May 2012 FAQs
May 2012 FAQs
Does metformin decrease the risk of breast cancer?
Does metformin decrease the risk of breast cancer?
Breast cancer is the most common site of cancer and is the second leading cause of cancer death in American women, accounting for approximately 40,000 deaths.1 Most of these deaths result from metastatic relapses after potentially curative therapy, which can include a combination of surgery, chemotherapy, and radiotherapy. Neoadjuvant chemotherapy, initially used only for locally advanced breast cancer, has become more common for patients with operable disease.2 This allows more individuals to undergo breast-conserving procedures and permits observation of response to treatment. Recent reports have eluded to the correlation between diabetes, specifically type 2, and the increased risk of breast cancer. Goodwin et al. retrospectively examined the prognostic associations of insulin in women with early-stage breast cancer and determined that high levels of fasting insulin were associated with distant recurrence and death.3 Additionally, Wolf et al. combined the results of 4 case-control and 6 cohort studies and found that diabetes was associated with a 13% and 25% increased risk of breast cancer in case-control and cohort studies, respectively. 4 Diabetes affects nearly 24 million Americans and the incidence is steadily increasing. The majority of diabetic patients are classified into 1 of 2 broad categories: type 1 diabetes, caused by an absolute deficiency of insulin due to destruction of beta cells of the pancreas, or type 2 diabetes, defined by the presence of insulin resistance and hyperinsulinemia.2
There are a number of proposed mechanisms that are thought to explain the correlation between breast cancer and diabetes.4 Insulin resistance leads to high plasma insulin concentrations, which activate extracellular pathways via activation of the insulin receptor (IR) or the insulin-like-growth-factor receptor (IGFR). Due to the increased expression of the IR in breast cancer, these pathways are altered and cell cycle progression in breast cancer cells can occur. Furthermore, patients with diabetes may have elevated plasma-free estrogen concentrations secondary to the increased production of sex hormones and decreased sex hormone binding globulin (SHBG). Estrogen stimulates breast cell division and supports the growth of estrogen responsive tumors.
Metformin, an oral antidiabetic drug in the biguanide class, is known to improve hyperinsulinemia and insulin resistance mainly by decreasing hepatic gluconeogenesis, increasing insulin sensitivity, and enhancing peripheral glucose uptake in skeletal muscle.2 There are 2 proposed mechanisms for metformin's potential benefit as an anti-breast cancer agent. First, as metformin systemically lowers circulating insulin levels, protein translation, cell growth, and proliferation of breast cancer cells, via activation of the IR or IGFR, is decreased indirectly.4 Second, metformin can directly activate AMP-dependent protein kinase (AMPK) which results in inhibition of cellular protein synthesis and growth. 5
There have been a number of trials evaluating the risk of cancer, including breast cancer, in diabetic patients taking metformin.6-9 Evans et al. investigated if metformin use in patients with type 2 diabetes reduces the risk of cancer.6 Investigators utilized record linkage databases based in Tayside, Scotland to identify patients diagnosed with malignant cancer and type 2 diabetes (n=983) and compared them in a 2:1 ratio to a control population (n=1846). The authors concluded that the risk of a subsequent cancer diagnosis was reduced in patients with type 2 diabetes who had any expose to metformin, with an odds ratio of 0.77 (95% confidence interval [CI] 0.64-0.92) for any metformin exposure versus no metformin exposure. In addition, there appeared to be a correlation between the increasing amount of metformin used and the incidence of cancer. Specifically, the odds ratio for cancer in patients who were dispensed greater than 964,000 mg of metformin was 0.57 (95% CI 0.43-0.75). Of note, the investigators did not distinguish between the different types of cancers, but included patients with a general diagnosis of malignant cancer.
