February 2010 FAQs
February 2010 FAQs
What revisions have been made to the ADA’s 2010 Clinical Practice Recommendations?
What revisions have been made to the ADA’s 2010 Clinical Practice Recommendations?
Each January the American Diabetes Association (ADA) publishes clinical practice recommendations for the medical care of diabetes. Year to year, changes in the standards can range from minor revisions such as new terminology to major changes like a reversal of previous recommendations. The 2010 ADA clinical practice recommendations include the following changes: a new section on cystic fibrosis-related diabetes, inclusion of A1C as a criteria for diagnosis of diabetes and a predictor of risk for future diabetes, and revisions to sections on gestational diabetes, diabetes self-management education, antiplatelet therapy, retinopathy screening, inpatient glycemic control, and diabetes care strategies.1 The summary below addresses the 2010 ADA standards for A1C criteria for diabetes diagnosis, antiplatelet therapy, and inpatient glycemic control.
The diagnosis of diabetes traditionally is made when 1 of 3 of the following criteria are met on 2 separate days: fasting plasma glucose (FPG) ≥ 126 mg/dL, a 2-hour plasma glucose ≥ 200 mg/dL with an oral glucose tolerance test (OGTT), or a casual plasma glucose ≥ 200 mg/dL with symptoms of diabetes.2 Added to the criteria in this year’s practice recommendations is A1C. A diagnosis of diabetes can be established when the A1C is ≥ 6.5% and it is confirmed on a separate day with a repeat A1C, a FPG, or an OGTT. Advantages of the A1C test include easier collection compared to FPG and less susceptibility to daily variations in glucose levels and acute illness.
Previous recommendations have not included A1C as a diagnostic option due to the lack of standardization of the assay.2 However, assays are now considered highly standardized and only those that are certified by the National Glycohemoglobin Standardization Program (NGSP) and standardized to the Diabetes Control and Complication Trial reference assay should be used to determine A1C. The A1C should not be used as a diagnostic tool for patients with hemolytic anemia and iron deficiency due to abnormal red cell turnover that renders the test inaccurate. On the other hand, specific A1C assays can be used for patients with hemoglobin variants such as HbS (sickle cell trait). A list of assays with information regarding interference from various hemoglobin variants can be found at www.ngsp.org/prog/index3.html.
Impaired fasting glucose (IFG), defined as FPG between 100-125 mg/dL, and impaired glucose tolerance (IGT), defined as an OGTT between 140-199 mg/dL, have been identified as risk factors for the development of diabetes.2 Patients with IFG and/or IGT, were previously categorized as having prediabetes. The new term used in the recommendations is “categories of increased risk for diabetes”. In addition to IFG and IGT, an A1C level between 5.7% to 6.4% is now considered a risk factor for future diabetes.
Historically, aspirin has been used for primary prevention of cardiovascular disease (CVD) for patients with diabetes over the age of 40 or with other CVD risk factors, such as smoking, hypertension, family history of CVD, hyperlipidemia, and albuminuria.3 Recent studies, however, have brought this practice into question.4-7
The Anti-Thrombotic Trialists’ (ATT) collaboration conducted a meta-analysis of trials evaluating low dose aspirin for primary (6 trials) and secondary (16 trials) CVD prevention.4 In the primary prevention trials, a relative 12% reduction in serious vascular events was observed with aspirin (0.51%) compared to placebo (0.57%, rate ratio 0.88, 95% confidence interval [CI] 0.82-0.94, p=0.0001). However, the incidence of stroke and mortality were not significantly different with aspirin use compared to placebo. Furthermore, major bleeding was significantly more frequent with aspirin (0.10% v. 0.07%, p<0.0001). Upon examination of the subgroup of patients with diabetes, the meta-analysis revealed no significant difference in vascular events for aspirin users compared to non-users (rate ratio 0.87, 95% CI 0.67-1.15).
The use of low dose aspirin (81 or 100 mg) for primary CVD prevention was evaluated in a randomized, controlled trial in over 2500 Japanese patients with well controlled type 2 diabetes but no previous CVD history.5 No significant difference in the primary endpoint of any atherosclerotic event was observed between the 2 groups with events occurring in 5.4% of patients on aspirin and 6.7% of control patients (hazard ratio [HR] 0.80, 95% CI 0.58-1.10, p=0.16). In the subgroup of patients 65 years and older, atherosclerotic events were significantly lower in the aspirin group compared to controls (6.3% vs. 9.2%, HR 0.68, 95% CI 0.46-0.99, p=0.47). Aspirin users did experience significantly fewer fatal coronary and cerebrovascular events (HR 0.10, 95% CI 0.01-0.79, p=0.0037). More adverse events, including gastrointestinal bleeding, retinal bleeding, and epistaxis, occurred in aspirin users compared to nonusers.
The prevention of progression of arterial disease and diabetes (POPADAD) trial studied the effects of aspirin and antioxidants, in combination or alone, on the primary prevention of cardiovascular events and mortality in more than 1200 patients over the age of 40 with type 1 or 2 diabetes and asymptomatic peripheral vascular disease.6 The composite endpoint, death from coronary heart disease or stroke, non-fatal myocardial infarction or stroke, and above the ankle amputation, was not found to be significantly different between aspirin and placebo (18.2% vs. 18.3%, p=0.86). Subgroup analysis did not reveal any advantage of aspirin over placebo with respect to the primary outcome. The authors concluded that aspirin is not beneficial in the primary prevention of cardiovascular events or mortality for patients with diabetes and asymptomatic peripheral arterial disease.
Similarly, the primary prevention project (PPP) failed to demonstrate the benefits of aspirin and vitamin E for primary prevention of cardiovascular events in the subgroup of patients with type 2 diabetes.7 Compared to the control group, more bleeding complications occurred with aspirin (0.2% vs. 1.9%, p=0.007).
