March 2012 FAQs
March 2012 FAQs
Do statins increase the risk of developing diabetes?
Do statins increase the risk of developing diabetes?
Cardiovascular disease (CVD) is by far the leading cause of death in the United States.1 Risk factors for CVD included hypertension, dyslipidemia, cigarette smoking, male gender, presence of diabetes, physical inactivity, obesity, and age. HMG Co-A reductase inhibitors (statins) are a class of medication that reduce low-density lipoprotein (LDL) cholesterol levels by competitively inhibiting the enzyme HMG-CoA reductase, which is the rate-limiting step in cholesterol biosynthesis.2 In addition to their lipid-lowering effects, statins are also believed to have pleiotropic effects that benefit cardiovascular health.3 It is no surprise, then, that lipid-modifying agents make up the largest percentage of US prescription volume by drug class.4
Statin therapy significantly reduces cardiovascular events in individuals with and without diabetes.5,6 However, there is emerging evidence that statin therapy may lead to an increased risk of new-onset diabetes.7-10 Individuals with diabetes are at increased risk of microvascular (retinopathy, for example) and macrovascular (myocardial infarction, for example) events. If statin therapy is associated with a significant increase in the incidence of new onset diabetes, health care providers may need to reconsider the ideal patient population for primary and secondary prevention of cardiovascular events with these drugs.
The 6000-patient West Scotland Coronary Prevention Study (WOSCOPS) examined a number of patient factors relative to the risk of developing diabetes in a group of subjects randomized to pravastatin or placebo and followed for a period of 3.5 to 6.1 years.11 Multivariate analysis revealed 4 characteristics that increased the risk of developing diabetes: body mass index (BMI) >25.65, natural log triglyceride level >0.5, baseline glucose >81 to 84.6 mg/dL, and randomization to the placebo group (instead of pravastatin). There was a 30% relative risk reduction from pravastatin therapy in the multivariate analysis. The authors of this study defined diabetes as a fasting blood glucose level >126 mg/dL, which is the agreed American Diabetes Association definition. However, the authors had 2 additional criteria that had to be met for a subject to be classified as a new-onset diabetic. To control for patients that may have forgotten to fast before lab testing, 2 fasting blood glucose levels of >126 mg/dL were required. Additionally, new-onset diabetes cases had to show a fasting blood glucose increase from baseline of >36 mg/dL. This criterion intended to identify only the subjects that had a significant deterioration of glucose control.
The 2008 JUPITER trial was a very large (n=17,802) clinical trial that intended to show a benefit in the primary prevention of cardiovascular events in a patient population without hyperlipidemia, but with elevated levels of high-sensitivity C-reactive protein.12 High-sensitivity C-reactive protein is an inflammatory biomarker, and elevated levels are associated with higher risk of cardiovascular events. Statins have been shown to reduce high-sensitivity C-reactive protein in a number of patient populations. Aside from the efficacy endpoints of the JUPITER trial, a number of adverse event parameters were reported as well over the median follow-up period of 1.9 years. Contrary to the findings of WOSCOPS, the 2008 JUPITER trial found a small increase in the risk of incident physician-reported diabetes in statin-treated patients (270 in the rosuvastatin group vs. 216 in the placebo group, p=0.01), though the mean fasting blood glucose level in both groups was identical during the follow-up period.
In an attempt to clarify the conflicting data on statins and diabetes risk, Rajpathak and colleagues performed a meta-analysis of large statin randomized controlled trials (n=6) that reported data on diabetes.9 In the study population of approximately 58,000 subjects, the authors found a small increase in diabetes risk for patients treated with statins versus placebo (relative risk [RR] 1.13, 95% confidence interval [CI] 1.03 to 1.24) with no significant heterogeneity across trials. The hypothesis-generating WOSCOPS study was not included in this initial analysis, but the larger and more recent JUPITER trial was included. When the WOSCOPS data were included in the meta-analysis, the risk of diabetes was no longer statistically significant (RR 1.06, 95% CI 0.93 to 1.23), and there was significant heterogeneity (p=0.03).
