May 2010 FAQs
May 2010 FAQs
What is the optimal timing of antibiotics for the prevention of postoperative infections for cesarean delivery?
What is the optimal timing of antibiotics for the prevention of postoperative infections for cesarean delivery?
Cesarean delivery is defined as the birth of a baby through surgical incisions in the abdomen and uterine walls.1,2 Cesarean deliveries are the most common surgical procedures in the United States.3-5 Over 1.3 million cesarean procedures were performed in 2006, and the rate of cesarean delivery has increased from 4.5% in 1970 to 31.8% in 2007.2,3 The most common indications for cesarean delivery include: failure to progress during labor, nonreassuring fetal heart rate, fetal malpresentations (i.e. breech), multiple gestation, prior cesarean delivery, placenta abnormalities, and maternal infection, such as active genital herpes and human immunodeficiency virus.1,2,6 Risk factors for cesarean delivery include: increased maternal age, use of electronic fetal monitoring, induction of labor, obesity, and preeclampsia.2
Infection is a common complication following cesarean delivery.2,4,5 The most common pathogens include enteric gram-negative bacilli, anaerobes, Group B streptococcus, and enterococci.7 Prophylactic antibiotics have been shown to reduce the rates of postpartum endrometritis by 60% to 70% and wound infections by 30% to 65% in both high-risk (i.e. laboring, ruptured membranes) and low-risk (i.e. intact membranes) patients.4,8 The goal of prophylaxis is to achieve therapeutic levels of antibiotic agents in the tissues at the time of microbial contamination. Preferred agents are those that are long-acting, have a low incidence of adverse effects, and are inexpensive. The first generation cephalosporin, cefazolin, is recommended for cesarean delivery.7 The dose of cefazolin is 1 to 2 grams given intravenously (IV). Alternative agents for patients allergic to penicillin and cephalosporins include clindamycin in combination with gentamicin, ciprofloxacin, levofloxacin, or aztreonam. In the majority of surgical procedures, prophylactic antibiotics are administered prior to skin incision.5,7 However, it has been usual practice in cesarean delivery for antibiotics to be administered at the time the umbilical cord is clamped to avoid unnecessary exposure of the drug to the fetus.4 Withholding antibiotic administration minimizes the concern of masking an infection in the newborn, which would increase the need for a sepsis workup, or affect microbiologic cultures.4,9,10 The optimal timing for prophylactic antibiotic administration in cesarean delivery has been questioned; dosing prior to skin incision appears to be more effective than dosing after clamping.7 The following is a review of the literature.
Sullivan and colleagues conducted a study to determine if the administration of cefazolin prior to skin incision was superior to the administration of cefazolin at the time of umbilical cord clamping for the prevention of postcesarean infections.5 In this randomized, double-blinded, placebo-controlled trial, 357 women requiring cesarean delivery were randomized to the study or control group. The study group (n=175) received cefazolin 1 gram IV 15 to 60 minutes preoperatively and placebo at cord clamp, while the control group (n=182) received placebo preoperatively or 1 gram cefazolin IV at cord clamp. The primary outcome was total postcesarean infectious morbidity; neonatal outcomes were secondary measures. Patients were followed through their hospital course and up to 6-weeks post-partum. The study was powered at 80% to detect a 50% decrease in overall infectious morbidity for patients receiving preoperative antibiotics.
Baseline characteristics between the 2 groups were similar with regard to age (mean 28.3±6.1), weight, parity, race, premature delivery (<37 weeks), indication for cesarean delivery, and surgical measures (i.e. operative time).5 There was a statistically significant difference in infectious morbidity between the groups. Total infectious morbidity was higher in the control group (n=21) compared to the study group (n=8); [relative risk (RR)=0.4, 95% confidence interval (CI) 0.18 to 0.87]. There were significantly more cases of endomyometritis in the control group (n=10) vs. the study group (n=2); RR=0.2, 95% CI 0.15 to 0.94. The number of wound infections was greater in the control group (n=10) vs. the study group (n=5); however, this did not reach statistical significance (RR=0.52, 95% CI 0.18 to 1.5). There were no significant differences in neonatal outcomes between the 2 groups including birth weight, gestational age, sepsis, septic workup, admission to the neonatal intensive care unit (NICU), total length of stay, and metabolic acidosis. The number of days spent in the NICU was lower in the group that received preoperative antibiotics and reached statistical significance; 19.7±24.9 (control group) vs. 14.2±15.8 (study group), p<0.01. The authors concluded that the administration of cefazolin prior to skin incision was superior to the administration of cefazolin at the time of umbilical cord clamping as shown by the decrease in total infectious morbidity and endomyometritis and no increase in neonatal complications.
A meta-analysis was conducted by Constantine and colleagues to determine the appropriate timing of prophylactic antibiotics during cesarean deliveries.4 Studies were included if patients were randomized to either preoperative antibiotics at cesarean delivery or antibiotics administered at the time of umbilical cord clamp. Additionally, studies were screened for the following outcomes: endometritis, wound infection, febrile morbidity (oral temperature >100.4˚F in 2 consecutive readings), neonatal sepsis, and NICU admissions. The primary outcome was the rate of postpartum endometritis; secondary outcomes included wound infection, a composite postpartum infectious morbidity, suspected neonatal sepsis, proven neonatal sepsis, and NICU admission. Of the 5 studies found in the literature that compared the timing of antibiotic prophylactic dose administration, only 3 were randomized controlled trials (RCT) and were included in the analysis, one of which was the study by Sullivan et al., summarized above.