Similar to Evans et al., Libby et al. utilized record linkage databases based in Tayside, Scotland to identify patients with type 2 diabetes on metformin versus a set of diabetic comparators not on metformin, individually matched using year of diabetes diagnosis.7 The primary outcome was diagnosis of cancer. Secondary outcomes included a diagnosis of bowel, lung, or breast cancers and all-cause mortality and mortality from cancer. A total of 4085 cancer-free patients with type 2 diabetes on metformin and a comparator group of 4085 patients not on metformin were included in the analysis. The primary outcome occurred in 7.3% and 11.6% of patients in the metformin and comparator groups, respectively (hazard ratio [HR], 0.46; 95% CI 0.40-0.53; p<0.001). When adjusted for variables such as sex, age, mean body mass index (BMI), and glycosylated hemoglobin A1C, smoking, and use of sulfonylureas and insulin, the adjusted HR was 0.63 (95% CI 0.53-0.75). All-cause and cancer-related mortality was lower in diabetic patients on metformin compared to non-users (14.9% versus 34.8%; 3.0% versus 6.1%, respectively). Specifically, the incidence of breast cancer in women was 1.3% versus 2.2% in the metformin and comparator groups, respectively (unadjusted HR 0.44; 95% CI 0.26-0.73). Furthermore, the incidence of bowel and lung cancers were also reduced in the metformin group (1.0% versus 1.9%, unadjusted HR 0.41; 95% CI 0.28-0.61; 0.9% versus 1.4%, unadjusted HR 0.49; 95% CI 0.32-0.74, respectively).
Jiralerspong et al. conducted a retrospective cohort analysis to evaluate whether metformin had an effect on pathologic complete response (pCR) rates in patients with diabetes and breast cancer.8 Investigators searched the Breast Cancer Management System Database at the University of Texas M.D. Anderson Cancer Center from January 1984 to May 2007. The finally study population was comprised of 2374 non-diabetic patients, 68 diabetic patients taking metformin, and 87 diabetic patients not taking metformin. Patients were administered 3 to 6 courses of anthracycline based chemotherapy. The rate of pCR was 24%, 8% and 16% in the metformin, non-metformin, and non-diabetic groups, respectively (p=0.02). Of note, there was no significant difference in the amount of chemotherapy delivered between the metformin and non-metformin groups; the average number of cycles was approximately 7 in both groups. Metformin use was found to be an independent predictor of pCR (p=0.04) after adjustment for diabetes status, BMI, age, stage, grade, estrogen receptor or progesterone receptor [ER/PR] and human epidermal growth factor receptor 2 [HER-2] status, and neoadjuvant taxane use.
The investigators performed an exploratory analysis of recurrence free survival [RFS] and overall survival [OS] at a median follow-up of 37 months. 8 The estimated RFS was not significantly different between each cohort occurring in 76% of patients in the metformin group, 66% of patients in the non-metformin group, and 73% of patients in the non-diabetic group (p=0.66). However, the OS rates were significantly different between the metformin, non-metformin and non-diabetic groups, respectively (81%, 78%, 86%; p=0.02).
Most recently, Bodmer et al. conducted a nested case-control analysis to evaluate the correlation between prolonged metformin use and other oral hypoglycemic medications and the risk of developing breast cancer.9 The UK-based General Practice Research Database (GPRD) was utilized to identify eligible patients. Women with type 2 diabetes who received at least 1 prescription for an oral hypoglycemic medication, such as a sulfonylurea, biguanides, thiazolidinediones, or other oral agents, with or without insulin were included. Within this diabetic population, women with invasive breast cancer or breast cancer in situ were identified and matched 4:1 with a control. Control patients (n=1153) were diabetics who were exposed to oral hypoglycemic medications, including metformin, but did not have breast cancer. The investigators concluded that long term use of metformin (>5 years or ≥ 40 prescriptions) was associated with a 56% decreased risk of breast cancer (p=0.01). Other oral hypoglycemic agents showed a reduction in occurrence of breast cancer with increasing use although the difference was not statistically significant.
The studies have produced significant epidemiological data that metformin reduces the risk of breast cancer and possibly other types of malignancies. Despite the positive outcomes, caution should be used when interpreting the findings of the above studies. The studies are observational in nature and a conclusion of association by causality cannot be drawn. As most of the data are obtained from medical review records, there may be certain confounders that were unidentified, such as concurrent medications, obesity, nutritional habits, and glycemic control, which may have influenced both the risk of cancer and the selection of metformin to treat diabetes. Additionally, misclassification of cancer diagnosis, various treatment regimens, time of diagnosis, staging, and histology may have affected the outcomes.
Metformin is an inexpensive medication with minimal side effects. Further evaluation of metformin as an anti-neoplastic agent can be vital in treatment of metastatic cancers, including breast cancer. A prospective analysis is warranted to appropriately define the role of metformin use in patients with type 2 diabetes and breast cancer on conventional chemotherapy.
1. Michaud LB, Barnett CM, Esteva FJ. Breast cancer. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds:Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York, NY: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=8007809. Accessed April 26, 2012.