A larger 2010 meta-analysis of more than 90,000 patients (including those in WOSCOPS and JUPITER) was performed, adding additional data from previously-unpublished trials (n=13).8 Of note, the primary analysis in this study eliminated the requisite blood glucose increase of >36 mg/dL from baseline diagnostic criterion from the WOSCOPS subjects. Without this additional requirement, the incident diabetes risk from WOSCOPS was different (and non-significant) versus the originally reported WOSCOPS data – odds ratio (OR) 0.79 (95% CI 0.58 to 1.10). In the end, the authors again found a small increase in the risk of diabetes for patients treated with statins (OR 1.09, 95% CI 1.02 to 1.17) with little heterogeneity between trials. The authors note that even when the original diabetes criteria from WOSCOPS were used, the end result of the meta-analysis did not change (data not shown in paper).
Culver and colleagues investigated the link between statin use and incident diabetes in more than 150,000 subjects from the Women's Health Initiative. 10 This broad study aimed to answer longitudinal questions about postmenopausal women's health by enrolling subjects into 1, 2, or all 3 clinical trial arms: the Dietary Modification Trial, the Hormone Trial, and the Calcium and Vitamin D trial. The subjects in this long-term study were postmenopausal women, with an average age of 63 years, enrolled from 1993 to 1998 with currently ongoing follow-up. Aside from the clinical trial medications, these women continued to be treated normally for other medical conditions, such as hyperlipidemia, resulting in a very large subject pool, some of whom were indicated for and received statin therapy, and some who did not. Incident diabetes was measured by semi-annual or annual patient survey in which subjects were asked if they had physician-diagnosed diabetes. Again, the authors found an increased risk of incident diabetes for women that were taking a statin at baseline. The increased risk found in this study was larger than the previously discussed meta-analyses, yielding a hazard ratio 1.48 (95% CI 1.38 to 1.59) in multivariate analysis. This model adjusted for age, race, education, smoking status, BMI, physical activity, alcohol intake, caloric intake, family history of diabetes, hormone therapy use, clinical study arm, and self-reported history of CVD at baseline. However, Culver's study was limited by its observational design and has a limited scope of external validity because of the specific patient population (postmenopausal women).
Additional literature has evaluated a potential for a dose-relationship between statins and diabetes. A 2011 meta-analysis by Preiss and colleagues showed an increased risk of incident diabetes with intensive-dose statin therapy versus moderate-dose (OR 1.12, 95% CI 1.04 to 1.22).7 A multivariate analysis of pooled data from 3 atorvastatin 80 mg/day trials found that risk of incident diabetes was increased with increasing baseline fasting blood glucose, BMI, hypertension, and fasting triglycerides.16
The mechanism behind this increase in incident diabetes is not known. In a systematic review/meta-analysis by Baker and colleagues, statins as a class had no impact on insulin sensitivity, though individually pravastatin increased insulin sensitivity and simvastatin worsened it.13 Statins increase intracellular LDL cholesterol, and cholesterol loading has been shown to inhibit the rate-limiting step of intracellular glucose metabolism in cultured cells.14,15
On February 28, 2012, the Food and Drug Administration (FDA) published a safety communication to alert the public and healthcare providers to changes in the prescribing information for statins.17 Specific to diabetes, the adverse event information has been updated to include the potential for increased blood sugar and glycosylated hemoglobin. The information about blood glucose was added based on much of the literature reviewed in this summary. Overall, the agency states that the cardiovascular benefits of statins outweigh the small increased risk of diabetes. The safety communication also included the following changes unrelated to blood glucose:
- Routine periodic monitoring of liver function tests (LFTs) no longer specified – LFTs should be checked at baseline and as clinically indicated thereafter
- Potential for non-serious and reversible cognitive side effects added to adverse event information
- Lovastatin's label has been extensively updated with regard to drug interactions including contraindications and dose limitations
The evidence linking statins to incident diabetes comes from post-hoc analyses, meta-analyses, and observational data. Though the link between statin use and diabetes has not been evaluated in as a primary outcome in prospective studies, the available data have consistently shown a small, but significant increased risk of new onset diabetes with statin use – a point noted by the FDA in support of statin labeling changes.
