Pharmaceutical expense reduction
The intervention by the pharmaceutical care unit via implementing clinical guidelines in a referral hospital in Southwest of Iran significantly decreased the direct cost of albumin and IV pantoprazole, but not IVIG. Although evidence-based medicine supports clinical effectiveness and theoretical as well as pharmacological benefits of albumin, IV pantoprazole, and IVIG in certain conditions, they can be overused or their usage pattern may be inappropriate.
In the past three decades, clinical studies from different countries have indicated that at least 50% to more than 90% of albumin prescriptions are inappropriate [
10‐
13]. Overuse of albumin can be challenging for healthcare systems due to its high cost, limited availability, and potential risk of pathogen transmission [
10]. Regarding the costs, a report by the Iranian Food and Drug Organization of Health Ministry indicated that 472,089 vials of albumin 20% have been used within the first 9 months of 2008, which amounts to $21,600,000 (13). By implementing clinical guidelines in our center, the number of administered vials of albumin and its direct cost significantly reduced by 50.83% and 55.8%, respectively. In line with these data, use of albumin guidelines in a surgical intensive care unit (ICU) of a tertiary teaching hospital in the Unites States resulted in the significant reduction of albumin use (54%) and substantial cost-saving (56%) [
14].
IV pantoprazole overuse, besides its high cost, can be associated with life-threatening side effects (e.g.,
Clostridium difficile diarrhea) and drug interactions (e.g., clopidogrel) [
15]. Batuwitage et al. reported that proton pump inhibitor (PPI) use was inappropriate in 54% of its recipients in general medical wards of the UK [
16]. Although the rate of inappropriate use of IV pantoprazole was unknown in the pre-intervention period in our study, clinical guideline implementation was associated with a significant reduction in the number of administrations by 60.29% and direct cost by 83.92%.
Reduction in PPI use through implementation of appropriate guidelines has been also reported by other researchers. For example, Van Vliet et al. in the Netherlands demonstrated that guideline implementation for PPI prescription was associated with significantly fewer patients starting on PPIs during their hospitalization in two pulmonary medicine wards, compared to the control group (13% versus 21%) [
17]. A recent study on implementation of pharmaceutical practice guidelines for three costly medications at a tertiary hospital in Iran resulted in a significant reduction in prescriptions of albumin (36%) and IV pantoprazole (40%) [
18].
The comparable direct cost of possible alternative medications for albumin (Amino Acid 5% and 10%) and IV pantoprazole (oral omeprazole, oral pantoprazole, and IV ranitidine) between the pre-intervention and post-intervention phases demonstrated that our intervention and switch in use from the studied medications to the alternatives did not result in an increase in the costs. However, in the post-intervention period, the monthly direct costs of parenteral corticosteroids and rituximab, as IVIG alternatives, were significantly higher than the pre-intervention phase. This may be mostly related to the ability of pharmacies to provide these drugs, and subsequently, the increase in their demand during the post-intervention phase. In this regard, higher consumption and direct cost of IVIG in the post-intervention period is another reason to confirm that switch in use from IVIG to its alternatives is not the cause of increase in their cost within the post-intervention phase.
Despite its high cost, global limited sources, several potential adverse effects (e.g., acute kidney injury and hypersensitivity reactions), and documented cases of hepatitis C transmission [
19], the list of possible indications and amount of consumed IVIG have grown rapidly worldwide [
20]. The annual global demand for IVIG has shown an increase from 7.4 to 55.0 metric tons from 1984 to 2004 [
20]. To the best of our knowledge, there is no official national report or published literature on the consumption rate or cost of IVIG in Iran. Our current intervention failed to result in a significant reduction in the administration rate or direct cost of IVIG. This may be due to two major reasons:
First, completing the indication forms by physicians cannot be the sole effective approach for improving the pattern of IVIG use. More than 50 known off-label indications, patients’ critical clinical conditions, pharmacists’ insufficient knowledge regarding patients’ conditions, and their reliance on diagnosis notes in the patients’ medical charts may explain this result. In this regard, Frayha et al. demonstrated that concurrent action plans, including guideline dissemination to all healthcare teams along with indication form use, were associated with the improved utilization pattern, as well as a 14% decrease ($41,000) in the expenditure of IVIG [
21]. In keeping with these data, use of IVIG utilization management tools, including distribution of IVIG guidelines among specialists, development of preprinted IVIG order forms, and IVIG dose adjustments based on trough IgG levels for physicians resulted in a total cost saving of $3,038,056 in 2 years in four Canadian Atlantic Provinces [
22].
Second, there was a relative shortage of IVIG formulation in the pre-intervention phase, compared to the post-intervention period. In addition, financial resources for providing IVIG were higher and more available during the post-intervention phase in our center due to the start of the Health Revolution Program since May 2013 in Iran. This issue may have resulted in the increased demand for IVIG in the later phase of the study.
Clinical outcomes
Although our pharmacist-based intervention significantly decreased the total direct cost of the studied medications, it was associated with an elevated all-cause in-hospital mortality rate (14.9% versus 16.4% in the pre- versus post-intervention periods), which was statistically significant. This remained statistically significant even after adjusting for confounding factors, including clinical and demographic characteristics of the population. Besides our intervention, advanced age and internal ward admission were also significantly associated with all-cause in-hospital mortality.