2. Triplitt CL, Reasner CA. Diabetes mellitus. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds: Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York, NY: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=7990956. Accessed April 26, 2012.
3. Goodwin PJ, Ennis M, Pritchard KI, et al. Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol. 2001(1):42-51.
4. Wolf I,Sadetzki S,Catane R, Karasik A, Kaufman B. Diabetes mellitus and breast cancer. Lancet Oncol. 2005;6(2):103-111.
5. Stamboli V, Woodgett JR, Fantus IG, Pritchard KI, Goodwin PJ. Utility of metformin in breast cancer treatment, is neogenesis a risk factor? Breast Cancer Res Treat. 2009; 114 (2):387-389.
6. Evans JM, Donnelly LA, Emsilie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005; 330 (7503): 1304-1305.
7. Libby G, Donnelly LA, Donna PT, Alessi D, Morris AD, Evans JMM. New users of metformin are at low risk of incident cancer: a cohort study among patients with type 2 diabetes. Diabetes Care. 2009;32(9):1620-1625.
8. Jiralerspong S, Palla SL, Giordano SH et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. 2009; 27(20): 3297-3302.
9. Bodmer M, Meier C, Krakenbuhl S, Jick SS, Meier CR. Long -term metformin use is associated with decreased risk of breast cancer. Diabetes Care. 2010; 33(6):1304-1308.
Written by: Yana Labinov, PharmD PGY-1 Resident
Is dexmedetomidine an appropriate agent for long-term sedation in mechanically ventilated ICU patients?
Is dexmedetomidine an appropriate agent for long-term sedation in mechanically ventilated ICU patients?
Sedation in critically ill patients can help facilitate mechanical ventilation by improving ventilator synchrony, preventing self-extubation, reducing myocardial oxygen demands, and increasing patient comfort and safety.1 Unfortunately, sedation is not without complications. Over-sedation may lead to prolonged intubation which can increase the risk of ventilator-associated pneumonia, prolong intensive care unit (ICU) length of stay, and increase costs. Inappropriate sedation can also place patients at a greater risk for delirium which is associated with its own complications, such as increased mortality and risk of long-term cognitive impairment.2 Sedation, therefore, should be both goal-directed and patient-specific to optimize outcomes and prevent complications.
The current guidelines from the Society of Critical Care Medicine (SCCM) for analgesia and sedation in critically ill adults were published in 2002 and are currently undergoing revision.1 These guidelines recommend to first provide adequate pain control to patients before considering sedative agents. If sedation is still indicated, a sedation goal or endpoint should be established prior to initiation of therapy and re-assessed regularly to evaluate both efficacy and the continued need for sedative agents. The guidelines also promote the use of a validated sedation assessment scale when evaluating patients.
The Richmond Agitation Sedation Scale (RASS) has been shown to be an effective tool in a broad range of medical and surgical ICU patients.3 It ranges from a score of -5, where the patient is completely unarousable to +4, where the patient is overtly combative. Mild to moderate sedation has been described in clinical trials as RASS scores ranging from -3, where patients have movement or eye opening to voice but with no eye contact, to 0 where patients are calm and cooperative.
The current SCCM guidelines also promote frequent assessment for delirium as it has been shown to occur in up to 80% of critically ill patients. Delirium is defined as a disturbance in consciousness or change in cognition that develops over a short period of time and fluctuates throughout the day. Symptoms include inattentiveness, disorganized thinking, and agitation.2 The Confusion Assessment Method for the ICU (CAM-ICU) is a validated instrument shown to have both high sensitivity and specificity for the diagnosis of delirium and can be applied to mechanically ventilated patients with a RASS score of -3 or greater.4
Several factors must be taken into consideration when choosing an appropriate sedative agent for a specific patient including onset/duration of action, potential adverse effects, and presence of active metabolites. Benzodiazepines are sedative-hypnotic agents that exert their actions on the GABA A receptor leading to a decrease in neuronal excitability. These agents may cause anterograde amnesia and block the acquisition of new information and potentially unpleasant experiences.1 The various benzodiazepines available differ with respect to their pharmacokinetic profiles (e.g., onset/duration of action, distribution, metabolism, and excretion). These differences must to be taken into account when selecting the appropriate agent for a patient. The current SCCM guidelines recommend the use of lorazepam for most patients given either via intermittent boluses or by continuous infusion. They also recommend the use of diazepam or midazolam for acutely agitated patients requiring rapid sedation due to the shorter onset of action of these agents. However, it is currently very common in clinical practice to use midazolam as a continuous infusion for long-term sedation in the ICU. Midazolam undergoes unpredictable hepatic metabolism with active metabolites and renal excretion which can lead to high inter-patient variability.5 Patients with organ dysfunction are at a greater risk of accumulation of this agent potentially resulting in prolonged intubation and associated complications. The current SCCM guidelines even state that midazolam is "recommended for short-term use only as it produces unpredictable awakening and time to extubation when infusions are continued longer than 48 to 72 hours".