Statins are by no means the only frequently used drug class that has been associated with increased risk of diabetes. Second-generation antipsychotics, beta blockers, and thiazide diuretics all have been associated with increased risk of diabetes but remain clinical mainstays due to a favorable balance between benefit and risk.14 Thus, it is important to put the cardiovascular benefits of statins and risk of diabetes into context. Sattar and colleagues reported that 255 patients would have to be treated with a statin for 4 years before a statin-induced case of diabetes is expected to occur.8 In the same 255 patients, 9 vascular events such as stroke or myocardial infarction are expected to be prevented by statins over the same time period. Furthermore, it is important to keep in mind that statins are highly effective in individuals with type 2 diabetes.6 In light of the observed increased risk of incident diabetes with statin therapy, subpopulations with low cardiovascular risk may have a more favorable risk/benefit with lifestyle modifications as opposed to statin therapy for primary prevention of cardiovascular events. The exact makeup of this subgroup and the actual risk/benefit remains to be seen. The small absolute increase in diabetes risk and the proven clinical utility of statins in primary and secondary prevention require clinicians to weight the risk and benefit of statin therapy for any given patient.
1. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143-3421.
2. Genser B, Grammer TB, Stojakovic T, Siekmeier R, Marz W. Effect of HMG CoA reductase inhibitors on low-density lipoprotein cholesterol and C-reactive protein: Systematic review and meta-analysis. Int J Clin Pharmacol Ther. 2008;46(10):497-510.
3. Robinson JG. Models for describing relations among the various statin drugs, low-density lipoprotein cholesterol lowering, pleiotropic effects, and cardiovascular risk. Am J Cardiol. 2008;101(7):1009-1015.
4. IMS Institute for Healthcare Informatics. The use of medicines in the United States: review of 2010. IMS Institute for Healthcare Informatics Web site. http://www.imshealth.com/imshealth/Global/Content/IMS%20Institute/ Documents/IHII_UseOfMed_report%20.pdf . Accessed February 28, 2012.
5. Cholesterol Treatment Trialists' (CTT) Collaboration, Baigent C, Blackwell L, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: A meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-1681.
6. Cholesterol Treatment Trialists' (CTT) Collaborators, Kearney PM, Blackwell L, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: A meta-analysis. Lancet. 2008;371(9607):117-125.
7. Preiss D, Seshasai SRK, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: A meta-analysis. JAMA. 2011;305(24):2556-2564.
8. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: A collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735-742.
9. Rajpathak SN, Kumbhani DJ, Crandall J, Barzilai N, Alderman M, Ridker PM. Statin therapy and risk of developing type 2 diabetes: A meta-analysis. Diabetes Care. 2009;32(10):1924-1929.
10. Culver AL, Ockene IS, Balasubramanian R, et al. Statin use and risk of diabetes mellitus in postmenopausal women in the women's health initiative. Arch Intern Med. 2012;172(2):144-152.
11. Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the development of diabetes mellitus: Evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation. 2001;103(3):357-362.
12. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195-2207.
13. Baker WL, Talati R, White CM, Coleman CI. Differing effect of statins on insulin sensitivity in non-diabetics: A systematic review and meta-analysis. Diabetes Res Clin Pract. 2010;87(1):98-107.
14. Sampson UK, Linton MF, Fazio S. Are statins diabetogenic? Curr Opin Cardiol. 2011;26(4):342-347.
15. Hao M, Head WS, Gunawardana SC, Hasty AH, Piston DW. Direct effect of cholesterol on insulin secretion: A novel mechanism for pancreatic beta-cell dysfunction. Diabetes. 2007;56(9):2328-2338.
16. Waters DD, Ho JE, DeMicco DA, et al. Predictors of new-onset diabetes in patients treated with atorvastatin: Results from 3 large randomized clinical trials. J Am Coll Cardiol. 2011;57(14):1535-1545.
17. FDA drug safety communication: important safety label changes to cholesterol-lowering statin drugs. U.S. Food and Drug Administration Web site. http://www.fda.gov/Drugs/DrugSafety/ucm293101.htm. Accessed February 28, 2012.
Written by: James Stevenson, PharmD, PGY1 Pharmacy Practice Resident
What is glucarpidase and what is its role in treatment of methotrexate toxicity?
What is glucarpidase and what is its role in treatment of methotrexate toxicity?
Methotrexate is an antifolate chemotherapeutic agent that is commonly used at a variety of doses in a number of chemotherapy regimens.1 High-dose methotrexate is used for certain cancers including acute lymphoblastic leukemia, lymphoma, and osteosarcoma.1,2 Without protective measures, high-dose methotrexate can result in neurologic, hematologic, hepatic, and renal toxicity.