The ADA recommends low dose aspirin (75 to 162 mg/day) for men > 50 years old and women > 60 years old who have type 1 or type 2 diabetes and a minimum of 1 other cardiovascular risk factor (smoking, dyslipidemia, hypertension, albuminuria, family history of CVD).3 These patients are estimated to have a 10-year risk of CVD of >10%. Aspirin 75 to 162 mg/day should continue to be used as secondary prevention in patients with a previous cardiovascular event. After an acute coronary syndrome, the use of aspirin in combination with clopidogrel is also supported by the ADA. The use of aspirin in men < 50 years old and women < 60 years old without other risk factors is not currently supported by clinical evidence and therefore, is not recommended. Clinical judgment is advised in choosing antiplatelet therapy for patients of this younger age group with CVD risk factors.
Inpatient Glycemic Control
Both hyperglycemia and hypoglycemia in critically ill and non-critically ill patients, in the presence or absence of diabetes, are known to lead to poor outcomes.3,10 The intensity or level to which hyperglycemia should be controlled, however, has been controversial due to conflicting evidence of the impact on mortality for patients in the intensive care unit (ICU). Although early studies indicated improved patient outcomes, more recent and larger controlled studies have demonstrated either no improvement or an increase in mortality, and a higher risk of hypoglycemia with intensive glycemic control. The largest of these trials was the Normoglycemia in Intensive Care Evaluation-Survival Using Glucose Algorithm Regulation (NICE-SUGAR) study that demonstrated an increase in mortality in over 6000 ICU patients with glycemic targets between 81 to 108 mg/dL compared to less intense control that targeted levels <180 mg/dL.8 (see http://dig.pharm.uic.edu/faq/nicesugar.aspx for details).
A recent meta analysis reviewed results from 26 trials, including the NICE-SUGAR data, that included over 13,000 critically ill patients who were randomized to intensive glycemic control (target blood glucose level < 150 mg/dl) or usual care.9 Overall, no mortality benefit was observed with intensive glycemic control (risk ratio [RR] 0.93, 95% CI 0.83-1.04). Of the various ICU populations evaluated, only surgical ICU patients derived benefit from intensive glycemic control (RR 0.63, 95% CI 0.44-0.91). Additionally, the risk of hypoglycemia (defined as glucose < 40 mg/dL) was significantly increased in the intensive therapy group (RR 5.99, 95% CI 4.47-8.03).
Based on current evidence, the ADA supports controlling hyperglycemia in hospitalized patients within certain targets.3,10 In critically ill patients, an initial glucose level of < 180 mg/dL should be targeted. Once treatment has started, glucose levels should be maintained between 140 and 180 mg/dL. Although some clinicians may aim for slightly lower levels, glucose targets <110 mg/dL are not recommended. For non-critically ill patients, the recommendations, based primarily on expert clinical judgment, are to target premeal glucose levels to <140 mg/dL and random glucose levels <180 mg/dL. For both populations, avoidance of hypoglycemia is of prime importance.
Intravenous insulin for ICU patients and subcutaneous insulin for non-critically ill patients are recommended to help achieve these targets.3,10 For non-critically ill patients, scheduled use of basal and prandial insulin should be instituted with use of supplemental insulin to decrease premeal hyperglycemia. The use of sliding scale insulin as the sole treatment strategy to control hyperglycemia is not recommended due to lack of evidence demonstrating its efficacy and the potential for severe hypoglycemia or hyperglycemia in patients with type 1 diabetes.
Other recommendations for management of hyperglycemia in the inpatient setting include:
scheduled glucose monitoring for patients receiving therapies known to increase blood glucose including high-dose glucocorticoids, enteral or parenteral nutrition, octreotide, and immunosuppressants
established action plans for treatment of hypoglycemic events
tracking of hypoglycemic events
follow-up care for patients identified with diabetes during hospitalization
The addition of a laboratory test, A1C, to aid in the diagnosis of diabetes, the use of aspirin in select patients with diabetes, and less stringent glycemic targets for hospitalized patients with hyperglycemia are among the revisions to the 2010 ADA clinical practice recommendations for diabetes management. For a review of other revisions, the full practice recommendation can be viewed at http://care.diabetesjournals.org/content/33/Supplement_1.
- American Diabetes Association. Summary of revisions for the 2010 clinical practice recommendations. Diabetes Care. 2010;33(suppl 1):S3.
- American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2010;33(suppl 1):S62-S69.
- American Diabetes Association. Standards of medical care in diabetes-2010. Diabetes Care. 2010;33(suppl 1):S11-S61.
- Antithrombotic Trialists’ Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized trials. Lancet. 2009;373(9678):1849-1860.
- Ogawa H, Nakayama M, Morimoto T, et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes. JAMA. 2008;300(18):2134-2141.
- Belch J, MacCuish A, Campbell I, et al. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomized placebo controlled trial of aspirin and antioxidants in patients with diabetes and peripheral arterial disease. BMJ. 2008;337:a1840. doi: 10.1136/bmj.a1840.
- Sacco, M, Pellegrini F, Roncaglioni MC, et al. Primary prevention of cardiovascular events with low dose aspirin and vitamin E in type 2 diabetic patients. Diabetes Care. 2003;26(12):3264-3272.
- The NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. NEJM. 2009;360(13):1283-1297.
- Griesdale DEG, de Souza RJ, van Dam RM, et al. Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data. CMAJ. 2009;180(8):821-827.
- Moghissi ES, Korytkowski MT, DiNardo M, et al. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Diabetes Care. 2009;32(6):1119-1131.
What is the current status of erythropoiesis-stimulating agents in chronic kidney disease?
What is the current status of erythropoiesis-stimulating agents in chronic kidney disease?
Erythropoiesis stimulating-agents (ESAs) are blood modifying agents that work by stimulating red blood cell (RBC) production and include epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp). These agents are most commonly used to treat anemia associated with chronic kidney disease (CKD), for patients both on and off dialysis, as well as to treat anemia associated with chemotherapy.1-3 The goal of ESA treatment is to maintain hemoglobin (Hb) levels within a therapeutic range and decrease the need for RBC transfusions.