In the 3 RCTs, 377 women received preoperative cefazolin and 372 women received cefazolin at the time of cord clamping.4 Preoperative administration was associated with a 53% overall reduction in the risk of postpartum endometritis (RR=0.47, 95% CI 0.26 to 0.85; p=0.012) and a 50% reduction in the risk of total infectious morbidity (RR=0.5, 95% CI 0.33 to 0.78; p=0.002). Although it did not reach significance, there was a trend toward a lower risk of wound infection (RR=0.6, 95% CI 0.3 to 1.21; p=0.151). Preoperative administration did not have a significant effect on suspected neonatal sepsis, proven neonatal sepsis, or NICU admission (p values not significant for all outcomes). The authors concluded that these results provide strong evidence for the administration of prophylactic antibiotics for cesarean delivery prior to skin incision, rather than after umbilical cord clamping.
Cesarean deliveries are the most common surgical procedures in the United States. Infectious complications are a frequent cause of postpartum morbidity. Prophylactic antibiotics have been shown to reduce the rates of postpartum endrometritis and wound infections. Usual practice in cesarean delivery is the administration of antibiotics at the time of umbilical cord clamping, as this avoids unnecessary exposure of drug to the fetus. Studies comparing the administration of antibiotics given at the time of skin incision to antibiotics administered at the time of cord clamping demonstrate that preoperative antibiotics significantly reduce total infectious morbidity and postpartum endometritis without affecting neonatal outcomes. Based on the data, the optimal timing of prophylactic antibiotics for cesarean delivery is at the time of skin incision.
- Berghella, V. Cesarean delivery: preoperative issues. In: Barss VA, Lockwood CJ, eds. UpToDate. Waltham, MA: UpToDate; 2010. http://www.uptodateonline.com/online/content/topic.do?topicKey=labordel/7964&selectedTitle=1%7E150&source=search_result. Accessed April 26, 2010.
- Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, Spong CY, "Chapter 25. Cesarean Delivery and Peripartum Hysterectomy" (Chapter). Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, Spong CY: Williams Obstetrics, 23e: http://www.accessmedicine.com/content.aspx?aID=6027599. Accessed April 25, 2010.
- Martin JA, Hamilton BE, Sutton PD, et al. Births: final data for 2006. National vital statistics reports volume 57, number 7. Centers for Disease Control and Prevention. http://www.cdc.gov/nchs/data/nvsr/nvsr57/nvsr57_07.pdf. Published January 7, 2009. Accessed April 27, 2010.
- Costantine MM, Rahman M, Ghulmiyah L, et al. Timing of perioperative antibiotics for cesarean delivery: a metaanalysis. Am J Obstet Gynecol. 2008;199(3):301.e1-301.e6.
- Sullivan SA, Smith T, Chang E, Hulsey T, Vandorsten JP, Soper D. Administration of cefazolin prior to skin incision is superior to cefazolin at cord clamping in preventing postcesarean infectious morbidity: a randomized, controlled trial. Am J Obstet Gynecol. 2007;196(5):455.e1-455.e5.
- Cain JM, ElMasci WM, Gregory T, Kohn EC. Gynecology. In: Brunicard FC, Anderson DK, Billiar TR, eds. Schwartz’s Principles of Surgery. 9th ed. New York, NY: McGraw-Hill; 2010:1475-1514.
- The Medical Letter. Antimicrobial prophylaxis for surgery. Treat Guidel Med Lett. 2009;7(82):47-52.
- ACOG. Prophylactic antibiotic in labor and delivery. Int J Gynaecol Obstet. 2004;84(3):300-307.
- Owens SM, Brozanski BS, Meyn LA, Wiesenfeld HC. Antimicrobial prophylaxis for cesarean delivery before skin incision. Obstet Gynecol. 2009;114(3):573-579.
- Thigpen BD, Hood WA, Chauhan S, et al. Timing of prophylactic antibiotic administration in the uninfected laboring gravida: a randomized clinical trial. Am J Obstet Gynecol. 2005;192(6):1864-1868.
