The safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia: Are all formulations created equal?

Original Citation

A randomized double blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. Wingard J, White MH, Anaissie E, Raffalli J, Goodman J, Arrieta A et al.

Overall Study Question

To determine the frequency of infusion-related reactions, nephrotoxicity and other safety parameters of amphotericin B lipid complex (ABLC) and two dose regimens of liposomal amphotericin B for empiric treatment of febrile neutropenic patients at risk for fungal infections.

Design:  A randomized, double-blinded, multicenter (18 centers) trial. Patients: Subjects aged >=2 years old who were neutropenic (ANC <500 cells/mm3) were enrolled in the study if investigators suspected a fungal infection, as demonstrated by fever after at least 72 h of broad-spectrum antibacterial therapy. Subjects were excluded from the study if they had liver disease (transaminase levels >10 times the upper limits of normal or a total bilirubin or alkaline phosphatase level >5 times the upper limit of normal), serum creatinine level >3 mg/dL, uncontrolled bacteremia, received greater than two doses of systemic amphotericin B or preparations containing amphotericin B within the previous 10 days, had an anticipated survival of less than 2 weeks or had clinical evidence indicating a deep or disseminated fungal infection.

Intervention: Patients were randomized to receive ABLC 5mg/kg/d or liposomal amphotericin 5mg/kg/d or 3mg/kg/d through central venous catheter over 2 hours. Treatment continued until the patient’s ANC was ³500 cells/mm3 or for up to 3 days after neutrophil recovery, to a maximum of 42 days. Administration of premedications prior to the first administration of medication was prohibited. After the first day, the clinician was allowed the option of prescribing premedications if a reaction to the first dose of a study drug occurred. Saline loading was used according to standard practices at each center.

Endpoints: The primary endpoint was the incidence of chills/rigors on day 1. Other outcome variables included the overall frequency infusion-related reactions (i.e., fever, nausea, vomiting, pain, hypertension, tachycardia, chest pain, vasodilation and hypotension), the incidence of medication use to treat infusion-related reactions (i.e. acetaminophen, meperidine, diphenhydramine, and hydrocortisone), nephrotoxicity (increase in serum creatinine >100% baseline), hypokalemia (potassium <3 mEq/L), anemia (hemoglobin <8 g/dL), and hepatotoxicity. The investigators also assessed clinical efficacy, although the study was not powered to evaluate this particular outcome.

Are the Results of the Study Valid?

Was assignment of patients randomized?

Yes. Patients were first stratified as “high risk” or “low risk” on the basis of use or nonuse of nephrotoxic immunosuppressants (i.e., cyclosporine or tacrolimus). Patients were then randomized to receive either ABLC, high or low dose liposomal amphotericin (1:1:1 randomization).

Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Yes.  All patients were accounted for and an intention-to-treat analysis was used.  Three hundred and forty-two patients underwent screening evaluation and 250 patients met the inclusion criteria.  Of these, 6 patients did not receive study drug for administrative reasons, thus a total of 244 patients who were randomized into the study were analyzed.

Were patients, their clinicians, and study personnel ‘blind’ to treatment?
Yes. The patient, investigator and study coordinators were blinded as to the treatment administered. When pharmacy staff prepared the study drug, they provided a blinded label and covered each dose with an opaque bag due to differences in colour and opacity of each agent. IV tubing was not masked, as visible differences between drugs were not discernable.
Were the groups similar at the start of the trial?

Yes. Baseline demographic, disease and other characteristics were similar across the groups.

Aside from the experimental intervention, were the groups treated equally?

Yes. Aside from the premedication after day 1 and saline loading that was allowed as medically indicated.  However, since the primary care provider was blinded, the groups were most likely treated similarly.

Overall, are the results of the study valid?
Yes.

What were the Results?

1. How large was the treatment effect?

Infusion-related reactions

The incidence of chills/rigors on day 1 was lower among patients administered liposomal amphotericin (3mg/kg 18.8% and 5mg/kg 23.5%) than in the ABLC group (79.5%, p<0.001).  In addition, the overall frequency infusion-related reactions on day 1 were also lower in the two liposomal amphotericin groups (3mg/kg 51.8% and 5mg/kg 48.1%) compared to ABLC (88.5%, p<0.001).  The lower incidence of reactions in the liposomal amphotericin arm was observed even after adjustment for age, sex, receipt of a bone marrow transplant, transplant type, or the use of immunosuppressants.  In addition, the number of medications used to treat infusion-related reactions was also lower in the liposomal amphotericin groups (3-mg/kg 43.5% and 5-mg/kg 37.0%) compared to ABLC (73.1%, p<0.001).

On days 2 to 5, when premedications for the prevention of infusion-related reactions were allowed, the incidence of infusion-related chills and the overall frequency of infusion-related reactions were lower in the ABLC group, but unchanged for the two liposomal amphotericin groups. The difference in the incidence of chills/rigors remained statistically significant in both liposomal amphotericin groups (3-mg/kg 21.0% and 5-mg/kg 24.3%) when compared to the ABLC group (50.7%, p<0.001). However, only the 5-mg/kg liposomal amphotericin and ABLC groups were different in terms of the incidence of overall frequency of infusion-related reactions (p=0.009).

Nephrotoxicity

Significantly less nephrotoxicity was observed in the liposomal amphotericin groups (3mg/kg 14.1%, 5mg/kg 14.8%) as compared to those the ABLC group (42.3%, p<0.001). This relationship persisted regardless of age, receipt of a bone marrow transplant, transplant type, or use of immunosuppressants. A peak creatinine value >2.5 mg/dL occurred in 7.1% of the 3-mg/kg liposomal amphotericin group, 3.7% of the 5-mg/kg liposomal amphotericin group, and 17.9% of the ABLC group (p=0.01).