Controversy has surrounded the use of ESAs in patients with CKD due to the results of randomized controlled clinical trials which re-evaluated the target Hb levels in pre-dialysis patients with CKD. In November 2006, 2 studies were published indicating that patients treated with ESAs, dosed to target Hb concentrations >12 g/dL, experienced an increased risk for death, cardiovascular events (including hypertension and congestive heart failure), and more rapid progression to hemodialysis compared to patients targeted to lower Hb levels.4,5 The results of the Correction of Hemoglobin Outcomes in Renal Insufficiency (CHOIR) and the Cardiovascular Risk Reduction by Early Anemia Treatment with epoetin beta (CREATE) studies prompted the Food and Drug Administration (FDA) to require the manufacturers to change product labeling and include boxed warnings (see FAQ Safety update: ESAs, August 2007).
Shortly after the results of the CHOIR and CREATE studies were revealed, Phrommintikul and colleagues published a meta-analysis to determine whether targeting various Hb concentrations when treating patients with anemia secondary to CKD with ESAs is associated with all-cause mortality and cardiovascular events.6 In this meta-analysis, 9 randomized controlled clinical trials that enrolled 5143 patients were assessed. The target Hb concentrations in the high Hb groups ranged from 12 to 16 g/dL; the range in the low groups was 9 to 10.5 g/dL. The risk of all-cause mortality was significantly increased in the high Hb target groups compared to the lower Hb target groups (risk ratio (RR) 1.17, 95% confidence interval (CI) 1.1 to 1.35, p=0.031). Of the 9 studies included, 7 reported data on myocardial infarction (MI); there was no difference found between the 2 groups (RR 0.98, 95% CI 0.73 to 1.81, p=0.067). Two additional endpoints included poorly controlled hypertension and arteriovenous (AV) access thrombosis. Both endpoints were significantly more frequent in the high Hb groups compared to the low Hb groups (RR 1.27, 95% CI 1.08 to 1.50, p=0.004) and (RR 1.34, 95% CI 1.16 to 1.54, p=0.0001), respectively for endpoints.
The TREAT Trial
The Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) was a randomized, double-blind, placebo-controlled, multi-center trial to determine if treatment of low Hb levels with darbepoetin alfa in anemic patients with type 2 diabetes and CKD not requiring dialysis would reduce the rates of death, cardiovascular events, and renal events.7 Patients were randomized to darbepoetin alfa administered every 2 weeks and titrated as needed to a target Hb concentration of 13 g/dL. Once at goal, the dose was doubled and administered monthly. Patients in the placebo group received rescue darbepoetin alfa if their Hb was <9 g/dL. The primary end points were the composite of death from any cause or cardiovascular event and the time to the composite outcome of death or end-stage renal disease. Secondary endpoints included time to death, death from cardiovascular causes, the components of the primary end points, renal outcomes, and quality of life (QOL) assessments.
The results of the study showed that for the primary outcome, composite events occurred in 632 patients (31.4%) in the darbepoetin alfa group vs. 602 patients (29.7%) in the placebo group (hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.94 to 1.17, p=0.41).7 For the secondary end points, there were no statistically significant differences in time to death, death from any cause, fatal or nonfatal heart failure, fatal or nonfatal MI, or hospitalization. Death or end-stage renal disease occurred in 652 patients (32.4%) in the darbepoetin alfa group vs. 618 patients (30.5%) in the placebo group (HR 1.06, 95% CI 0.95 to 1.19, p=0.29). However, fatal or nonfatal stroke occurred in 101 patients (5%) in the darbepoetin alfa group vs. 53 patients (2.6%) in the placebo group (HR 1.92, 95% CI 1.38 to 2.68, p<0.001). Patients treated with darbepoetin alfa required less RBC transfusions (297 patients vs. 496 patients, p<0.001). There was a significantly higher rate of thromboembolic events in the darbepoeitin alfa group. A greater degree of improvement in fatigue was reported in patients treated with darbepoetin alfa; however, other QOL endpoints (i.e. energy and physical functioning) did not differ significantly between the groups.
The authors concluded that treatment with darbepoetin alfa, to target Hb concentrations of 13 g/dL in anemic patients with type 2 diabetes and CKD and low Hb did not show a reduction in all-cause mortality, cardiovascular morbidity, including MI, heart failure hospitalization for MI, or end-stage renal disease.7 The risk of stroke was increased in the darbepoetin alfa group by almost 2-fold.
Summaries of the safety literature of ESAs are presented in table 1.
Table 1. Summary of safety evidence of ESAs in CKD.4,5,7,8
Primary and secondary endpoint(s)
RCT, DB, PC, MC
Trial was event driven; median duration of follow up 29.1 months
n=4038 with T2DM, CKD, and anemia not on dialysis
Darbepoetin alfa (n=2012) to maintain Hb levels at 13 g/dL or placebo (n=2026)
Darbepoetin alfa was initially dosed 0.75 mcg/kg (route not specified) every 2 weeks and titrated as needed; once Hb reached 12 to 13.5 g/dL, the dose was doubled and administered monthly.
- Composite endpoint of death from any cause or a cardiovascular event including, MI, stroke, or hospitalization for HF
- Time to the composite endpoint of death or end-stage renal disease
- Time to death
- Death from cardiovascular causes
- Components of the primary end points
- Rate of decline in GFR
- QOL (2 validated instruments)
Safety was assessed.
Interim analysis planned when approximately 20, 40, 60, and 80% of the total expected cardiovascular composite events occurred.
- Composite events occurred in 632 patients (31.4%) in the darbepoetin alfa group vs. 602 patients (29.7%) in the placebo group (HR 1.05, 95% CI 0.94 to 1.17, p=0.41).
- No statistically significant differences in time to death, death from any cause, fatal or nonfatal HF, fatal or nonfatal MI, or hospitalization.
- Fatal or nonfatal stroke occurred in 101 patients (5%) in the darbepoetin alfa group vs. 53 patients (2.6%) in the placebo group (HR 1.92, 95% CI 1.38 to 2.68, p<0.001).
