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2011 American Society of Consultant Pharmacists (ASCP) Annual Meeting and Exhibition
November 16-18, 2011; Phoenix, AZ
Optimizing Diabetes Management With Insulin Analogs Levemir and NovoLog
Diabetes, particularly the type 2 variant, is becoming more prevalent and increasing the burden on clinicians in long-term care. Residents with diabetes are more likely to require extended hospital stays, develop significant neuropathic pain, and experience depression. Effective management of diabetes in older patients requires overcoming several barriers, including comorbid diseases, preexisting complications of poorly managed diabetes, an elevated risk of hypoglycemia, and greater insulin resistance. As a result, many patients have difficulty achieving a glycated hemoglobin (A1c) level of <7%, which is the level the American Diabetes Association (ADA) considers evidence of optimal glucose control, said Brian Tulloch, MD, clinical endocrinologist and associate professor, Diagnostic Clinic of Houston, TX. In a product theater sponsored by Novo Nordisk at the 2011 ASCP annual meeting, Tulloch discussed the benefits of two insulin analog therapies—Levemir (insulin detemer) and NovoLog (insulin aspart)—and addressed current standards for managing and treating diabetes in long-term care.
Levemir is administered as a subcutaneous injection once or twice daily in diabetic patients who require basal insulin. Tulloch said the effectiveness of once-daily Levemir at controlling blood glucose was demonstrated in TITRATE, a 20-week, open-label, multicenter trial. TITRATE’s researchers randomized 244 insulin-naïve patients taking an oral antidiabetic drug (OAD) for type 2 diabetes to one of two groups. One group was instructed to self-titrate Levemir to achieve a target fasting glucose level of 70 mg/dL to 90 mg/dL, as measured with a fasting plasma glucose (FPG) test, and the target for the other group was set at 80 mg/dL to 110 mg/dL. Every 3 days, patients adjusted their insulin dose as needed to achieve the target, with the increase or decrease in insulin based on the mean FPG values from the prior 3 days. By the study’s conclusion, 64.3% of patients in the 70 md/dL to 90 mg/dL target group and 54.5% of patients in the 80 mg/dL to 110 mg/dL group had achieved A1c levels <7%. The mean A1c level for the groups combined was 6.9%. From baseline, A1c levels declined a mean of 1.2% for patients assigned to the group with the lower FPG target versus 0.9% for patients assigned to the group with the higher FPG target.
Tulloch explained that human insulin comprises 51 amino acids; 21 of these constitute the A polypeptide chain and the remaining 30 constitute the B polypeptide chain. A disulfide bond links the A chain to the B chain. Levemir was engineered to attach a fatty acid chain to amino acid B29. He said the fatty acid chain enhances Levemir’s ability to bind to albumin. Studies comparing Levemir with insulin glargine have observed a similar 24-hour effect on blood glucose with both agents but more consistent absorption and action and significantly less weight gain with Levemir. Unlike insulin glargine, Levemir is soluble at neutral pH.
The second analog discussed, NovoLog, is absorbed faster than human insulin and thus has a faster onset and shorter duration of action. Tulloch said NovoLog is typically injected 5 to 10 minutes before meals. In the 48-week randomized, multinational STEPwise trial, researchers compared two step-wise schedules for gradually increasing the NovoLog dose in adults (N=296) with type 2 diabetes that was poorly controlled despite the use of basal insulin and OADs. In the “SimpleSTEP” group, an initial injection of NovoLog was given with the largest meal, blood glucose was measured prior to subsequent meals, and additional doses were based on those results. Individuals assigned to the “ExtraSTEP” group took the initial NovoLog dose prior to the meal associated with the greatest increases in blood sugar as measured before and after the meal, with the primary NovoLog dose adjusted according to the level of glucose control achieved. Nearly one-third (31%) of patients in the SimpleSTEP group achieved the A1c goal of <7%. Tulloch said another study—the 3-year 4-T study—involving 708 insulin-naïve patients with type 2 diabetes found that a majority achieved and maintained the target A1c level when using NovoLog as part of a basal-bolus therapy.
A NovoLog 70/30 mix (70% insulin aspart protamine suspension, 30% insulin aspart injection) is also available. The mix has a faster onset than human insulin premix 70/30. The open-label, nonrandomized, observational IMPROVE study was used to demonstrate the effectiveness of this NovoLog formulation.
During the presentation, Tulloch also demonstrated the convenience of the NovoLog FlexPen. He said NovoLog remains stable in the FlexPen, in the 3-mL PenFill cartridges, and in 10-mL vials for up to 28 days when stored at room temperature or until its expiration date if refrigerated.—David Despain
This product theater was sponsored by Novo Nordisk.