Propofol is another option for long-term sedation of critically ill patients. This agent acts as an agonist on the GABAA receptor as well as blocks excitatory NMDA receptors leading to a reduction in excitatory conduction. Propofol has a quick onset of action of approximately 1 to 2 minutes as well as short duration of action. Some significant potential adverse effects include dose-dependent hypotension, bradycardia, pain at the infusion site, and hypertriglyceridemia as it is formulated in a lipid emulsion. Currently, the SCCM guidelines recommend propofol as the preferred agent in patients where rapid awakening is important such as those requiring frequent neurological assessments.
Dexmedetomidine is approved for sedation in mechanically ventilated patients in the ICU and for perioperative sedation in non-ventilated patients. 6 It has a unique mechanism of action as a selective, centrally-acting alpha2 receptor agonist. Dexmedetomidine acts within the locus coeruleus- a main center of noradrenergic activity involved in the regulation of arousal, sleep-wakefulness, pain, anxiety, and agitation. Also, its actions upon presynaptic alpha2 receptors regulate sympathetic outflow from the brain by decreasing the amount of norepinephrine released leading to reductions in heart rate and blood pressure. Dexmedetomidine provides sedation along with sympatholysis, anxiolysis, and mild analgesic properties.7 Patients receiving dexmedetomidine experience a lighter sedation, remain more easily arousable, and are better able to cooperate with care and communicate with the healthcare team compared to other traditional agents. Also, since it has no activity on GABA or opioid receptors, dexmedetomidine does not produce respiratory depression so it does not require discontinuation prior to extubation.
The currently FDA-approved dosing for dexmedetomidine includes a loading dose of 1 mcg/kg given over 10 minutes followed by an infusion rate of 0.2 to 0.7 mcg/kg/hr for less than 24 hours.6 In clinical practice, the loading dose is typically omitted as it has been associated with an increased risk for hemodynamic compromise. Without a loading dose, dexmedetomidine has an onset of action of approximately 15 to 30 minutes. It undergoes hepatic metabolism and renal excretion so dose adjustments may be necessary in patients with organ dysfunction, although no specific guidelines are available. The most common adverse effects of dexmedetomidine include bradycardia and hypotension.
Dexmedetomidine has been compared to benzodiazepine infusions for sedation of mechanically ventilated ICU patients in 2 previous prospective, double-blind, randomized controlled trials.8,9 In both these trials, dexmedetomidine was given at higher doses and for a longer duration than currently approved by the FDA.
In the MENDS trial, dexmedetomidine was compared to continuous infusion lorazepam for sedation in 106 medical and surgical ICU patients requiring mechanical ventilation.8 Patients could receive doses of dexmedetomidine up to 1.5 mcg/kg/hr, and patients received study medication for a maximum of 120 hours or until extubation. Sedation was monitored using the RASS and delirium with the CAM-ICU. The primary endpoints were the number of delirium- and coma-free days and the percentage of time spent within 1 point of the desired RASS score. While the prevalence of delirium was about 80% in both arms, patients receiving dexmedetomidine had significantly more delirium- and coma-free days compared to patients who received lorazepam (median 7 days vs. 3 days; p = 0.01). When evaluating delirium-free days alone, there was no significant difference (median 9 vs. 7; p =0.09) while there was a significant difference for coma-free days (median 10 vs. 8; p= <0.001). Patients in the dexmedetomidine arm also spent a significantly greater percentage of time within 1 point of their nurse-targeted sedation goal (mean percentage of days, 80% vs. 67%; p = 0.04) and physician-targeted sedation goal (67% vs. 55%; p = 0.008). No differences were found in regards to days free of mechanical ventilation, ICU length of stay, or 28-day mortality. For safety endpoints, there was no difference in hypotension between the groups; however, more patients in the dexmedetomidine arm did experience bradycardia (17% vs. 4%; p = 0.03). This was the first trial to suggest that dexmedetomidine could safely be used at higher doses and for longer durations than approved, and may result in less delirium compared to benzodiazepine infusions. One of the main concerns regarding this trial was the use of a continuous infusion of lorazepam. Due to its longer half-life, critics felt this could have biased the trial in favor of dexmedetomidine.