- Death or end-stage renal disease occurred in 652 patients (32.4%) in the darbepoetin alfa group vs. 618 patients (30.5%) in the placebo group (HR 1.06, 95% CI 0.95 to 1.19, p=0.29).
- There was a greater degree of improvement in fatigue in patients treated with darbepoetin alfa; however, other QOL endpoints (i.e. energy and physical functioning) did not differ significantly between the groups.
- Venous thromboembolic events occurred in 41 patients (2%) in the darbepoetin alfa group vs. 23 patients (1.1%) in the placebo group (p=0.02)
- Arterial thromboembolic events occurred in 178 patients (8.9%) in the darbepoetin alfa group vs. 144 patients (7.1%) in the placebo group (p=0.04).
RCT, OL, MC
Median duration 16 months (planned for 3 years)
n=1432 with anemia secondary to CKD not on dialysis
High Hb group: initial target 13 to 13.5 g/dL (n=715)
Low Hb group: initial target 10.5 to 11 g/dL (n=717)
Hb targets were changed to 13.5 g/dL (high) and 11.3 g/dL (low) after enrollment of about 24% of patients.
Epoetin was administered as a weekly SC injection and dose titrated as needed; the dose could be given every 2 weeks in patients with stable Hb levels.
- Time to composite endpoint of death, MI, stroke, or hospitalization for HF
- Individual components of the primary outcome
- Time to renal replacement therapy
- Hospitalization (cardiac and all cause)
- QOL (3 validated instruments)
Four interim analyses were planned.
The study was prematurely discontinued at the second interim analysis. At 16 months, the composite endpoint event occurred in 17.5% of patients in the high Hb group vs. 13.5% of patients in the low Hb group (HR 1.34, 95% CI 1.03 to 1.74, p=0.03).
- Composite events occurred in 125 (17.5%) of 715 patients in the high Hb group vs. 97 (13.5%) of 717 patients in the low Hb group (HR 1.34, 95% CI 1.03 to 1.74, p=0.03).
- Hospitalization for HF (45.5% of patients) was the largest component of composite events, followed by death (29.3%), MI (11.3%), and stroke (10.4%); no difference was seen between groups.
- Renal replacement therapy; 155 (21.7%) in the high and 134 (18.7%) in the low groups (HR 1.19, 95% CI 0.94 to 1.49, p=0.15).
- Hospitalization for cardiac cause: 233 (32.6%) of 715 vs. 197 (27.5%) of 717, HR 1.23, 95% CI 1.01 to 1.48, p=0.03 or any cause 369 (51.6%) vs. 334 (46.6%), HR 1.18, 95% CI 1.02 to 1.37 was more frequent among high Hb recipients.
- Overall QOL improved when anemia was treated with epoetin; however, aiming for a target Hb of 13.5 g/dL provided no additional benefit (p>0.05 for all measures).
RCT, OL, MC
Mean duration 3 years
n=603 with anemia and stage 3 or 4 CKD not on dialysis
High Hb group: immediate treatment with epoetin beta (n=301) to a target Hb of 13 to 15 g/dL
Low Hb group: treatment with epoetin beta triggered by decrease in Hb to <10.5 g/dL (n=302) to a target of 10.5 to 11.5 g/dL
Epoetin beta was administered to both groups as a weekly SC injection and the dose titrated as needed.
- Composite of time to first cardiovascular event, MI, HF, stroke, TIA, angina requiring ≥24 hours of hospitalization, amputation or necrosis due to peripheral vascular disease, or cardiac arrhythmias requiring ≥ 24 hours of hospitalization
- Death (any cause or cardiac)
- Worsening HF
- Need for cardiac intervention
- Hospitalization and duration of hospitalization for cardiac causes
- Left ventricular changes
- Hb levels
- Change in epoetin dose
- Decrease in GFR
Safety was assessed.
Interim analyses were planned.
- At the end of the 3 year study, 58 patients in the high Hb group had reached the primary endpoint vs. 47 patients in the low Hb group (HR 0.78, 95% CI 0.53 to 1.14, p=0.20).
Secondary (high vs. low Hb group):
- Death: no significant difference in death from any cause 31 (10%) of 301 vs. 21 (7%) of 302 (HR 0.66, 95% CI 0.38 to 1.15) or cardiac death 4% vs. 3% (HR 0.74, 95% CI 0.33 to 1.70)
- Worsening HF: no difference (p=0.97)
- Cardiac intervention: 7% vs. 6% (p=NR)
- Hospital admission: 61% vs. 59% (p=NR); duration for cardiac causes 33 vs. 28.2 days (p=NR)
- Left ventricular changes: no significant differences (p>0.05 for all comparisons)
- QOL: significantly better for the high Hb group for health (p=0.008) and vitality (p=0.01) at year 2
- Hb level difference: 1.5 g/dL at year 2 (p=NR)
- Epoetin dose: average weekly dose 5000 Units vs. 2000 Units (p=NR)
- Time to dialysis was shorter in the high Hb group beginning at month 18 (p=0.03).
- Transfusions: 26 vs. 33 patients (p=NR)
- Decrease in GFR: no significant difference between groups (p=0.36 at study end)
There were more vascular disorders in the high Hb group (p<0.001) attributed to a higher incidence of hypertension (p=0.005) and headaches (p=0.03).
Besarab 1998 8
RCT, OL, MC
Median duration 13 months (planned for 3 years)
n=1233 with HF or IHD and ESRD receiving dialysis
Epoetin alfa to target normal hematocrit of 42% (n=618) or low hematocrit of 30% (n=615)
Epoetin was given IV or SC; 90% received it IV and 88% were receiving TIW dosing.
- Time to death or nonfatal MI
- HF requiring hospitalization
- Angina requiring hospitalization
- All cause hospitalization
- Change in cardiac medications
The trial was stopped at the third interim analysis. At 14 months, 33% of patients in the normal hematocrit group had died or had a non-fatal MI vs. 27% in the low hematocrit group (RR 1.3, 95% CI 0.9 to 1.9, p=NR).