Clostridium difficile clinical practice guidelines: summary of treatment recommendations
Clostridium difficile clinical practice guidelines: summary of treatment recommendations
The Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) have recently published guidelines for the diagnosis and treatment of Clostridium difficile infections (CDIs).1 The guidelines consist of 4 major content areas: collecting and reporting of surveillance data, diagnostic testing, infection control measures including prevention, and treatment. The purpose of this summary is to review the guidelines’ recommendations for appropriate prevention and treatment of CDIs. For further information, the reader is referred to the IDSA website, where copies of the full guidelines may be downloaded: http://www.idsociety.org/content.aspx?id=4430#cd.2
Clostridium difficile, a gram-positive spore-forming anaerobe, is the most common cause of hospital-acquired diarrhea.3-4 Infections with Clostridium difficile can result in severe disease such as pseudomembranous colitis, but some patients are asymptomatic carriers and others have only mild or moderate diarrhea. The current guidelines define a CDI as: the presence of diarrhea (3 or more unformed stools in 24 or fewer consecutive hours) with either a stool test positive for toxigenic Clostridium difficile (or its toxins) or findings of pseudomembranous colitis with colonoscopy.1
One important element for the prevention of CDIs is the use of appropriate infection control measures such as hand washing and contact precautions to limit the spread from person to person.1 However, it is also important to minimize an individual patient’s risk for developing a CDI. Proper antimicrobial use is vital in helping to minimize the occurrence of CDIs, as prior exposure to antibiotics is a major risk factor. An increase in the number of antimicrobials, the number of doses, or duration of therapy can increase the risk of infection. The role of probiotics in preventing CDIs has recently prompted a great deal of discussion; however, the guidelines do not recommend their use for primary prevention at this time based on limited clinical efficacy data and the possibility for bacteremia or fungemia resulting from their use.
The guidelines identify a number of key points for the treatment of CDIs.1 One of the primary recommendations is to discontinue the offending antimicrobial agent to reduce the risk of CDI recurrence. Vancomycin and metronidazole are the antimicrobials recommended for treatment. The choice of agent is based on the severity of the infection and whether it is a first episode or recurrence. Table 1 summarizes the antimicrobial therapy recommendations.
Table 1. CDI treatment recommendations.1
Mild or moderate
WBC < 15,000/µL
SCr < 1.5 times baseline level
Oral metronidazole 500 mg 3 times daily for 10 to 14 days
WBC > 15,000/ µL
SCr > 1.5 times baseline level
Oral vancomycin 125 mg 4 times daily for 10 to 14 days
Hypotension, shock, ileus, megacolon
Oral (or by nasogastric tube) vancomycin 500 mg 4 times daily PLUS IV metronidazole 500 mg every 8 hours; for complete ileus consider addition of rectal vancomycin
Same as initial episode
Tapered and/or pulsed vancomycina
WBC=white blood cell count; SCr=serum creatinine.
aA variety of regimens may be used, the guidelines suggest something similar to: 125 mg 2 times per day for the first week following the initial course of therapy, then 125 mg once daily for 1 week, and finally 125 mg every 2 or 3 days for 2 to 8 weeks.
Although the systemic absorption of oral vancomycin is low, patients with renal failure may achieve high serum levels with 2 grams per day for an extended duration.1 In these cases, serum trough monitoring is recommended. Metronidazole is not recommended for use beyond the first recurrence due to cumulative neurotoxicity. The use of intravenous immunoglobulins (150 to 400 mg/kg) has been reported in patients with severe, complicated cases or in those with recurrence. In addition, fecal transplants are being used for some patients with recurrent infections. In these cases, stool (administered either via nasogastric tube or enema) from a healthy donor is given to the patient. Other antibiotics such as nitazoxanide can also be considered.
Other key treatment measures include recommendations to:1
- Initiate empiric therapy as soon as possible in patients with suspected severe or complicated CDI
- Make a patient-specific decision to initiate, continue, or discontinue therapy in patients with negative stool toxin assays
- Avoid antiperistaltic agents when possible
- Consider colectomy for patients who are severely ill
Conclusion/role of the pharmacist
These guidelines are a reminder that although antimicrobial agents are a beneficial and necessary part of the care of many hospitalized patients; their use is not without risk. It is important for pharmacists to remain vigilant of the antimicrobial use within their institution and serve as advocates for appropriate use. When treating patients with CDIs, pharmacists should recommend appropriate therapy with metronidazole, vancomycin, or the combination in select cases.
- Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431-455.
- Infectious Diseases Society of America. Clinical practice guidelines for Clostridium difficile infection in adults. http://www.idsociety.org/content.aspx?id=4430#cd. Accessed April 15, 2010.
- Huang H, Weintraub A, Fang H, Nord CE. Antimicrobial resistance in Clostridium difficile. Int J Antimicrob Agents. 2009;34(6):516-522.
- Bauer MP, van Dissel JT, Kuijper EJ. Clostridium difficile: controversies and approaches to management. Curr Opin Infect Dis. 2009;22(6):517-524.
What weight should be used when dosing unfractionated heparin for treatment of thromboembolism in obese patients?
What weight should be used when dosing unfractionated heparin for treatment of thromboembolism in obese patients?