Strategies used to protect against methotrexate toxicity include hydration to promote renal output, urine alkalinization to increase methotrexate solubility in the urine, and administration of folic acid derivatives such as leucovorin.1,2 Despite these preventative actions some patients develop methotrexate-induced renal dysfunction from drug precipitation or direct toxicity on the renal tubules, with reported incidences ranging from 1.8% to 48% depending on the population. In the setting of renal dysfunction, methotrexate elimination is delayed leading to increased plasma concentrations and a greater potential for ongoing toxicities including worsening nephrotoxicity. High-dose leucovorin may not provide sufficient rescue in the setting of elevated methotrexate concentrations for an extended period of time, and there is some concern that high-dose leucovorin may promote tumor progression.2 Dialysis has been reported to decrease methotrexate levels by 26% to 82%; however, the usefulness of dialysis is limited due to the invasive nature of the procedure and the rebound in methotrexate concentrations that can occur after dialysis is stopped.1
Another treatment option for methotrexate toxicity in the setting of renal dysfunction was recently approved in the United States.3 Glucarpidase (formerly known as carboxypeptidase G2) is approved for the treatment of methotrexate plasma concentrations >1 µMol/L in patients with delayed methotrexate clearance due to renal dysfunction. This agent has been available in the United States since 2007 for both systemic and intrathecal methotrexate toxicity under an emergency use protocol.4,5 It is currently only approved for systemic toxicity but is still available from the manufacturer for emergency use for intrathecal methotrexate toxicity.4 Glucarpidase is a recombinant carboxypeptidase enzyme produced by genetically modified Escherichia coli.3 The enzyme cleaves the terminal glutamate residue from folic acid and antifolate drugs such as methotrexate, which converts methotrexate to its inactive metabolite 2,4-diamino-N10-methylpteroic acid (DAMPA), thus providing a nonrenal route for methotrexate elimination. There is a small risk of anaphylaxis or other allergic reactions (<1%) with glucarpidase, but it has not been associated with other serious adverse effects and is generally well-tolerated.
Glucarpidase is administered as a single intravenous bolus injection of 50 units/kg over 5 minutes.3 There are limited data regarding the efficacy of repeat doses. Each glucarpidase unit corresponds to the enzymatic cleavage of 1 µMol/L of methotrexate per minute at 37°C. According to the product labeling, glucarpidase distribution is limited to the plasma, and plasma activity declines with a half-life of 5.6 hours. Methotrexate immunoassays should not be drawn for 48 hours after administration of glucarpidase because DAMPA can interfere with these assays. If it is necessary to obtain a methotrexate concentration within 48 hours, a chromatographic assay method must be used.
Patients who receive glucarpidase for methotrexate toxicity should continue to receive hydration, urine alkalinization, and replenishment of folic acid stores.3 Administration of leucovorin within 2 hours before or after glucarpidase is not recommended since leucovorin is also a substrate of glucarpidase. The pre-glucarpidase leucovorin dose should be given for the first 48 hours starting 2 hours after the administration of glucarpidase. After 48 hours, methotrexate concentrations can be used to guide subsequent leucovorin dosing.
Efficacy of glucarpidase for management of methotrexate toxicity has been described in numerous case reports due to its availability for emergency use. In addition, 3 clinical trials with this agent have been published.6-8 Schwartz and colleagues conducted an open-label, uncontrolled evaluation of glucarpidase in a cohort of 43 adult patients (mean age 54 years) receiving methotrexate >1 g/m2 of body surface area for either solid or hematopoietic malignancies.6 Patients were given a single dose of glucarpidase 50 units/kg over 5 minutes if their methotrexate concentrations remained >5 µMol/L at ≥42 hours after the start of methotrexate therapy, or if they had evidence of renal failure (serum creatinine [SCr] >1.5 times the upper limit of normal or the presence of oliguria) with methotrexate concentrations >1 µMol/L. Hydration, urine alkalinization, and leucovorin therapy were also provided. At baseline, the median methotrexate concentration was 10.5 µMol/L (range 1 to 1187 µMol/L) and 93% had an elevated SCr. Glucarpidase was administered a median of 56 hours from the start of the methotrexate infusion. Twenty-four patients (56%) provided serum samples for analysis of methotrexate concentrations, which identified a median decrease to <0.1 µMol/L after a median of 15 minutes (range 7 to 50 minutes). Serum creatinine normalized or improved in 93% of patients after glucarpidase administration. The authors concluded that glucarpidase effectively reduced methotrexate levels in patients with impaired renal function.