Primary (normal vs. low hematocrit):
- Death or nonfatal MI: 183 deaths and 19 nonfatal MIs vs. 150 deaths and 14 nonfatal MIs (RR 1.3, 95% CI 0.9 to 1.9. p=NR)
Secondary (normal vs. low hematocrit):
- HF requiring hospitalization: no difference (p=0.41)
- Angina requiring hospitalization: no difference (p=0.93)
- CABG: no difference (p=0.88)
- PTCA: no difference (p=0.86)
- All cause hospitalization: no difference (p=0.29)
- Change in cardiac medications: no difference
- Transfusion: 129 (21%) of 618 vs. 192 (31%) of 615 (p<0.001)
- QOL: One portion of the QOL measure, physical function, improved with increases in hematocrit (p=0.03).
About 3 times the dose of epoetin was needed to achieve a normal hematocrit as compared to the dose during run-in period.
ESAs= erythropoiesis-stimulating agents; CKD=chronic kidney disease; RCT=randomized controlled trial; DB=double-blind; PC=placebo-controlled; MC=multi-center; T2DM=type 2 diabetes mellitus; Hb=hemoglobin; MI=myocardial infarction; HF=heart failure; GFR=glomerular filtration rate; QOL=quality of life; HR=hazard ratio; CI=confidence interval; OL=open-label; SC=subcutaneously; TIA=transient ischemic attack; NR=not reported; IHD=ischemic heart disease; ESRD=end-stage renal disease; IV=intravenous; TIW=3 times weekly; CABG=coronary-artery bypass grafting; PTCA=percutaneous transluminal coronary angioplasty; RR=relative risk.
TREAT has been criticized for targeting Hb concentrations to 13 g/dL, which are higher than what was recommended in the ESA labeling.9 During the trial, Amgen, the manufacturer of Aranesp, worked with the FDA to develop dosing and monitoring methods to limit overshoots of the Hb target. The dosing strategies did not follow those outlined in the prescribing information and were designed specifically for the study to ensure gradual increases and avoid excessive increases in the Hb concentration. Published editorials have addressed the need for re-evaluation of ESAs.9,10 The authors point out that the results of TREAT do not confirm the findings of CHOIR but support the harm associated with the use of ESAs to target Hb concentrations >13 g/dL in CKD patients. Results of TREAT reinforce the safety concerns with targeting higher Hb levels. Randomized trials are necessary to determine the optimal Hb target, dosing regimen, and appropriate monitoring in patients with CKD.
As a result of TREAT, the boxed warning in the product labeling for darbepoetin alfa (Aranesp) and epoetin alfa (Epogen, Procrit) has been updated to include an increased risk of stroke.11 The WARNINGS section includes a paragraph summarizing the results of TREAT as it relates to stroke. The FDA anticipates convening a public advisory meeting in 2010 to re-evaluate the use of ESAs in the treatment of anemia secondary to CKD.9
TREAT is a compelling trial that adds to the safety concerns of ESAs. TREAT failed to meet its primary objectives of demonstrating a reduction in all-cause mortality, cardiovascular morbidity, and progression to end-stage renal disease by targeting Hb concentrations to 13 g/dL. Additionally, the risk of stroke was increased by almost 2-fold in patients treated with darbepoeitin alfa. The results of CHOIR and CREATE showed that Hb targets >12 g/dL result in an increased risk for death, cardiovascular events (including hypertension and congestive heart failure), and more rapid progression to hemodialysis compared to patients targeted to lower Hb levels. Per the National Kidney Foundation Disease Outcomes Quality Initiative (KDOQI) guidelines for the treatment of anemia in CKD, and the product labeling of the ESAs, Hb levels must be maintained within the range of 10 to 12 g/dL in CKD patients.1-3,12 Diligence is needed when using these agents and practitioners must weigh the increased risks of cardiovascular events and stroke.
- Aranesp [package insert]. Thousand Oaks, CA: Amgen; 2009.
- Procrit [package insert]. Raritan, NJ: Ortho Biotech Products; 2009.
- Epogen [package insert]. Thousand Oaks, CA: Amgen; 2009.
- Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355(20):2085-2098.
- Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355(20):2071-2084.
- Phrommintikul A, Haas SJ, Elsik M, Krum H. Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis. Lancet. 2007;369(9559):381-388.
- Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361(21):2019-2032.
- Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998;339(9):584-590.
- Unger EF, Thompson AM, Blank MJ, Temple R. Erythropoiesis-stimulating agents–time for a reevaluation. N Engl J Med. 2010;362(3):189-192.
- Marsden PA. Treatment of anemia in chronic kidney disease–strategies based on evidence. N Engl J Med. 2009;361(21):2089-2090.
- Amgen and Centocor Ortho Biotech Products, L.P. Dear healthcare professional letter. http://wwwext.amgen.com/pdfs/misc/DHCP_Letter_TREAT-Label.pdf. Accessed January 21, 2010.
- National Kidney Foundation. KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis. 2007;50(3):471-530.
Does Voluven (hydroxyethyl starch 130/0.4) cause less bleeding than hetastarch?
Does Voluven (hydroxyethyl starch 130/0.4) cause less bleeding than hetastarch?