A recent case report highlighted in Pharmacotherapy provides an example of a clinical dilemma becoming more common for which there are limited data available to guide decision-making. The case report discusses the treatment of a morbidly obese patient (388 kg) with unfractionated heparin empirically for a suspected pulmonary embolism.1 The patient was given a 5000 unit heparin bolus and started on a heparin infusion rate of 1500 units/hour based on the maximum dose and rate (dosing cap) according to the institution’s protocol. Subsequent titrations were based on a dosing weight (DW) defined as ideal body weight (IBW) + 0.3(actual body weight [ABW] – IBW). After 55 hours of titration of the heparin infusion rate, a therapeutic activated partial thromboplastin time (aPTT) was finally reached. The heparin infusion was discontinued due to concerns for heparin-induced thrombocytopenia, but was ultimately reinitiated 4 days later after concerns of a pulmonary embolism arose despite treatment with prophylactic fondaparinux. The patient ultimately expired. The authors explain that maximum doses of the nomogram are an attempt to decrease the potential for adverse bleeding; however, achieving therapeutic efficacy in a timely manner may be hindered, especially in the obese or morbidly obese patients. They suggest the use of a DW for calculation of the heparin bolus dose and initial infusion rate when treating a morbidly obese patient instead of arbitrarily capping the heparin dose. The DW they recommend is as above or substitution of 0.4 for 0.3 in the equation.
For many years unfractionated heparin empiric dosing was a 5000 unit intravenous (IV) bolus followed by a 1000 units/hour IV infusion.2 In 1993, a study published by Raschke and colleagues produced results which showed that dosing heparin based on ABW (bolus of 80 units/kg followed by 18 units/kg/hour) achieved therapeutic aPTT at 24 hours more often than the standard dosing regimen.3 Additionally, this study found no difference between the 2 regimens with regards to bleeding events, though the weight-based subjects had a higher percentage of supratherapeutic aPTTs. The rate of recurrent venous thromboembolism was statistically significantly higher in the standard dosing regimen when compared to the weight-based regimen.
Given the findings above, the American College of Chest Physicians’ (ACCP) guidelines for the treatment of venous thromboembolism suggest 2 possible dosing strategies for intravenous heparin.4 One strategy is the empiric dosing of a 5000 unit bolus and 1300 unit/hour infusion. The second strategy is a weight-based strategy of an 80 units/kg bolus and 18 units/kg/hour infusion. The guidelines are, however, without comment on the weight that should be used for dosing and do not mention a maximum bolus or infusion rate. Given the lack of direction from the guidelines as to a dosing weight, one must look to the available studies to determine an appropriate dosing weight, especially in the obese population. The authors of the case report in Pharmacotherapy, review the available evidence, some which will be summarized below.1
The study published by Raschke and colleagues concludes that a weight-based regimen using ABW produces effective and safe anticoagulation. However, one must consider that only 9 patients included in the weight-based arm were greater than 100 kg, with 131 kg being the largest patient represented.3 The ability to extrapolate these findings to the obese patients seen in practice today becomes difficult, especially when considering the pharmacokinetics of heparin and the vascularity of adipose tissue. The volume of distribution of heparin approximates that of blood volume.2 Though blood volume is increased in obesity, adipose tissue has less blood volume when compared to lean body mass. Therefore, using ABW for the morbidly obese may increase the incidence of supratherapeutic aPTTs as well as bleeding risk.1
These concerns over using ABW in obese patients prompted Yee and Norton to conduct a retrospective study with the goal of determining which body weight should be used in a weight-based heparin protocol.5 Their institution’s protocol was based on that of Raschke and colleagues, 80 units/kg bolus and 18 units/kg/hour infusion. Non-obese patients were dosed according to ABW, and a DW (DW = IBW + 0.3[ABW – IBW]) was used for the obese patients (patients who were >10 kg above their IBW). The chart review was prompted when data revealed that more than half of the patients treated according to the heparin protocol had supratherapeutic aPTTs (>70 seconds), and 20% had aPTTs above 200 seconds. Data collected during the chart review included: heparin bolus and initial infusion rate, the rate that produced a therapeutic aPTT, number of dose adjustments required to reach the therapeutic aPTT, number of aPTT draws, and duration of therapy. Two groups of patients were considered, obese (³10 kg above IBW) and non-obese (<10 kg over the IBW). The infusion rate at time of first therapeutic aPTT was divided by the ABW, IBW, and DW in order to determine which weight most accurately predicted the appropriate heparin drip rate.
A total of 213 patients met the inclusion criteria and were evaluated in the review.5 Overall, the ranges of heparin infusion rates were similar for all weights evaluated; however, the least amount of variability was found when the dose was calculated according to ABW. In non-obese patients there were no differences among infusion rates calculated using IBW, ABW, or DW. However, there were differences noted in the obese patients among the 3 weights. The mean value of the initial aPTT was significantly lower when DW was used to calculate the dose in obese patients compared to use of ABW in non-obese subjects. In terms of efficacy and safety of the protocol used at the institution, the authors found that 168 (79%) of 213 patients had therapeutic aPTTs within 24 hours, 39(18%) had an initial aPTT of greater than 200 seconds; no adverse events were reported for either the obese or non-obese subjects.
The authors concluded that the infusion dose should be decreased to 15 units/kg/hour in order to decrease the patients with supratherapeutic aPPTs based on the heparin infusion rate that produced therapeutic aPTT. It is unknown how the results would have changed had the institution’s protocol specified the use of ABW for obese patients instead of the DW. This can be illustrated using the example of the largest patient included in the study. The patient, who weighed 184 kg, was found to have a therapeutic aPTT at an infusion rate of 1700 units/hour almost half of the 3300 units/hour that the patient would have been initiated had ABW been utilized to calculate the infusion rate. Because of this patient’s values, the authors instituted a dosing cap of 10,000 units for the bolus and 1500 units/hour for the initial infusion rate. Based on their findings and this example, the authors concluded that ABW in both non-obese and obese patients should be used to calculate heparin infusion rates with the dosing cap mentioned above. The authors proposed that dosing limits should be specified in nomograms in order to avoid adverse events; however, no such events were found in this study.