The SEDCOM trial compared dexmedetomidine to continuous infusion midazolam for sedation in 375 medical and surgical ICU patients requiring mechanical ventilation.9 Dexmedetomidine was given at a rate of 0.2 to 1.4 mcg/kg/min to maintain light sedation, defined as a RASS score of -2 to +1, for up to 30 days or until extubation. Sedation was monitored using the RASS and delirium with the CAM-ICU. The primary endpoint was the percentage of time spent within the target RASS range. No difference was found between the 2 treatment groups (77.3% for dexmedetomidine vs. 75.1% for midazolam; p = 0.18). One of the secondary endpoints was to compare the prevalence and duration of delirium. Patients given dexmedetomidine had a significantly lower prevalence of delirium compared to patients who received midazolam (54% vs. 76.6%; p = <0.001) as well as more delirium-free days. Also, median time to extubation was 1.9 days shorter in patients who received dexmedetomidine (3.7 days vs. 5.6 days; p = 0.01); however, there was no difference found between the groups for ICU length of stay. For the safety endpoints, there was no difference between the groups in regards to hypotension. Dexmedetomidine patients were more likely to develop bradycardia (42.2% vs. 18.9%; p = 0.001). However, in the dexmedetomidine arm, only 4.9% of patients required an intervention (either stopping the infusion or the administration of atropine). The authors concluded from this trial that there was no difference between dexmedetomidine and midazolam in time spent at targeted sedation level, and patients receiving dexmedetomidine experienced less delirium and a shorter time to extubation. The median duration of study drug treatment for dexmedetomidine was 3.5 days (interquartile range 2-5.2). This trial also demonstrated that dexmedetomidine could safely and effectively be used at higher doses and longer durations without a loss of efficacy or increase in adverse events.
Both the SEDCOM and the MENDs trials used a benzodiazepine as their comparative treatment, which left clinicians to question how dexmedetomidine compared to propofol. In their pilot study, Ruokonen and colleagues compared dexmedetomidine to standard care, either propofol or midazolam depending on study center, for long-term sedation in 85 mechanically ventilated patients.10 Dexmedetomidine was initiated at a rate of 0.8 mcg/kg/hr and could be titrated to a maximum rate of 1.4 mcg/kg/hr. This trial incorporated daily sedation stops and measured the level of sedation by RASS every 2 hours. The primary endpoints were to evaluate the noninferiority of dexmedetomidine compared to standard care for maintaining target RASS score by measuring the proportion of time spent within range without the need for rescue medication as well as to evaluate length of ICU stay. Noninferiority of dexmedetomidine versus standard care was defined as a less than 10% difference between treatments; to meet criteria, the lower confidence interval (CI) of the estimated ratio of dexmedetomidine to standard care had to be greater than 0.90. Noninferiority for proportion of time at target sedation was not confirmed (dexmedetomidine 64% vs. standard care 63%; ratio 0.97 [0.79-1.15]). Target sedation at baseline was shown to influence time spent in the target RASS range. Patients with an RASS target of -3 to 0 were at target sedation 74% of the time with dexmedetomidine versus 64% with standard care; patients with a target of -4 or less reached the target 42% of the time with dexmedetomidine versus 62% with standard care. The length of ICU stay was similar between the groups. Results from the pilot study suggested that dexmedetomidine is comparable to standard care for moderate to light sedation (RASS -3 to 0) but may not be suitable for deeper sedation (RASS -4 or less).
Following the results of their pilot study, the authors conducted the MIDEX/PRODEX trial, and the results were published in March 2012.11 The study was designed as 2 parallel, phase 3, multicentered, randomized, double-blind, double-dummy, noninferiority trials and was conducted in Europe from 2007 to 2010. After patients were enrolled, they were randomized 1:1 to either continue standard care or to dexmedetomidine. The trial included 998 medical, surgical, and trauma ICU patients.
The main inclusion criteria were that the patients must have been adults (≥ 18 years) requiring mechanical ventilation with a clinical need for light-to-moderate sedation, defined as a target RASS score of -3 to 0, for 24 hours or more. Patients also had to be randomized within 72 hours of ICU admission and within 48 hours of starting continuous sedation. Important exclusion criteria were patients with an acute severe neurological disorder; a mean arterial pressure less than 55 despite adequate intravenous fluids and vasopressors; heart rate less than 55 beats per minute; type II or III AV nodal block; and the use of an alpha2 agonist or antagonist within the previous 24 hours.