Hydroxyethyl starch (HES) refers to a class of synthetic colloid solutions that are similar to glycogen.1-3 Starches were developed in response to the need for a synthetic colloid with less immunogenic potential than dextran.1 Hetastarch (Hespan, hydroxyethyl starch in saline), the most common agent in this class, is derived from corn starch and has a molecular weight of 600,000 daltons. Hydroxyethyl starch 6% is also commercially available in a balanced electrolyte solution (Hextend) with a molecular weight of 670, 000 daltons.4 In January 2008 a new lower substituted and lower molecular weight (130,00 daltons) hydroxyethyl starch in saline formulation (130/0.4, Voluven) was approved for use in the United States.5 Hydroxyethyl starch preparations are efficient volume expanders used primarily for the treatment of hypovolemia; however, their use is associated with significant adverse effects.6 The main safety concerns include coagulation abnormalities, renal failure, and refractory pruritus.7 The coagulation abnormalities include decreased platelet count, prolonged prothrombin and partial thromboplastin times, and a decrease in clot strength.1
The available hydroxyethyl starch preparations differ in terms of molecular weight and molar substitution.6-8 Clinical bleeding is not usually seen when total daily doses are less than 1500 mL/day of hetastarch (Hespan, Hextend).1 Coagulation abnormalities are believed to be due to the degree of substitution and molecular weight of hydroxyethyl starch preparations, with larger and more highly substituted compounds leading to the abnormalities.9 The greater the substitution, the longer it takes the starch to be degraded.7 Persistence of the starch molecule may lead to increased side effects, notably pruritus, which is due to tissue storage of the molecule. In addition to molecular weight and degree of substitution, the pattern of substitution is important.6-7 The pattern of substitution refers to the C2/C6 ratio, which is based on the location of hydroxylation.6-8 The higher the ratio, the slower the breakdown of starch. Although Voluven has a lower mean molecular weight and lower degree of substitution, its C2/C6 ratio is high.7
The published literature is limited to 1 comparative, controlled trial involving Voluven and hetastarch. There are several published comparisons of Voluven to hydroxyethyl starch 200/0.5 (Pentastarch), a starch with a lower molecular weight than hetastarch. Pentastarch is no longer commercially available in the United States as of August 2007 so these trials are not applicable to clinical practice in this country.10
Ghandi and colleagues conducted a multicenter, randomized, double-blind, controlled trial to compare the safety and efficacy of Voluven with standard hetastarch for volume replacement during orthopedic surgery.8 Patients undergoing orthopedic surgery who were expected to lose more than 500 mL of blood were randomized to hetastarch (n=51) or Voluven (n=49). The starch solutions were infused according to hemodynamic requirements, central venous pressure, and mean arterial blood pressure. The primary outcome measure was volume of starch administered intraoperatively. Secondary endpoints included fluid intake and output and use of vasoactive medications. Safety was assessed by monitoring markers of coagulation. Three subgroups were prospectively identified for analysis: stable patients, patients without major blood loss, and those who received more than a liter of starch.
There was no difference between groups for total volume of fluid administered (Voluven = 1613 mL vs. 1584 mL for hetastarch, ratio [Voluven:hetastarch]=1.024, 95% confidence interval 0.83 to 1.254).8 Furthermore, results did not differ for any of the subgroups. There was no difference between the groups in terms of the secondary outcomes or need for blood transfusion. One of the coagulation parameters, factor VIII activity nadir within 2 hours after surgery, was lower for hetastarch compared to Voluven (p=0.0499). These results were similar in the subgroup of patients who received more than 1 liter of either product (p=0.0487). In addition, hetastarch-treated subjects who received more than 1 liter of starch experienced a lower vonWillebrand factor concentration compared to those who received Voluven (p=0.008). The authors concluded that both preparations were efficacious, but Voluven had less of a negative impact on coagulation parameters.
Theoretically, based on its lower molecular weight and lower degree of substitution, Voluven is expected to be better tolerated than hetastarch. The single published comparative trial demonstrated similar efficacy in terms of volume expansion (based on volume required for replacement) with Voluven and hetastarch, as well as similar effects on coagulation overall. At this time, there are no compelling data to support that Voluven is safer than traditional preparations of hetastarch.
- Rainey TG, Read CA. Pharmacology of colloids and crystalloids. In Chernow, B, editor. The Pharmacologic Approach to the Critically Ill Patient. 3rd ed. Baltimore: Williams & Wilkins; 1994:272-290.
- Griffel MI, Kaufman BS. Pharmacology of colloids and crystalloids. Crit Care Clin. 1992;8(2):235-253.
- Wagner BKJ, D'Amelio LF. Pharmacologic and clinical considerations in selecting crystalloid, colloidal, and oxygen-carrying resuscitation fluids, part 1. Clin Pharm. 1993;12(2):335-346.
- Hextend [package insert]. Lake Forest, IL; Hospira: 2004.
- Voluven [prescribing information]. Lake Forest, IL: Hospira; 2007.
- Cada DJ, Levien T, Baker DE. Hydroxyethyl starch 130/0.4. Hosp Pharm. 2008;43(5):396-408.
- Wiedermann CJ. Hydroxyethyl starch – can the safety problems be ignored? Wien Klin Wochenschr. 2004;116(17-18):583-594.
- Gandhi SD, Weiskopf RB, Jungheinrich C, et al. Volume replacement therapy during major orthopedic surgery using Voluven (hydroxyethyl starch 130/0.4) or hetastarch. Anesthesiology. 2007;106(6):1120-1127.
- Langeron O, Doelberg M, Ang ET, Bonnet F, Capdevila X, Coriat P. Voluven, a lower substituted novel hydroxyethyl starch (HES 130/0.4) causes fewer effects on coagulation in major orthopedic surgery than HES 200/0.5. Anesth Analg. 2001;92(4):855-862.
- DRUGDEX System [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically.
What are the clinical data for dronedarone (Multaq)?
What are the clinical data for dronedarone (Multaq)?
In July 2009, the Food and Drug Administration (FDA) approved dronedarone (Multaq; Sanofi-Aventis) for the treatment of atrial fibrillation and flutter.1 Although initially rejected for approval by the FDA in 2006 due to an observed increase in mortality as compared to placebo in patients with heart failure, Sanofi-Aventis has since completed multiple studies involving dronedarone that specifically address efficacy and safety concerns.2
Dronedarone is structurally related to amiodarone, but has undergone 2 major structural changes.3 First, the iodine molecule present in amiodarone has been removed from dronedarone. Second, a methane sulfonyl group has been added to the structure of dronedarone. These 2 changes should improve safety, when compared to amiodarone, by eliminating iodine-related organ toxicity and reducing lipophilicity and subsequent tissue accumulation of dronedarone. Pharmacologically, dronedarone blocks sodium, potassium, and calcium channels.1,3,4 In addition, dronedarone has alpha- and beta-blocking properties. The approved dose of dronedarone is 400 mg orally twice daily taken with meals; food increases absorption 2- to 3-fold.1,4 Dronedarone is contraindicated for use in second- or third-degree atrioventricular block, sick sinus syndrome (unless a pacemaker is present), Class IV heart failure, Class II-III heart failure with recent decompensation, bradycardia (< 50 beat/minute), if a patient has or develops a QTc interval ≥ 500 ms, and pregnancy.1 Dronedarone is metabolized primarily by cytochrome (CYP)4503A4, is a moderate inhibitor of CYP3A4 and 2D6, and inhibits P-glycoprotein. Interactions with medications that are metabolized or transported via these mechanisms are of concern with concurrent administration.