Spruill and colleagues evaluated whether or not there was a need for different heparin protocols for obese and non-obese patients.2 The retrospective chart review included 40 patients, 20 obese (defined as greater than 30% over IBW) and 20 non-obese patients (defined as less than 20% over IBW). Though Yee and colleagues concluded that a dosing cap should be utilized, the nomogram in place at Spruill and colleagues’ institution was 70 units/kg bolus followed by 15 units/kg/hour infusion without a dosing cap. This chart review found no difference between obese and non-obese patients in initial aPPT, first therapeutic aPPT, or time to first therapeutic aPPT. The study does not mention if any adverse bleeding events occurred. Given the results, the authors concluded that ABW is appropriate for both the obese and non-obese patients.
Bauer and colleagues published data from a retrospective cohort study that evaluated efficacy and safety of a weight-based heparin regimen without dosing caps when comparing patients (n=1054) in pre-specified body mass index (BMI) quartiles (15.9 to 25.9, 26 to 29.4, 29.5 to 34.2, and >34.3 kg/m2).6 The heparin dosing regimen used in this study was a 60 unit/kg bolus followed by a 12 units/kg/hour infusion, using ABW of the patient to dose the heparin. The indications for heparin were primarily cardiac including acute coronary syndromes and atrial fibrillation; however, a small percentage of patients had venous thromboembolism/pulmonary embolism. The therapeutic aPPT range was 60 to 90 seconds. Efficacy was analyzed by comparing percentage of patients with an initial therapeutic aPPT in each of the BMI quartiles, and safety was analyzed based on bleeding rates. There was no difference found between the 4 groups for percentage of patients with a therapeutic aPPT. However the groups did differ when evaluating percentage with aPPTs <45 seconds as well as >110 seconds; with patients in the lowest BMI quartile were more likely to have an aPPT <45 seconds and patients in the highest BMI quartile were more likely to have aPPT >110 seconds. No difference was found among the 4 groups in terms of bleeding frequency. In addition, a logistic regression analysis did not find a correlation between BMI and first aPPT being within the therapeutic range or bleeding events. The authors conclude that it is safe to use a weight-based heparin nomogram based on ABW without a dose cap.
Barletta and colleagues have published a retrospective chart review to compare heparin anticoagulation outcomes in morbidly obese patients (BMI ³40 kg/m2, n=38) to patients with BMI values <40 kg/m2 (n=63).7 The heparin nomogram in place at the institution was a 80 unit/kg bolus followed by an infusion of 18 units/kg/hour without a dose cap. Dosing was based on ABW with a goal range of 70 to 110 seconds for aPTT values. The main outcome measures included mean aPTT values at 6 and 12 hours, percentage of patients in the therapeutic range at these time points, and bleeding complications. The morbidly obese patients had significantly higher mean aPTT values at both 6 (155 vs. 135 seconds, p=0.02) and 12 hours (141 vs. 117 seconds, p=0.012), respectively compared to non-morbidly obese patients. At the 6-hour assessment, 16% of morbidly obese patients were in the therapeutic range compared to 22% of non-morbidly obese patients (p not reported). By the 12-hour assessment, these percentages increased slightly to 18% in the morbidly obese group and to 43% of patients in the non-morbidly obese group (P=0.012). A significantly higher rate of supratherapeutic aPTT values was seen at 12 hours for morbidly obese patients compared to non-morbidly obese (71% vs. 43%, p=0.006). Four patients experienced bleeding events, but none of them had a BMI >40 kg/m2. The authors concluded that morbidly obese patients dosed according to ABW on a weight-based heparin nomogram are more likely to experience supratherapeutic aPTT values compared to non-morbidly obese patients. Furthermore, they suggest that a dose cap may be warranted, but further data are necessary to support these findings.
The majority of the literature supports the use of ABW for calculating heparin bolus doses and initial infusion rates for obese patients in order to achieve therapeutic aPPTs in a timely manner; however, experience with morbidly obese patients is limited. There is some evidence to suggest a higher incidence of supratherapeutic aPTTs when ABW is used to dose morbidly obese patients. Though ABW was used for initial dosing, all of the protocols had an institution specific nomogram that allowed for the adjustment of the infusion rate based on aPPT values. The use of a dose cap appears to be controversial and not well supported by the literature. The primary limitation of the current literature is the retrospective nature of the data. Furthermore, few morbidly obese subjects were evaluated and there is no standard definition of obesity used among the trials. It is important to note that no increase in adverse bleeding events was observed in obese patients in any of the studies presented here, even when ABW was used to dose heparin.