When rates of nephrotoxicity were evaluated by patient-risk strata, there were no statistical differences between the 3 treatment groups, in either the high or low risk strata although there was a trend toward higher nephrotoxicity in the high-risk stratum than in the low-risk stratum for the 5-mg/kg liposomal amphotericin group (36.4% vs. 11.4%; p=0.053). However, there were no statistical differences between high- and low-risk patients in the 3-mg/kg liposomal amphotericin group (15.4% vs. 13.9%) or the ABLC group (45.5% vs. 41.8%).

When patients were divided into 3 age groups (<16 years, 16-40 years, and >40 years), there was no association between age and any of the nephrotoxicity end points for the two liposomal amphotericin groups. For the ABLC cohort there were no differences by age with regard to doubling of creatinine value, but there was a nonsignificant trend toward higher peak creatinine values at the 2.0, 2.5, and 3.0 mg/dL end points for older individuals in this group.

Hepatotoxicity, hypokalemia, and anemia

There were no statistically significant differences between the treatment groups with respect to hepatotoxicity, which occurred in 11.5% of all patients. [Note: The authors identify that no adjustments were made for multiple comparisons, however the p value was adjusted to p<=0.01 to avoid chance differences.]  Although there was no difference in frequency of hypokalemia between patients who received 5mg/kg liposomal amphotericin and ABLC, there was a nonsignificant trend toward a higher frequency of hypokalemia among patients receiving ABLC (37.2%) than among those receiving the 3-mg/kg dose of liposomal amphotericin (22.4%; p=0.041). The authors also claim a nonsignificant trend toward a higher frequency of anemia among patients receiving ABLC (59.0%) than among those receiving either the 3-mg/kg dose of liposomal amphotericin (36.5%) although the documented p value was p=0.004. [Note: Our recalculation also suggests a p<0.01]  Both liposomal amphotericin groups (3-mg/kg/d and 5-mg/kg/d) had lower rates of toxicity-related discontinuations of therapy than ABLC (12.9% and 12.3% vs. 32.1%; P=0.004).

2. How precise was the estimate of the treatment effect?

No 95% confidence intervals were reported by the authors.

Will the Results Help Me in Caring for My Patients?

Can the results be applied to my patient care?
Yes. While there are already published comparisons of toxicity between the conventional deoxycholate formulation and either amphotericin B colloidal dispersion (ABCD) or liposomal amphotericin B, there have been no published, randomized, blinded comparisons of the relative toxicity of ABLC and liposomal amphotericin B.  Thus, this study is the first randomized, double-blind evaluation of the safety of two lipid formulations of amphotericin B showing that ABLC at a dose of 5mg/kg is more toxic than liposomal amphotericin at a dose of 3mg/kg (with the exception of overall IRAE after the first day of treatment) or 5mg/kg.  The results of the study are consistent across categories of toxicity and encompass both infusion-related toxicity and renal toxicity.

Were all clinically important outcomes considered?

Yes.
Are the likely treatment benefits worth the potential harms and costs?

Depending on the type of fungal infection being treated, the recommended dose of liposomal amphotericin B may vary from 3-5mg/kg/day compared to 5mg/kg/day for ABLC.  In Canada, the approximate daily cost of liposomal amphotericin B (AmbisoneR, Fujisawa) for a 70 kg patient at a dose of 3mg/kg and 5mg/kg is $882 CAN and $1,470 CAN, respectively.  A 5mg/kg regimen of ABLC (AbelcetR, The Liposome Company) for this patient would cost approximately $800 CAN.

Commentary

Up until recently, liposomal amphotericin was much more expensive than ABLC and thus the obvious question arising from this trial is whether the reduced toxicity of liposomal amphotericin B is compelling enough to justify the extra dollars?  However, recently Fujisawa has decreased the acquisition cost for liposomal amphotericin in Canada such that the difference between preparations is currently less than $100 CAN/day for a 3mg/kg dose and $500 CAN/day for a 5mg/kg dose in a 70 kg patient.  While the apparently superior safety profile of liposomal amphotericin may justify the increased cost associated with it, one must also consider the available efficacy data when trying to determine which agent to use.  Unfortunately these agents have been used to treat different invasive fungal infections, in different patient populations and with varying dosage regimens.  In addition, all the comparative studies have been in small numbers of patients using historical controls or for empiric therapy.  While this study does not provide conclusive data with respect to the efficacy of the various lipid formulations, it does provide compelling toxicity data.

To date, there have been studies comparing toxicity between amphotericin B and the lipid formulations; however, there have not been any head to head comparisons of the various lipid-based agents.  Thus, this is the first well-designed study to look at infusion-related reactions and nephrotoxicity between two different amphotericin-lipid formulations.  This study was designed to examine relative product toxicities and although the efficacy of the two formulations is a secondary endpoint, the trial does not have sufficient statistical power to detect a difference.  Laying aside the issue of efficacy, the results of the study show that liposomal amphotericin had a lower incidence of chills/rigors as well as overall frequency of infusion-related reactions on day 1 (when no premedications were allowed) as well as after the first day (when premedications were allowed) compared to ABLC.  However, with premedications, the differences between liposomal amphotericin and ABLC were substantially lower.

The adverse event of greater concern with amphotericin is nephrotoxicity. These investigators found that the incidence of nephrotoxicity was higher for the ABLC group than the liposomal amphotericin treated neutropenic patients in the dosage regimens employed.  In a different study conducted by the same investigators, increases in serum creatinine to >2.5mg/dL with the use of amphotericin led to hemodialysis and was associated with greater mortality.  This trial clearly showed a larger percentage of patients reached serum creatinine levels >2.5mg/dL with ABLC than liposomal amphotericin B.

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