Efficacy and Safety Data
A summary of efficacy and safety data for dronedarone is presented in table 1. The majority of the trials compare dronedarone to placebo; however, the unpublished DIONYSOS trial directly compares dronedarone to amiodarone. Data for the DIONYSOS trial were obtained from information submitted to the FDA by the manufacturer.
Table 1. Clinical trial data involving dronedarone.5-9
Citation Design/ Duration Population Interventions Primary and secondary endpoints Outcomes and conclusions DIONYSOS 2010 5 MC, DB, PG, RCT
Duration: at least 6 months
N = 504 patients (age ≥ 21 years) with atrial fibrillation who had a need for cardioversion, antiarrhythmic therapy, and anticoagulation Dronedarone 400 mg PO twice daily (n = 249)
Amiodarone 600 mg PO daily for 28 days, then 200 mg PO daily thereafter (n = 255)
Primary: composite of time to first atrial fibrillation recurrence or premature study discontinuation for intolerance or lack of efficacy at 12 months
The main safety endpoint was the time to first occurrence of thyroid, hepatic, pulmonary, neurological, skin, eye, or gastrointestinal specific events or premature study drug discontinuation following any adverse events.
The primary endpoint occurred in 75.1%; of patients receiving dronedarone and 58.8%; of patients administered amiodarone at 12 months (HR = 1.589, 95%; CI: 1.275 to 1.980; p < 0.0001).
Overall, recurrence of atrial fibrillation was more frequent with dronedarone (63.5%; vs. 42%;), but drug discontinuation due to intolerance was more frequent with amiodarone (34%; vs. 25%;).
The main safety endpoint occurred in 39.3%; of patients on dronedarone and 44.5%; of patients on amiodarone after 12 months (HR = 0.80, 95%; CI: 0.60 to 1.07; p = 0.13.
Hohnloser et al 2009 6
MC, DB, PC, RCT
Minimum follow-up duration of 12 months and maximum follow-up of 2.5 years
N = 4628 patients with paroxysmal or persistent atrial fibrillation or flutter with additional risk factors for death Dronedarone 400 mg PO twice daily (n = 2301)
Placebo (n = 2327)
Primary: first hospitalization due to cardiovascular events or death from any cause
Secondary: death from any cause; death from cardiovascular causes; first hospitalization due to cardiovascular events
The primary outcome occurred in 31.9%; of patients receiving dronedarone and 39.4%; of patients administered placebo (HR = 0.76, 95%; CI: 0.69 to 0.84; p < 0.001).
Death from any cause was similar between the groups (5%; dronedarone vs. 6%; placebo; HR = 0.84, 95%; CI: 0.66 to 1.08; p = 0.18).
Death from cardiovascular causes and first hospitalization due to cardiovascular events occurred more frequently with placebo than dronedarone. Death from cardiovascular causes: 2.7%; dronedarone vs. 3.9%; placebo; HR = 0.71, 95%; CI: 0.51 to 0.98; p = 0.03. First hospitalization: 29.3%; vs. 36.9%;; HR = 0.76, 95%; CI: 0.69 to 0.84; p < 0.001.
Adverse effects that were significantly more common with dronedarone included bradycardia, QT prolongation, diarrhea, nausea, rash, and an increase in serum creatinine.
Dronedarone reduced death and hospitalization due to cardiovascular events among patients with atrial fibrillation.
Davy et al 2008 7
MC, DB, PG, RCT
Duration: 6 months of therapy following an initial 2-week screening period
N = 174 adults (≥ 21 years) with persistent atrial fibrillation for which cardioversion was not an option Dronedarone 400 mg PO twice daily with meals (n = 85)
Placebo (n = 89)
These interventions were given in addition to standard therapy.
Primary: change in mean ventricular rate from baseline to day 14
Secondary: change in mean ventricular rate during submaximal and maximal exercise from baseline to day 14; change in maximal exercise from baseline to day 14; change in mean ventricular rate at 4 months from baseline; safety and tolerability
The change in mean ventricular rate from baseline to day 14 with dronedarone (mean reduction: 11 beats/min) was significant when compared to placebo (mean increase: 0.7 beat/min; p < 0.0001).
Results were similar after stratification for the presence or absence of other rate lowering drugs.
Results favoring dronedarone were also seen for the change in mean ventricular rate during submaximal (mean reduction of 25.6 beats/min for dronedarone vs. 2.2 beats/min for placebo; p < 0.0001) and maximal (mean reduction of 27.4 beats/min vs. 2.9 beats/min; p < 0.0001) exercise.
Mean increase in maximal exercise duration was similar between groups (0.14 mins dronedarone vs. 0.26 mins placebo; p = 0.514).
Mean change in ventricular rate at 4 months continued to favor dronedarone (-10.1 beats/min vs. -1.3 beats/min; p < 0.001).
The incidence of treatment emergent adverse events was slightly increased with dronedarone. One death in the dronedarone group was reported. This patient had a history of congenital heart disease, family history of sudden death, and significant ECG changes at baseline that should have excluded the patient from the study.
Dronedarone is an effective treatment option for atrial fibrillation.