Patients received continuous infusions of standard care or dexmedetomidine without loading doses. The dosing range of dexmedetomidine was 0.2 to 1.4 mcg/kg/hr. After randomization, patients were started at a dose matching the pre-randomization level for 1 hour and then the study medication could be titrated by nursing to maintain the target RASS score. Fentanyl boluses were used to treat pain and rescue medications (first-line propofol in MIDEX, first-line midazolam in PRODEX) if needed. Study treatments were titrated to individual sedation goals, and sedation was monitored using the RASS score. Target RASS scores were determined at the start of therapy and at daily sedation. Patients' RASS scores were monitored every 2 hours and prior to the use of any rescue treatment. Daily sedation stops were performed if possible and followed by a spontaneous breathing trial. Study medication was continued for a maximum of 14 days from randomization or until extubation. Patients were followed for a total of 45 days.
One of the primary efficacy endpoints was the proportion of time spent in the target sedation range without the use of rescue therapy. The noninferiority margin was set at 15% such that the lower 95% CI of the dexmedetomidine-to-standard care ratio must lie above 0.85 to meet criteria for noninferiority. Dexmedetomidine was shown to be noninferior to both midazolam and propofol based on percent of time spent at target sedation (midazolam 56.6% vs. dexmedetomidine 60.7%; propofol 64.7% vs. dexmedetomidine 64.6%). Of note, patients in both dexmedetomidine groups had higher actual RASS scores. This finding relates to a secondary endpoint of the nurses' assessment of arousability, ability to cooperate with care, and ability to communicate pain using a visual analogue scale. Patients receiving dexmedetomidine had better scores for all individual variables and overall when compared to both standard treatments (p < 0.001 for all comparisons).
Another primary efficacy endpoint was the duration of mechanical ventilation from randomization until the patient was free of all types of ventilation, including non-invasive techniques, for 48 hours. In the MIDEX trial, the median duration of mechanical ventilation was shorter with dexmedetomidine; however, there was no difference found in the PRODEX arm. In MIDEX, the median duration was 164 hours for midazolam and 123 hours for dexmedetomidine (p = 0.03) while in PRODEX, it was 118 hours for propofol and 97 hours for dexmedetomidine (p = 0.24). The median time to extubation was significantly shorter with dexmedetomidine compared to both standard agents. There were no significant differences between the groups for ICU length of stay, length of hospital stay, or 45-day mortality.
In regards to adverse events, compared to midazolam, patients receiving dexmedetomidine experienced significantly more hypotension (11.6% vs. 20.6%, p = 0.007) and bradycardia (5.2% vs. 14.2%, p < 0.001). The authors did not report what percentage of patients with these adverse effects required an intervention. In the PRODEX trial, there was no difference found for either hypotension or bradycardia between the 2 agents. Unlike previous trials where the presence of delirium was frequently measured, patients were only assessed for delirium using the CAM-ICU once at 48 hours after stopping study sedation. The authors provided rates of overall neurocognitive adverse events which included agitation, anxiety, and delirium. In the MIDEX trial, rates of neurocognitive events were not different between the 2 groups while in PRODEX, there was a significant difference favoring dexmedetomidine (18% vs. 29%; p = 0.008).
The MIDEX/PRODEX trials demonstrated that dexmedetomidine was noninferior to both midazolam and propofol for maintaining target sedation levels and to midazolam when compared for reduced the time of mechanical ventilation. While dexmedetomidine also reduced time to extubation compared to both agents, there was no significant difference in ICU or hospital length of stay. Patients who received dexmedetomidine did experience higher incidences of hypotension and bradycardia compared to the midazolam group, but there was no difference in these adverse effects between the propofol and dexmedetomidine groups. The authors of this trial concluded that dexmedetomidine is a feasible agent for long-term sedation.
Dexmedetomidine has been shown to have potential advantages when compared to standard therapy. In the SEDCOM and MIDEX/PRODEX trials, patients receiving dexmedetomidine had a shorter time to extubation compared to standard of care. A shorter duration of mechanical intubation could lead to potential benefits including a decreased length of stay in the ICU or hospital and a decrease in complications such as ventilator-associated pneumonia. Unfortunately, significant differences in these secondary endpoints have not yet been demonstrated in clinical trials.