The case report described above exemplifies the balance which must be achieved when dosing heparin in obese patients; attempting to achieve a therapeutic aPPT within 24 hours while minimizing adverse bleeding events.1 The authors of the case report suggest the use of a DW for initiating heparin in obese patients; however, this is not fully supported by the retrospective studies. Another important issue raised by the case report is the potentially detrimental effects of a dose cap. Although the case patient did not have a confirmed thromboembolic event, a therapeutic aPTT was not achieved for 55 hours, which may have implications for future patients. As always, careful patient monitoring is recommended, especially when dosing anticoagulants in obese patients.
- Myzienski AE, Lutz ME, Smythe MA. Unfractionated heparin dosing for venous thromboembolism in morbidly obese patients: case report and review of the literature. Pharmacotherapy. 2010;30(3):105e-112e.
- Spruill WJ, Wade WE, Huckaby WG, Leslie RB. Achievement of anticoagulation by using a weight-based heparin dosing protocol for obese and nonobese patients. Am J Health-Syst Pharm. 2001;58(22):2143-2146.
- Raschke RA, Reilly BM, Guidry JR, Fontana JR, Srinivas S. The weight-based heparin dosing nomogram compared with a “standard care” nomogram. Ann Intern Med. 1993;119(9):874-881.
- Kearon C, Kahn SR, Agnelli G et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest. 2008; 133(6): 454-545.
- Yee WP, Norton LL. Optimal weight base for a weight-based heparin dosing protocol. Am J Health-Syst Pharm. 1998;55(2):159-162.
- Bauer SR, Ou NN, Dreesman BJ, et al. Effect of body mass index on bleeding frequency and activated partial thromboplastin time in weight-based dosing of unfractionated heparin: a retrospective cohort study. Mayo Clin Proc. 2009;84(12):1073-1078.
- Barletta JF, DeYoung JL, McAllen K, Baker R, Pendleton K. Limitations of a standardized weight-based nomogram for heparin dosing in patients with morbid obesity. Surg Obes Relat Dis. 2008;4(6):748-753.
By: Amanda Ries, PharmD
Intensive blood pressure and lipid control in patients with type 2 diabetes mellitus: results of the ACCORD Lipid and ACCORD BP trials.
Intensive blood pressure and lipid control in patients with type 2 diabetes mellitus: results of the ACCORD Lipid and ACCORD BP trials.
The primary cause of morbidity and mortality in patients with diabetes is cardiovascular disease (CVD).1 Relative risk of CVD in a patient with diabetes is 2 to 4 times greater compared to a patient without diabetes. Patients with type 2 diabetes mellitus (DM) are at increased risk for coronary events; the risk is comparable to a patient without diabetes with a history of myocardial infarction. Based on recommendations in the Adult Treatment Panel III (ATP III) guideline of the National Cholesterol Education Program (NCEP), diabetes should be considered a coronary heart disease risk equivalent and aggressive management to reduce risk factors (hypertension and dyslipidemia) should be implemented. Due to this increased risk, the ATP III guidelines recommend patients with diabetes achieve a goal low-density lipoprotein (LDL) of <100 mg/dL, and patients with diabetes and CVD achieve a goal LDL <70 mg/dL. Also, patients with both hypertension and diabetes are at increased risk of CVD compared to patients with only 1 of these disease states. Due to this increased risk, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommends controlling blood pressure in patients with diabetes to obtain a blood pressure goal of <130/80 mmHg.2,3 These recommendations have been incorporated into the 2010 American Diabetes Association Standards of Medical Care in Diabetes, which recommend treating patients with diabetes to a goal blood pressure of <130/80 mmHg and goal plasma LDL cholesterol <100 mg/dL, plasma high-density lipoprotein (HDL) cholesterol >50 mg/dL, and triglycerides (TG) <150 mg/dL.4
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was conducted to determine whether targeting lower glycated hemoglobin levels (A1C) as well as controlling hypertension or dyslipidemia in patients with type 2 DM reduces cardiovascular events.5 A total of 10,251 patients with type 2 DM and A1C of 7.5% were enrolled in the ACCORD trial. To meet inclusion criteria, patients had to be ≥40 years of age with CVD or ≥55 years of age with anatomical evidence of atherosclerosis, albuminuria, left ventricular hypertrophy, or at least 2 additional risk factors for CVD (dyslipidemia, hypertension, smoking, or obesity) with an upper age limit of 79 years. Patients were randomly assigned to either the intensive glycemic control group (goal A1C <6%) or the standard glycemic control group (goal A1C 7 to 7.9%). After 3.5 years of follow-up, mortality was higher in the intensive glycemic control group (HR 1.22, 95% CI 1.01 to 1.46, p=0.04). A summary of this trial is available at the Drug Information Group’s website.
Per the original study design, patients in the ACCORD trial were further randomized to either the ACCORD Lipid or the ACCORD BP trials.5,6 These subsequent trials were designed to determine whether intensive blood pressure control and combination lipid therapy with a HMG-CoA reductase inhibitor (statin) plus fibric acid derivative (fibrate) would reduce cardiovascular events in patients with type 2 DM. The patients were randomized in a double 2×2 factorial design based on each trial’s eligibility requirements. As shown in Figure I, all 10,000 patients were randomized to the standard or intensive glycemic control groups, then further randomized into 3 groups: eligible for BP trial only, eligible for both BP and Lipid trials, and eligible for Lipid trial only. Researchers determined 4200 participants were needed for the BP trial and 5800 participants were needed for the Lipid trial to achieve adequate power. Due to this sample size requirement, the majority of the patients eligible for both the BP and Lipid trials were allocated to the Lipid trial arm.