Another open-label, uncontrolled trial of glucarpidase was conducted in 65 patients from 13 European countries.7 Patients (median age 15.4 years, range 0.9 to 71.8 years) were included if they had methotrexate concentrations >10 µMol/L at 36 hours, >5 µMol/L at 42 hours, or >3 µMol/L at 48 hours after the start of methotrexate therapy and evidence of renal failure (SCr >1.5 times the upper limit of normal or the presence of oliguria). At baseline, median serum methotrexate concentrations were 11.93 µMol/L (range 0.52 to 901 µMol/L). A single dose of glucarpidase 50 units/kg was administered over 5 minutes at a median of 52 hours (range 25 to 178 hours) after the start of the methotrexate infusion. Patients also received leucovorin but other supportive care measures were not specified. Methotrexate levels decreased by a median of 97% (range 73% to 99%) within 15 minutes. The effect of glucarpidase on renal function was not reported, but 3 patients did not respond adequately to glucarpidase and experienced progressive renal failure. The authors concluded that glucarpidase is beneficial to most patients with elevated methotrexate concentrations and renal dysfunction especially when administered between 48 and 72 hours after the methotrexate.
The largest trial with glucarpidase to date included 100 patients (median age 17 years, range 0.3 to 82 years) who received concurrent therapy with leucovorin with or without the experimental drug thymidine under an emergency use protocol.8 Only the data for patients who did not receive thymidine are presented here (n=56). Patients were eligible to receive glucarpidase if they had methotrexate concentrations ≥10 µMol/L at ≥42 hours after the start of the methotrexate infusion, or if SCr was >1.5 times the upper limit of normal or creatinine clearance was ≤60 mL/min/m2 and methotrexate concentrations were ≥2 standard deviations above the mean at ≥12 hours. Most patients received a single dose of glucarpidase 50 units/kg over 5 minutes but a few patients received 2 or 3 doses if they met protocol-specified criteria. Prior to glucarpidase therapy, median methotrexate concentrations were 12.3 µMol/L (range 0.76 to 835 µMol/L). Glucarpidase administration at a median of 66 hours (range 22 to 192 hours) after the start of the methotrexate infusion decreased methotrexate levels by 98.8% (range 86.1% to 99.5%) within 15 minutes. Further decreases in methotrexate concentrations were not observed after second or third glucarpidase doses. In the total study population, SCr normalized after a median of 22 days (range 5 to 77 days) and 27 patients underwent hemodialysis or hemoperfusion procedures. Multiple logistic regression analysis identified a statistically significant association between glucarpidase administration >96 hours after the start of the methotrexate infusion and the development of ≥grade 4 toxicity, suggesting that earlier administration is most effective. The authors concluded that early administration of glucarpidase effectively treats patients with methotrexate-induced renal dysfunction.
Patients receiving high-dose methotrexate should be closely monitored for the development of renal toxicity. Frequent monitoring of methotrexate concentrations may allow for early detection of delayed elimination. Renal function should also be closely monitored. Clinicians can consider glucarpidase therapy in patients with evidence of methotrexate-induced renal toxicity and plasma concentrations >1 µMol/L along with ongoing supportive care with hydration, urine alkalinization, and leucovorin therapy. Use of glucarpidase in patients with methotrexate-induced renal dysfunction may promote efficient methotrexate elimination and prevent ongoing toxic effects. Published trials suggest that glucarpidase may be most beneficial when administered within 48 and 72 hours of the start of the methotrexate infusion.
- Widemann BC, Adamson PC. Understanding and managing methotrexate nephrotoxicity. Oncologist. 2006;11(6):694-703.
- Patterson DM, Lee SM. Glucarpidase following high-dose methotrexate: update on development. Expert Opin Biol Ther. 2010;10(1):105-111.
- Voraxaze [package insert]. Brentwood, TN: BTG International, Inc; 2012.
- Voraxaze U.S. Treatment Protocol. BTG International Web site. http://www.btgplc.com/products/voraxaze-us-treatment-protocol/voraxaze174-us-treatment-protocol . Accessed February 21, 2012.