Another potential benefit of dexmedetomidine is that it has been shown to be a delirium-sparing agent. Delirium is associated with an increase in mortality, length of stay, and costs as well as significant complications such as long-term cognitive impairment; utilizing strategies to decrease the prevalence and duration of delirium should be a major concern in critical ill patients. In both the MENDS and SEDCOM trials, patients receiving dexmedetomidine experienced less delirium compared to patients receiving benzodiazepine infusions. This finding was not reproduced in the MIDEX/PRODEX trial; however, this is possibly due to the fact that the CAM-ICU was only performed once during the trial and the prevalence of delirium was much lower than found in the previous trials. When compared to propofol in this trial, dexmedetomidine was shown to be associated with less delirium.
Dexmedetomidine does have the potential to cause adverse effects in patients due its mechanism of action as an alpha2 agonist. When compared to benzodiazepine infusions, dexmedetomidine has been associated with a higher incidence of bradycardia; however, in the SEDCOM trial, only about 5% of patients experiencing bradycardia required an intervention. Hypotension is another common side effect of dexmedetomidine. Compared to benzodiazepines in MENDS and SEDCOM, there was no difference found between the 2 groups while significantly more patients in MIDEX did experience hypotension in the dexmedetomidine group. In the PRODEX arm, there was no difference in either hypotension or bradycardia. Overall, dexmedetomidine appears to be a safe agent when compared to other standard therapies for sedation.
Lastly, an issue pharmacists often face with dexmedetomidine is cost. It is currently only available as a branded product while midazolam and propofol are both available generically. Dasta and colleagues performed an economic analysis utilizing data from the SEDCOM trial and compared costs from start of study drug until ICU discharge, including costs associated with ICU stay, mechanical ventilation, drug acquisition, and treatment of adverse effects.12 It was determined that dexmedetomidine was associated with a median total savings of $9679 (95% CI, $2314-17,045) stating that the primary drivers were reduced costs of mechanical ventilation and ICU length of stay. While the SEDCOM trial did show a statistically and clinically significant difference with a shorter time to extubation with dexmedetomidine, there was no difference found between the groups for ICU length of stay. While these conclusions are dependent on the superiority of dexmedetomidine for ICU length of stay, even if it was the same between the 2 groups, days without mechanical ventilation do, overall, cost less. It is plausible then that dexmedetomidine could be cost-savings when compared to midazolam. The authors did provide the drug acquisition costs based on 2007 average sales price and the dexmedetomidine cost was $58.31 for a 200 mcg vial compared to $1.56 for a 5 mg vial of midazolam.
Together, the results from the MENDS, SEDCOM, and MIDEX/PRODEX trials support the use of dexmedetomidine as a safe and effective agent for maintaining long-term, mild-moderate sedation in critically ill patients requiring mechanical ventilation. It has been shown to be noninferior to both of the commonly used agents, midazolam and propofol, for maintaining patients within their target sedation ranges. Also, these studies demonstrate that dexmedetomidine can safely be used for longer durations and higher doses than the current FDA-approved dosing.
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12. Dasta JF, Kane-Gill SL, Pencina M, et al. A cost-minimization analysis of dexmedetomidine compared with midazolam for long-term sedation in the intensive care unit. Crit Care Med. 2010;38(2):497-503.
Written by: Katherine Jennings, PharmD PGY-1 Resident
What is the Adverse Event Reporting System (AERS)?
What is the Adverse Event Reporting System (AERS)?
The US Food and Drug Administration (FDA) is a federal agency that has authority to regulate a variety of drugs, biologics, foods, cosmetics, and devices. As part of its oversight role, FDA continuously monitors the safety of approved drugs and biologics. One mechanism FDA uses to observe for new adverse events and medication errors potentially associated with marketed products is the Adverse Event Reporting System (AERS).1 AERS is a computerized information database that the FDA utilizes not only for identifying safety concerns, but also for evaluating a manufacturer's compliance with reporting regulations or for responding to outside requests for information. Data within AERS is continuously monitored by clinical reviewers at the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). If a potential serious risk signal is identified, further evaluation may be warranted such as conducting an epidemiologic study. In addition, FDA may determine that regulatory action is appropriate. This action could include updating a product's labeling information, restricting access or use of a medication, communicating new safety information to the public, and, in rare circumstances, removing the medication from the market.