Kober et al 2008 8
MC, DB, PG, RCT
Duration: minimum of 12 months of treatment with trial lasting 2 years
Trial stopped at 7 months per the DSMB; follow-up continued until at least 6 months after drug withdrawal
N = 627 hospitalized adults with new or worsening heart failure who had at least 1 episode of shortness of breath on minimal exertion or at rest or paroxysmal nocturnal dyspnea within the month prior to admission Dronedarone 400 mg PO twice daily (n = 310)
Placebo (n = 317)
Primary: combined endpoint of death from any cause or hospitalization for worsening heart failure
Secondary: death from all causes; hospitalization for cardiovascular causes or worsening heart failure; atrial fibrillation or flutter occurrence; death from arrhythmia; sudden death
The study was terminated early due to an increase in mortality in the dronedarone group (25 deaths vs. 12 with placebo; HR = 2.13, 95%; CI, 1.07 to 4.25; p = 0.03).
The vast majority of deaths in the dronedarone group were cardiovascular in nature including progressive heart failure, arrhythmia, and sudden death.
The primary combined endpoint was not statistically different between groups (53 events dronedarone vs. 40 events placebo; p = 0.12).
The number of patients who had an initial hospitalization for a cardiovascular cause was higher with dronedarone (71 vs. 50 placebo; p = 0.02).
Treatment with dronedarone in patients with heart failure and left ventricular systolic dysfunction causes an increase in early mortality primarily due to worsening heart failure.
Singh et al 2007 9
(EURIDIS and ADONIS)
Two identical MC, DB, PC, PG, RCTs
Duration: 12 months
N = 612 adults (≥ 21 years) with at least 1 episode of atrial fibrillation in the prior 3 months and in sinus rhythm for at least 1 hour prior to randomization Dronedarone 400 mg PO twice daily (n = 828)
Placebo (n = 409)
The number of patients randomized to each treatment is from combined data of both trials.
Primary: time from randomization until the first documented recurrence of atrial fibrillation
Secondary: atrial fibrillation symptoms and mean ventricular rate during first recurrence
In EURIDIS, the median time until a documented recurrence of atrial fibrillation was 96 days for dronedarone and 41 days for placebo. At 12 months, 67.1%; of patients in the dronedarone group vs. 77.5%; of patients in the placebo group had a recurrence (HR = 0.78, 95%; CI: 0.64 to 0.96; p = 0.01).
In ADONIS, the median time was 158 days for dronedarone and 59 days for placebo. At 12 months, 61.1%; of patients in the dronedarone group and 72.8%; of patients in the placebo group had a recurrence (HR = 0.73, 95%; CI: 0.59 to 0.89, p = 0.002).
For the combined trials, the recurrence rates at 12 months were 64.1%; for dronedarone and 75.2%; for placebo (HR = 0.75, 95%; CI: 0.65 to 0.87, p < 0.001).
Hospitalization or death occurred at 12 months in 22.8%; of patients on dronedarone and 30.9%; of patients receiving placebo in the combined analysis (HR = 0.73, 95%; CI: 0.57 to 0.93, p = 0.01).
The mean ventricular rate at first recurrence in the combined analysis was 103.4 beats/min for dronedarone and 117.1 beats/min with placebo (p < 0.001).
Rates of pulmonary, thyroid, and hepatic adverse effects were not significantly increased with dronedarone.
Dronedarone is a new antiarrhythmic agent that is structurally related to amiodarone, but purportedly has an improved safety profile. The medication was initially rejected for approval by the FDA in 2006 due to an increase in mortality among patients with heart failure as seen in the ANDROMEDA trial. Since that time, the manufacturer of dronedarone has completed 4 placebo- and 1 active-controlled trial. Results from the 4 placebo-controlled trials (ATHENA, ERATO, EURIDIS, and ADONIS) have shown dronedarone therapy to result in significant improvements in a variety of endpoints including initial hospitalization due to cardiovascular events or death from any cause, change in mean ventricular rate, and time until the first documented recurrence of atrial fibrillation. DIONYSOS, a trial that compares dronedarone to amiodarone, revealed amiodarone to be significantly better than dronedarone with regard to the composite primary endpoint of time to first atrial fibrillation recurrence or premature study discontinuation for intolerance or lack of efficacy after 12 months. Safety was improved with dronedarone; however, not significantly as compared to amiodarone for the main safety endpoint. Further studies are needed to clearly define the place in therapy of dronedarone.
- Abramowicz M, editor. Dronedarone (Multaq) for atrial fibrillation. Med Lett Drugs Ther. 2009;51(1322):78-80.
- Wall Street Journal. Multaq approval marks comeback for Sanofi’s heart drug.
- http://blogs.wsj.com/health/2009/07/02/multaq-approval-marks-comeback-for-sanofis-heart-drug/tab/article/. Accessed January 28, 2010.
- Duray GZ, Ehrlich JR, Hohnloser SH. Dronedarone: a novel antiarrhythmic agent for the treatment of atrial fibrillation. Curr Opin Cardiol. 2010;25(1):53-58.
- Patel C, Yan GX, Kowey PR. Dronedarone. Circulation. 2009;120(7):636-644.
- Sanofi Aventis. Multaq® (dronedarone). Briefing document. Advisory committee meeting of the Cardiovascular and Renal Drugs Division of the US Food and Drug Administration. March 18, 2009.
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/UCM134981.pdf Accessed January 28, 2010.
- Hohnloser, SH, Crijns HJGM, van Eickels M, et al for the ATHENA investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360(7):668-678.
- Davy JM, Herold M, Hoglund C, et al for the ERATO study. Dronedarone for the control of ventricular rate in permanent atrial fibrillation: the efficacy and safety of dronedarone for the control of ventricular rate during atrial fibrillation (ERATO) study. Am Heart J. 2008;156(3):527.e1-e9.
- Kober L, Torp-Pederson C, McMurray JJV, et al for the Dronedarone Study Group. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med. 2008;358(25):2678-2687.
- Singh BN, Connolly SJ, Crjins HJGM, et al for the EURIDIS and ADONIS investigators. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007;357(10):987-999.