Figure I: ACCORD trial double 2×2 factorial design of allocation to Blood Pressure (BP) and Lipid Trials.7
The ACCORD Lipid trial included 5518 patients to determine whether combination therapy with simvastatin plus a fibrate (n=2765) versus simvastatin monotherapy (n=2753) would reduce CVD events in patients with type 2 DM.8,9 The administration of simvastatin was open-label, and fibrate therapy was blinded. The hypothesis of this trial was that combination therapy would be more effective for achieving lipid profile goals because statins effectively decrease LDL cholesterol and fibrates effectively increase HDL cholesterol and lower TG. The ACCORD BP trial was an open-label trial that included 4733 patients to determine whether intensive antihypertensive therapy (systolic pressure <120 mmHg) compared to standard antihypertensive therapy (systolic pressure <140 mmHg) would reduce CVD events in type 2 DM patients.10,11
ACCORD Lipid trial
The primary endpoint of the ACCORD Lipid trial was the first occurrence of a major cardiovascular event including nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes.8,9 The secondary endpoints were the combination of primary endpoints plus revascularization or hospitalization for congestive heart failure; a combination of a fatal coronary event, nonfatal myocardial infarction, or unstable angina; nonfatal myocardial infarction; fatal or nonfatal stroke; nonfatal stroke; death from any cause; death from cardiovascular causes; and hospitalization or death due to heart failure. Eligibility was based on meeting the study’s inclusion criteria determined by lipid measurements taken within the previous year. Inclusion criteria consisted of the following: observed (or estimated if currently on a lipid-altering medication) LDL between 60 and 180 mg/dL, inclusive; HDL <55 mg/dL for women and black patients, or <50 mg/dL for all other groups; and TG <750 mg/dL if not on a lipid-altering medication or <400 mg/dL if on a lipid-altering medication. Patients were excluded if they were using a medication known to interact with statins or fibrates, had a history of pancreatitis, myositis/myopathy, or gallbladder disease, or refused to discontinue any lipid-altering medications.
Eligible participants were randomized to receive simvastatin plus fenofibrate or simvastatin plus placebo. The initial dose of simvastatin was based on the national lipid guidelines at the time of study enrollment, and modification of the simvastatin dose occurred in response to changes to the national lipid guidelines throughout the duration of the study. The initial dose of fenofibrate was 160 mg per day and the dose was adjusted based on estimated glomerular filtration rate (GFR) with the use of the abbreviated Modification of Diet in Renal Disease (MDRD) equation. Fasting lipid profiles were obtained at 4, 8, and 12 months after randomization and then annually. The final fasting lipid profile was measured at the conclusion of the study. The study was designed to enroll 5800 patients for a power of 87% to detect a 20% reduction in the rate of the primary outcome for patients in the fenofibrate group versus patients in the simvastatin only group. Primary and secondary outcomes in the intent-to-treat population were analyzed with the use of time-to-event methods.
Baseline characteristics of participants were similar in both groups; mean age was 62 years, and 31% were female. Sixty percent of patients were taking simvastatin before study enrollment, and 37% had a history of a cardiovascular event. Mean LDL levels at baseline were 100.6 ± 30.7 mg/dL, mean HDL levels were 38.1 ± 7.8 mg/dL, and mean TG were 162 mg/dL. The mean duration of follow-up for the primary outcome was 4.7 years, but follow-up for total death rates was 5 years. At the conclusion of the study, the simvastatin plus fenofibrate group had 77.3% compliance and the simvastatin group had 81.3% compliance. The average daily dose of simvastatin in the fenofibrate and placebo groups was 22.3 mg and 22.4 mg, respectively. The investigators found no clinically or statistically significant differences between the simvastatin plus fenofibrate group and the simvastatin group in the primary and secondary outcomes. Patients in the fenofibrate group had a significant increase in the incidence of serum creatinine elevation to >1.3 mg/dL in women and to >1.5 mg/dL in men (p <0.001), increase of ALT >5 times the upper limit of normal (p=0.03), post-randomization increase of microalbuminuria ≥30 and <300 mg/g (p=0.01), and post-randomization increase of microalbuminuria ≥300 mg/g (p=0.03).
The study was limited due to the open-label administration of simvastatin, and that it enrolled too few patients to achieve the predetermined power. Also, it only included patients >40 and <79 years of age which might not accurately represent the effects simvastatin plus fenofibrate therapy may have in patients outside of this range. A subgroup analysis of patients with signs of dyslipidemia (defined as a baseline TG level >203 mg/dL and an HDL level <33 mg/dL) showed a trend toward benefit with the addition of fenofibrate; therefore, the authors suggest larger studies with fenofibrate in high-risk patients with dyslipidemia and diabetes may be warranted. Future trials should be conducted with caution due to the renal adverse effects associated with fenofibrate use in this trial. Based on these results, the addition of fenofibrate seems to provide more risk than benefit, with no change in cardiovascular risk and increased incidence of adverse events associated with the combination therapy.