- U.S. National Institutes of Health. Treatment Protocol of Voraxaze for Patients Experiencing or at Risk of Methotrexate Toxicity. Clinicaltrials.gov Web site. http://clinicaltrials.gov/ct2/show/NCT00481559?term=Voraxaze&rank=3 .Accessed February 22, 2012.
- Schwartz S, Borner K, Müller K, et al. Glucarpidase (carboxypeptidase g2) intervention in adult and elderly cancer patients with renal dysfunction and delayed methotrexate elimination after high-dose methotrexate therapy. Oncologist. 2007;12(11):1299-1308.
- Buchen S, Ngampolo D, Melton RG, et al. Carboxypeptidase G2 rescue in patients with methotrexate intoxication and renal failure. Br J Cancer. 2005;92(3):480-487.
- Widemann BC, Balis FM, Kim A, et al. Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome. J Clin Oncol. 2010;28(25):3979-3986.
What are the post-marketing safety concerns with dabigatran?
What are the post-marketing safety concerns with dabigatran?
Dabigatran etexilate (Pradaxa) was approved by the Food and Drug Administration (FDA) on October 19, 2010 to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF).1 Approved at a dose of 150 mg twice daily, this oral medication is a direct thrombin inhibitor that prevents the conversion of fibrinogen to fibrin.2
Prior to the introduction of dabigatran, warfarin was the standard of care for anticoagulation in AF patients.3 The 2006 American College of Cardiology (ACC), American Heart Association (AHA), and European Society of Cardiology (ESC) guidelines for AF recommended that patients with 1 moderate-risk factor receive either aspirin or warfarin and those with a high-risk factor or those with more than 1 moderate-risk factor for stroke receive warfarin. High-risk factors include previous stroke, transient ischemic attack, or thromboembolism; mitral stenosis; or the presence of a prosthetic heart valve. Moderate-risk factors include age greater than or equal to 75 years, hypertension, heart failure, left ventricular ejection fraction less than or equal to 35%, or diabetes. In 2011, the ACC/AHA Task Force on practice guidelines published an update regarding dabigatran use in patients with AF.4 This update stated that dabigatran is useful as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in AF patients who do not have a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure (defined as a creatinine clearance of <15 mL/minute), or advanced liver disease (characterized as impaired baseline clotting function).
One published phase 3 clinical trial supports the use of dabigatran in AF patients. The RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) trial was a noninferiority study conducted in more than 18,000 patients with AF.5 Patients were randomized to 1 of 3 treatment groups: dabigatran 110 mg twice daily, dabigatran 150 mg twice daily, or unblinded, adjusted-dose warfarin to maintain an INR between 2.0 and 3.0. The primary outcome of stroke or systemic embolism occurred at a similar rate for the dabigatran 110 mg (1.53% annually) and warfarin groups (1.69% annually), but was lower in the dabigatran 150-mg group (1.11% annually). Both dabigatran doses were noninferior to warfarin for the primary outcome, and the dabigatran 150 mg group was also superior to warfarin with a relative risk of 0.66 (95% confidence interval [CI] 0.53 to 0.82, p<0.001). Rates of hemorrhagic stroke were lower in both dabigatran groups (0.12% annually for 110 mg and 0.10% annually for 150 mg) compared with the warfarin group (0.38% annually, p<0.001 for both dabigatran doses); however, mortality was similar among the groups (range 3.64% to 4.13% annually).
Although RE-LY had a large study population, adverse events are better quantified in post-marketing surveillance. This summary will focus on the recent reports of 2 major safety concerns with dabigatran─myocardial infarction (MI) and bleeding.
Data from the RE-LY trial indicated that the annual rate of MI was higher in the dabigatran groups (0.72% for 110 mg [p=0.07], 0.74% for 150 mg [p=0.048]) compared with warfarin (0.53%).5 Shortly after dabigatran received FDA approval and nearly 1 year after RE-LY was published, the authors issued an update of the RE-LY primary efficacy and safety data.6 This analysis was aimed to ensure consistency of the data as well as to reevaluate for possible underreporting of events. The investigators found that the rate of MI was increased from the original publication in all 3 treatment arms due to the discovery of numerous silent MIs not reported in the original data collection (Table 1). However, they concluded that identification of these additional events did not change the study conclusions.