There are limitations to AERS data.1 First off, adverse event reporting in the United States is primarily voluntary (although manufacturers are required to report events to the FDA) and received directly from healthcare professionals and consumers. Reported information may not be detailed enough to effectively determine a causal relationship between a medication and an adverse event. Second, adverse events reported to FDA are not all-encompassing. There are a variety of factors that may influence whether or not a medication-related adverse event is reported including media publicity about an event; therefore, AERS data are not useful for calculating the overall incidence of an adverse event in the US population.
AERS Potential Signals of Serious Risks/New Safety Information
Since 2008, FDA has been publishing quarterly reports regarding potential signals of serious risks/new safety information identified from AERS. 2 These reports may be accessed at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/ Surveillance/AdverseDrugEffects/ucm082196.htm . Table 1 summarizes the most recent AERS quarterly report (October to December 2011). The appearance of a medication on these quarterly lists does not mean that FDA has determined that a definite causal relationship between the medication and the risk exists. Rather, it means that FDA has identified a potential safety risk. Patients prescribed medications on these lists should contact their healthcare provider if concerned. The appearance of a medication on these lists should also not be read as a determination by FDA that a medication is unsafe – providers may continue to prescribe these medications. However, continued evaluation of the potential risk by FDA may lead to additional public communications or regulatory actions when appropriate.
Table 1. Potential Signals of Serious Risks/New Safety Information Identified from AERS – October to December 2011. 2
Product name Potential Risk Signal/New Safety Information Additional Information (as of February 15, 2012) Bortezomib (Velcade) Medication error -death from intrathecal administration Updated labeling to include language on fatal events with intrathecal administration. Brentuximab vedotin (Adcetris) Progressive multifocal leukoencephelopathy Updated boxed warning and warnings/precautions sections of the product labeling. Fluoroquinolone products Peripheral sensorimotor neuropathy FDA continues to evaluate. Current labeling contains information on peripheral sensorimotor neuropathy. Gabapentin (Neurontin) Increase in creatine phosphokinase levels and rhabdomyolysis FDA continues to evaluate potential for regulatory action. Gadolinium-based contrast agents Acute renal injury FDA continues to evaluate. Current labeling contains information on acute renal injury. Iloprost inhalation (Ventavis) Hemoptysis FDA continues to evaluate potential for regulatory action. Loperamide-containing products Pancreatitis FDA continues to evaluate potential for regulatory action. Magnesium sulfate for injection Fetal skeletal demineralization, hypermagnesemia, and other bone abnormalities with continuous long-term use in pregnant women FDA continues to evaluate potential for regulatory action. Milnacipran (Savella) Homicidal ideation FDA continues to evaluate potential for regulatory action. Pegloticase (Krystexxa) Anaphylaxis/infusion reactions FDA continues to evaluate potential for regulatory action. Phenytoin (Dilantin) and non-depolarizing neuromuscular blocking agents Drug interaction resulting in reduced efficacy of the non-depolarizing neuromuscular blocking agent FDA continues to evaluate potential for regulatory action. Polyethylene glycol (PEG) 3350 over-the-counter oral laxative (Miralax) Neuropsychiatric events FDA decided no action is needed at the present time. Proton pump inhibitors over-the-counter products Clostridium difficile-associated diarrhea FDA Drug Safety Communication issued. FDA continues to evaluate potential for regulatory action. Rubidium Rb 82 generator (CardioGen-82) Unintended radiation exposure to strontium isotopes following myocardial imaging scans CardioGen-82 voluntarily recalled in July 2011 with planned return to market. Boxed warning, dosage and administration, and warnings/precautions sections of labeling updated in February 2012. Sorafenib (Nexavar) Osteonecrosis of the jaw FDA continues to evaluate potential for regulatory action. Telaprevir (Incivek) Serious skin reactions including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Stevens-Johnson Syndrome (SJS) FDA continues to evaluate potential for regulatory action.
AERS is a computerized information database that FDA utilizes to primarily monitor safety concerns associated with approved drugs and biologics. Although limitations exist with regard to AERS data, FDA does publish quarterly reports regarding potentially serious medication-related risks based upon continuous monitoring of the AERS system.
1. Adverse Event Reporting System (AERS). Food and Drug Administration Website. Accessed April 25, 2012.
2. Potential signals of serious risks/new safety information identified from the Adverse Event Reporting System (AERS). Food and Drug Administration Website. Accessed April 25, 2012.