The sub-group analysis revealed that the in-hospital mortality rates were higher in patients receiving albumin and IVIG during the post-intervention phase in comparison to the pre-intervention phase (1.4% and 0.5%, respectively). However, these differences were not statistically significant; also, these differences had no clinical relevance. In line with our data, a two-year evidence-based sequential multifaceted intervention was done on the use of albumin in eight ICUs in the USA. The intervention was associated with the estimated total cost saving of $2.5 million without any significant difference in ICU and in-hospital mortality rates between the baseline and post-intervention [
23].
The case appears to be somewhat different for IV pantoprazole, compared to albumin and IVIG in our cohort. The sub-analysis implicated that mortality rate was slightly higher (0.3%) in the pre-intervention period, compared to the post-intervention period. Although this rate was statistically significant, it was unlikely to be therapeutically important. Since stress-related mucosal damage prophylaxis is one of the major indications of IV pantoprazole, it seems crucial to determine the incidence of upper GI bleeding episodes in both pre- and post-intervention periods as a more direct and relevant clinical outcome index. However, extracting these data from the medical records of patients or the Hospital Information System in our center was not feasible during this study.
At least two studies by Van Vliet et al. [
17] and Mahmoudi et al. [
18] demonstrated that guideline implementation for PPI prescription did not increase the risk of upper GI disorders and GI bleeding, respectively. Finally, a systematic review of 20 randomized clinical trials in adult ICU patients (
n = 1971) regarding stress ulcer prophylaxis showed no significant difference between stress ulcer prophylaxis and placebo (no prophylaxis) in terms of mortality and GI bleeding [
24].
The average LOS in hospital, as another studied clinical outcome in our investigation, was one day longer in the post-intervention period in comparison with the pre-intervention phase. Although the difference was statistically significant, this should not be essentially interpreted as the direct effect of our intervention on prolonging LOS in hospital. In this regard, Freitas et al. examined variables related to high LOS outliers in nearly nine million inpatient episodes in the Portuguese National Health System. They demonstrated that different variables, such as teaching hospitals (versus non-teaching hospitals), increased age, emergent surgeries (versus planned or elective surgeries), and number of comorbidities, were significantly associated with increased LOS [
25].
Data regarding the number of comorbidities and type of surgery were not available in our population to evaluate their possible confounding effects on LOS. Furthermore, patients in the pre- and post-intervention periods were not matched in terms of age and hospital wards. In contrast to our findings, the mean LOS was comparable before and after guideline implementation for three costly medications (albumin, IV pantoprazole, and enoxaparin) in a teaching hospital in Iran [
18]. Differences in the complexity of both hospitals and patients, as major determinants of LOS, can partially explain LOS disparities in our study and the study by Mahmoudi and colleagues.
Inappropriate use
The two most common inappropriate uses of albumin in the post-intervention period were management of edema in patients without severe hypoalbuminemia (24.58%) and a component of parenteral nutrition (19.87%). Similarly, Jahangard-Rafsanjani et al. reported that 46.6% of albumin administrations in a healthcare setting in Tehran were for nutritional support [
13]. Tanzi et al. in a study on 1672 patients from 53 different healthcare facilities in the USA showed that all 142 indications of albumin for individuals with serum albumin levels below 2 g/dL were inappropriate [
12]. It has been demonstrated that enteral and/or parenteral nutrition with amino acids, along with adequate calorie intake rather than albumin, can improve serum albumin level in malnourished patients [
10].
Regarding IV pantoprazole, oral tolerance in the absence of enteral tube and lack of indications for prophylaxis of stress-related mucosal damage are the two leading causes of disapproving the medication requests in the intervention phase of our study. Accordingly, there is a misconception by a number of physicians that parenteral PPIs may be more efficacious than their oral formulations. However, no head-to-head or comparative clinical studies have confirmed this idea. Nevertheless, since PPIs degrade in acidic environments and are formulated in a delayed-release formulation, they should not be crushed for administration through the enteral feeding tube [
26]. In the Netherlands, preventing medication-associated complications in two pulmonary medicine wards, including NSAIDs, corticosteroids, and antibiotics, was the most common reason for PPI use [
27].
In contrast to albumin and IV pantoprazole, inappropriate use of IVIG in our cohort in the post-intervention period was only limited to five cases. Similarly, Constantine et al. demonstrated that after implementing IVIG guidelines and feedback reports in the Atlantic Canada, IVIG utilization for labeled indications remained unchanged (37.1% and 36.1% in the baseline and post-intervention, respectively). The rate of unlabeled but potentially indicated use of IVIG increased from 52.4% at baseline to 58.1% in the implementation phase [
22].
A four-year experience in an academic center in Italy implicated that the majority of IVIG uses in neurological and neuromuscular disorders were identified to be either recommended (60.4%) or reasonable (25.6%) [
28]. Therefore, according to the findings of our cohort and other relevant studies, as well as suggestions by Pendergrast et al., guideline implementation seems unlikely to have significant decreasing effects on the total amount of IVIG consumption in academic and teaching environments [
20].
Conducting clinical trials regarding IVIG indications, which have been only proposed in case reports and uncontrolled case series, using effective and cheaper treatments rather than IVIG, and developing a multispecialty team along with multiple-level surveillance for evaluating and approving IVIG indications can be taken into account as effective approaches to improve the usage pattern of this highly popular and commonly prescribed, but limited-source and costly medication.