicians in writing and approving the guidelines for use so they are aware of what is being done and can assist in creating an atmosphere of ownership and peer accountability. One of the most challenging issues is ensuring that guidelines are followed prior to dispensing these products; continual education and communication has helped reinforce evidence-based approaches behind our guidelines.

Ensuring Continued Efforts
After the most recent MUEs, we decided to organize a multidisciplinary task force for each of these drugs with the goals of providing a forum for discussion, gathering and presenting conflicting opinions on how to use these agents, and, ultimately, resolving how best to use these biologics. The rFVIIa task force is co-chaired by a cardiothoracic surgeon and cardiothoracic surgery specialty pharmacist and involves other physicians, including trauma surgeons, hematologists, and hepatologists. Some of the issues we are currently addressing include:

• Identifying a tiered system of who can order this agent to prevent inappropriate use for bleeding that requires surgical intervention
• Identifying and empowering a gatekeeper for approved use and guideline adherence to optimize hemostasis before rFVIIa administration

Checklists and order sets are used at our institution to ensure certain steps are taken prior to dispensing other high risk or costly medications. Another goal of the task force is to approve a step-wise approach for using rFVIIa, which includes tables guiding blood product use with rFVIIa and alternative agents to rFVIIa (see Tables 2 and 3). A similar task force has been formed for albumin to ensure we monitor use and identify areas for improvement.

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Management efforts with both rFVIIa and albumin have required a significant time and staff commitment, but our efforts have paid off: between 2004 and 2005, $282,000 was saved because of monitoring the use of rFVIIa, and over the years costs have remained the same or decreased. As a result of these cost savings, pharmacy has been able to justify additional clinical pharmacist positions.

Conclusion
To ensure patients benefit from high-risk agents such as rFVIIa and albumin, developing guidelines for use is essential. However, efforts cannot end there, and pharmacy needs to be an integral part of endeavors to better use these drugs. Creating clinical pharmacist positions to manage these efforts through a collaborative approach that engages physician leadership and incorporates MUEs has been paramount to our success. In addition, guidelines need to be dynamic to accommodate new developments, and educational efforts and oversight must remain ongoing.

The authors would like to acknowledge Tony Gerlach, PharmD, BCPS, FCCM; Pam Burcham, PharmD; Erin Reichert, PharmD; and Tracy Macaulay, PharmD, BCPS, for their assistance with the MUEs discussed in this article.

References

1. Shander A, Goodnough LT, Ratko T, et al. Consensus recommendations for the off-label use of recombinant human factor VIIa (NovoSeven) therapy. Pharm Ther. 2005;30:644-58.
2. Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010;363(19):1791-800.
3. Cochrane Injuries Group Albumin Reviewers. BMJ. 1998;317(7153):235-40.
4. Wilkes MM, Navickis RJ. Ann Intern Med. 2001;135(3):149-64.
5. Finfer S, et al; SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. New Engl J Med. 2004;350(22):2247-56.

Danielle Blais, PharmD, BCPS, has practiced as a clinical assistant professor and clinical specialist in the areas of cardiothoracic surgery and cardiology for the past six years at OSUMC.

Erik Abel, PharmD, BCPS, has practiced as a clinical assistant professor and clinical specialist in the area of cardiothoracic surgery for the past three years at OSUMC.

The Albumin Debate: Colloids vs Crystalloids

For more than fifty years, albumin has been used in the treatment of the critically ill, but controversy still rages over the ideal resuscitative fluid, and there has been much debate on the value of crystalloids versus colloids. Despite the proposed benefits of more efficient volume expansion using colloids compared with crystalloids, albumin has risks, and the drug has been implicated in safety issues, such as acute lung injury and risk of infection—not to mention its high cost.

Two meta-analyses conducted to review the benefits and risks of colloids and crystalloids produced conflicting results. The first analysis3 suggested albumin use in critically ill patients afforded no additional treatment advantage and was actually associated with a 6% increase in risk of death. The second, larger meta-analysis4 reaffirmed no treatment advantage, but did not find any increased risk of death associated with albumin use. A randomized, controlled trial known as the SAFE trial,5 including over 6900 patients, reported that 28 days after randomization, albumin or saline fluid resuscitation resulted in equivalent mortality rates. Additionally, there were no statistically significant differences in length of mechanical ventilation, length of stay, or time until death of those that died during the study. While the results of this landmark trial are sometimes extrapolated to the cardiac surgery population, cardiac surgery patients were excluded from this study, leaving room for disparity and lack of robust data to support limiting albumin use in this population.

Alternative, less expensive, non-protein colloids, most commonly hydroxyethyl starch (HES), are also often discussed. The available HES solutions in the United States are shown, along with other resuscitative fluids, in Table 1. While less expensive than albumin, data has shown increasing doses of HES is associated with increased risk of bleeding, mediated by depletion of von Willebrand factor and factor VIII complex. Renal impairment also can be seen causing oncotic injury or viscosity-induced renal tubular obstruction.

Our surgeons prefer albumin as a colloid in cardiac surgery, and we have been working with the medical staff on this unit to start with crystalloids before turning to albumin.

Safety Considerations with IVIG Stabilizers

By Jerry Siegel,
PharmD, FASHP

Stabilizers are used to prevent IgG aggregation in IVIG products, as without them the aggregates could activate a complement cascade,
causing a severe anaphylactoid-type reaction. IVIG stabilizers are either carbohydrates or amino acids; each has significant anti-complementary
activity, which allows for safe intravenous administration. The challenge is that either stabilizer may initiate adverse events in individual patients based on their particular comorbidities. To prevent this, it is important to become familiar with the IVIG products and the specific stabilizer used therein.

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