Table 1. Myocardial infarction data from RE-LY.5,6
Dabigatran 110 mg Dabigatran 150 mg Warfarin Dabigatran 150 mg vs. Warfarin MI # of pts %/yr # of pts %/yr # of pts %/yr Relative risk (95% CI) p value Published in RE-LY 86 0.72 89 0.74 63 0.53 1.38 (1.00-1.91) 0.048 Revised 98 0.82 97 0.81 75 0.64 1.27 (0.94-1.71) 0.12
More recently in the February 7, 2012 issue of Circulation, the authors of RE-LY published a paper which closely examined the reported occurrence of all ischemic events reported in the trial.7 These ischemic events included not only MIs but also unstable angina (UA), cardiac arrest, cardiac death, coronary artery bypass graft (CABG), and percutaneous coronary intervention (PCI). In addition, the authors conducted a subgroup analysis of these endpoints in patients with existing ischemic heart disease (known coronary artery disease or previous MI) at baseline. An on-treatment sensitivity analysis was also performed. In the intention-to-treat analysis, there were no significant differences between warfarin and the 150 mg twice daily dose of dabigatran in terms of total MI, fatal MI, UA, cardiac death, cardiac arrest, PCI, or CABG. Two composite outcomes occurred significantly less frequently in the dabigatran 150 mg twice daily group than in the warfarin group (Table 2). Both the subgroup analysis and on-treatment analysis had results consistent with the intention-to-treat group. Conclusions from this analysis must be drawn with caution as the data set is limited to the RE-LY study which was not powered to detect safety differences between dabigatran and warfarin.
Table 2. Composite events that were significantly different between dabigatran 150 mg and warfarin.7
Dabigatran 150 mg Warfarin Dabigatran 150 mg vs. Warfarin # of pts Rate per 100 person-years # of pts Rate per 100 person-years Hazard ratio (95% CI) p value Composite A 538 4.47 601 5.10 0.88 (0.78-0.98) 0.03 Composite B 855 7.11 933 7.91 0.90 (0.82-0.99) 0.02
Composite A: stroke, systemic embolic events, MI, UA, CABG, PCI, cardiac arrest, cardiac death
Composite B: stroke, MI, cardiovascular death, pulmonary embolism, systemic embolic event, or major bleeding
A meta-analysis was published simultaneously in The Archives of Internal Medicine which examined the risk of MI in clinical data from RE-LY as well as additional trials investigating dabigatran's use for other indications.8 Overall, 30,514 patients in 7 trials were included, 2 examining dabigatran use for stroke prophylaxis in AF, 1 in acute venous thromboembolism, 1 in acute coronary syndrome (ACS), and 3 in short-term prophylaxis of deep vein thrombosis. The control agent was primarily either warfarin or enoxaparin; however, 1 trial was placebo-controlled. Dabigatran was associated with a significantly higher risk of MI and ACS (dabigatran, 237 of 20,000 [1.19%] versus control, 83 of 10,514 [0.79%]; OR 1.33; 95% CI,1.03 to 1.71; p=0.03). The authors of this analysis concluded that dabigatran was associated with an increased risk of MI or ACS when compared to agents such as warfarin, enoxaparin, or placebo. Additionally the authors advised clinicians to consider these serious risks when choosing to use dabigatran in their patients. This meta-analysis is not without limitations. These trials included a variety of dabigatran doses, both lower and higher than the FDA-approved dosage. Also, the patients included had indications for treatment other than AF, which could present different inherent risk factors for MI and ACS when compared to AF patients.
After reviewing both recent papers, the lead author of the meta-analysis stated that the meta-analysis demonstrated an increased risk of MI when other studies were considered in addition to the RE-LY study.9 Authors from both articles state that although data have shown an increased risk of MI with the use of dabigatran compared to warfarin, when used in AF patients this risk is small and not increased in those patients with pre-existing ischemic heart disease.