ACCORD BP trial
The primary and secondary endpoints of the ACCORD BP trial were the same as the ACCORD lipid trial.10,11 Participants were included if systolic blood pressure fell into one of the following categories: 130 to 160 mmHg, inclusive, if the participant was on 0 to 3 antihypertensive agents; 161 to 170 mmHg, inclusive, if the participant was on 0 to 2 antihypertensive agents; or 171 to 180 mmHg, inclusive, if the patient was on 0 to 1 antihypertensive agents. Other inclusion criteria were dipstick protein in the spot urine test <2+, protein/creatinine ratio <700 mg/g, or 24-hr protein excretion <1 g/24 hr. Patients were excluded for body mass index >45 kg/m2, baseline serum creatinine >1.5 mg/dL, or in cases of serious illness.
Eligible participants were randomized to intensive therapy (target systolic blood pressure <120 mmHg) or standard therapy (target systolic blood pressure <140 mmHg). Any clinical therapeutic strategy currently available was utilized to strive for the blood pressure targets for each group. For the intensive therapy group, blood pressure was measured once per month for 4 months and then every 2 months; in the standard therapy group, blood pressure was measured at months 1 and 4, and then every 4 months. The study was designed to enroll 4200 patients for a power of 94% to detect a 20% reduction in the rate of the primary outcome for patients in the intensive therapy group compared to patients in the standard therapy group. Primary and secondary outcomes in the intent-to-treat population were analyzed with the use of time-to-event methods.
Baseline characteristics between the 2 groups were similar except the intensive therapy group had significantly higher total cholesterol (p=0.04) and LDL (p=0.03) levels. Mean age was 62.2 years, 47.7% were female, and 33.7% had history of CVD. Mean baseline systolic and diastolic blood pressures were 139.2 mmHg and 76 mmHg, respectively. The mean duration of follow-up for the primary outcome was 4.7 years, but follow-up for total death rates was 5 years. The investigators found no clinically or statistically significant differences between the intensive therapy and standard therapy groups in the primary outcome. There was a statistically significant benefit seen in the intensive therapy group compared to the standard group in the rates of total stroke (p=0.01) and nonfatal stroke (p=0.03); however, the intensive therapy group had a higher rate of adverse events compared to the standard therapy group. These participants had significantly more adverse events attributed to antihypertensive agents (p <0.001), higher incidence of hyperkalemia (p=0.01), bradycardia and arrhythmias (p=0.02), hypotension (p <0.001) and elevations in serum creatinine levels (p <0.001).
The study was limited due to its open-label design, which may have affected the self-reporting of adverse events. The results of the ACCORD BP trial do not favor targeting lower blood pressure goals in patients with type 2 DM to decrease the overall incidence of cardiovascular disease, and the optimal blood pressure goal in patients with type 2 DM is still unknown.
Conclusion of ACCORD Lipid and ACCORD BP trials
Due to the factorial design and the inclusion/exclusion criteria of the overall ACCORD trial, the study’s statistical power was reduced, and the event rate was lower than expected. The majority of patients enrolled in the study were well-controlled at baseline for the modifiable risk factors studied (blood pressure and lipids) which may also have contributed the low event rates. The ACCORD Lipid and BP trials did not control for several potentially confounding cardiovascular risk factors such as weight, BMI, and prior cardiovascular events. These limitations increase the possibility that a larger, adequately powered trial or a trial assessing higher-risk patients may demonstrate benefit for fenofibrate add-on therapy and/or intensive blood pressure control. While the ACCORD Lipid and BP trials found no morbidity or mortality benefit for the interventions studied, they do highlight a need for further studies to confirm efficacy and safety of the current lipid treatment recommendations and determine the optimal blood pressure goal in patients with diabetes. Until further studies and results are available, clinicians should continue to follow the current American Diabetes Association guidelines regarding blood pressure control and lipid management in the setting of type 2 DM.
- 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.
- Chobanian AV, Bakris Gl, Cushman WC, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206-1252.
- American Diabetes Association. Treatment of hypertension in adults with diabetes.
Diabetes Care. 2003(suppl1);26:S80-S82.
- American Diabetes Association Standards of Medical Care in Diabetes. Diabetes Care. 2010(suppl1);33:S11-S61.
- The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(4):2545-2559.
- Buse JB, Bigger JT, Byington RP, et al. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol. 2007;99(12A):21i-33i.
- Goff DC Jr, Gerstein HC, Ginsberg HN, et al. Prevention of cardiovascular disease in persons with type 2 diabetes mellitus: current knowledge and rationale for the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol. 2007;99(12A):4i-20i.
- Ginsberg HN, Bonds DE, Lovato LC, et al. Evolution of the lipid trial protocol of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol. 2007;99(12A):56i-67i.
- The ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010. Epub ahead of print.
- Cushman WC, Grimm RH Jr, Cutler JA, et al. Rationale and design for the blood pressure intervention of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol. 2007;99(12A):44i-55i.
- The ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010. Epub ahead of print.
By: Megan Musselman, PharmD