When comparing the FDA-approved dose of dabigatran to warfarin, RE-LY demonstrated similar bleeding rates per year with the exception of an increased incidence of major gastrointestinal (GI) bleeds in dabigatran-treated patients and an increased risk of intracranial bleeding in warfarin-treated patients (Table 3).5
Table 3. Bleeding events from the RE-LY trial.5
Dabigatran 110 mg Dabigatran 150 mg Warfarin Dabigatran 150 mg vs. Warfarin # of pts %/yr # of pts %/yr # of pts %/yr Relative risk (95% CI) p value Major bleeding 322 2.71 375 3.11 397 3.36 0.93 (0.81-1.07) 0.31 GI bleeding 133 1.12 182 1.51 120 1.02 1.50 (1.19-1.89) <0.001 Minor bleeding 1566 13.16 1787 14.84 1931 16.37 0.91 (0.85-0.97) 0.005 Intracranial bleeding 27 0.23 36 0.30 87 0.74 0.40 (0.27-0.60) <0.001 Extracranial bleeding 299 2.51 342 2.84 315 2.67 1.07 (0.92-1.25) 0.38
In a paper published in May 2011, the relative risk of major bleeding in pre-specified subgroups of RE-LY patients was evaluated.10 Patients were categorized into subgroups by age (<65 years, 65-74 years, and ≥75 years), sex, body weight (<50 kg, 50-99 kg, and ≥ 100 kg), creatinine clearance (<50 mL/minute, 50-79 mL/minute, and ≥80 mL/minute) and baseline use of aspirin, amiodarone, or a proton pump inhibitor. This study reported a significant treatment-by-age interaction. A lower risk of intracranial bleeding was seen with both dabigatran doses compared to warfarin; however, an increased risk of extracranial hemorrhage for patients ³75 years old with both dosage strengths of dabigatran was reported. There was no interaction between concomitant use of amiodarone or proton pump inhibitors, sex, or weight and treatment group. In conclusion, the authors stated that at ages < 75 years the 150 mg dabigatran dose seems preferable as the prevention of stroke benefit outweighs any increased risk of bleed. At older ages, the authors propose that use of the lower dabigatran dose (110 mg twice daily) might be considered as a means to reduce the risk of bleeding in those patients at high risk of bleeding. This recommendation has not been validated in clinical trials. The risk of bleeding associated with dabigatran is a major concern since the reversal of bleeding has not been well studied and there are no established reversal agents.
The FDA released a statement in December 2011 reporting that evaluation of post-marketing reports of serious bleeding events in patients taking dabigatran is underway.11 This evaluation hopes to determine whether reports of bleeding in patients taking dabigatran is occurring at rates higher than that displayed in the RE-LY trial. Until further information is available, the FDA states that dabigatran may be safely used according to the package labeling.
Clinical data from the RE-LY trial demonstrated lower rates of stroke and systemic embolism in AF patients treated with dabigatran 150 mg twice daily compared to patients treated with warfarin. Two major safety concerns revealed in this data, as well as with clinical use since dabigatran's FDA-approval, are the risks of MI and bleeding. Closer examination of the RE-LY trial by the primary authors confirmed the non-significant increased risk of MI in dabigatran-treated patients when compared to warfarin-treated patients. The authors also returned to the RE-LY data to examine the risk of major bleeding in pre-specified subgroups where a significant increase in extracranial bleeding risk was seen with dabigatran use in older patients.
In conclusion, dabigatran 150 mg twice daily lowers the risk of stroke or systemic embolism compared with warfarin in AF patients. However, the safety of dabigatran in these patients is somewhat unclear. Continued post-marketing evaluation of dabigatran may help clarify these issues.
1. Drug Details: Pradaxa. U.S. Food and Drug Administration Web site. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails . Accessed February 12, 2012.
2. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2012.
3. Fuster V,Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation–executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol. 2006;48(4):854-906.
4. Wann LS,Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran): a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2011;57(11):1330-1337.
7. Hohnloser SH,Oldgren J, Yang S, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial. Circulation. 2012;125(5):669-676.
8. Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials [published online ahead of print January 9, 2012]. Arch Intern Med. doi: 10.1001/archinternmed.2011.1666.
9. Dabigatran: new data on MI and ischemic events. theheart.org Web site. http://www.theheart.org/article/1338427.do. Accessed February 12, 2012.
10. Eikelboom JW,Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation. 2011;123(21):2363-2372.
11. FDA Drug Safety Communication: safety review of post-market reports of serious bleeding events with the anticoagulant Pradaxa (dabigatran etexilate mesylate). U.S Food and Drug Administration Web site. http://www.fda.gov/Drugs/DrugSafety/ucm282724.htm. Accessed February 12, 2012.
Written by: Kathryn Culos, PharmD, PGY1 Pharmacy Practice Resident