Xarelto Reduces Stroke Risk in Patients With Nonvalvular Atrial Fibrillation
Long-term care clinicians now have Xarelto (rivaroxaban) as an option for reducing the risk of stroke and noncentral nervous system systemic embolic events in patients with nonvalvular atrial fibrillation (AF). The US Food and Drug Administration approved Xarelto despite limited data on its effectiveness based on a lack of
placebo-controlled trials. Associate professor at the University of Sciences in Philadelphia, PA, Richard Stefanacci, DO, MGH, MBA, discussed use of the anticlotting drug, along with data from the ROCKET-AF trial in a product theater at the 2011 ASCP annual meeting. Stefanacci said AF affects more than 2.2 million individuals in the United States, and its prevalence is predicted to top 12 million by 2050. AF increases the risk of ischemic stroke, a too-frequent occurrence among nursing home residents, and is more likely to produce severe disability, to recur, or to prove fatal in residents with AF.
According to Stefanacci, Xarelto’s mechanism of action and its convenience make it worth considering for managing patients who have demonstrated an inadequate response to warfarin. Xarelto selectively inhibits Factor Xa, acting upstream of the thrombin burst, and is administered as a single daily dose. He said that, unlike warfarin, routine coagulation monitoring (prothrombin time/international normalized ratio [INR] testing) is not required with Xarelto.
ROCKET-AF was a prospective, randomized, double-blind trial in which more than 14,000 patients (mean age, 71 years) with nonvalvular AF were randomized to receive 20 mg of Xarelto daily (15 mg for patients with moderate renal impairment) or warfarin targeted to an INR of 2 to 3. In this patient population, Xarelto was found to be noninferior to dose-adjusted warfarin in reducing the risk of stroke and noncentral nervous system embolic events. Stefanacci explained that the trial was not powered to demonstrate superiority with Xarelto and did not do so.
The rate of major bleeding events in ROCKET-AF was somewhat higher with Xarelto than with warfarin and consisted primarily of intracranial bleeds. The Xarelto group had lower rates of critical organ and fatal bleeding events, but higher rates of transfusion and gastrointestinal bleeding. The proportion of patients who discontinued because of treatment-related adverse events (bleeding and nonbleeding events) were similar between the two study arms.
Stefanacci cautioned that renal function should be assessed in patients 65 years and older before initiating treatment with Xarelto. Patients with creatinine clearance (CrCl) >50 mL per minute should receive 20 mg daily, with a dose adjustment to 15 mg daily for patients with CrCl between 15 mL and 50 mL per minute; Xarelto should not be used in patients with CrCL <15 mL per minute. If a dose is missed, the patient should receive the next dose as soon as possible on the same day and resume taking Xarelto once daily with the following day.
Black box warnings for Xarelto include the risk of epidural or spinal hematomas in surgical settings (eg, when undergoing anesthesia or spinal puncture). Stefanacci said these hematomas can also arise in patients who use an indwelling epidural catheter, in those who take concomitant medications that affect hemostasis (eg, nonsteroidal anti-inflammatory drugs [NSAIDs] and platelet inhibitors), and in patients with a history of traumatic or repeated epidural or spinal punctures or spinal surgery or who have spinal deformity. Contraindications discussed include active pathological bleeding and severe hypersensitivity to Xarelto.
Other warnings and precautions include the need to discontinue the drug in the absence of adequate alternative anticoagulation and the increased risk of serious or fatal bleeding for which no antidote is available. With overdose, Xarelto may cause untreatable hemorrhage. In such cases, clinicians should discontinue Xarelto immediately and provide appropriate therapy; activated charcoal may be an option for reducing absorption. The medicine is not believed to be dialyzable. Stefanacci discussed the possibility of drug-drug interactions, such as the use of Xarelto with medications that inhibit or induce CYP3A4 enzymes and drug transport systems; and with other drugs that increase the risk of bleeding, such as NSAIDs and Plavix.—David Despain
This product theater was sponsored by Janssen Pharmaceuticals, Inc.
Brilinta for Acute Coronary Syndrome
The US Food and Drug Administration (FDA) approved Brilinta (ticagrelor) in July 2011 to improve cardiac outcomes in patients with acute coronary syndrome (ACS). In a product theater sponsored by AstraZeneca and held at the 2011 ASCP annual meeting, associate professor of pharmacy practice Zachary Stacy, PharmD, BCPS, St. Louis College of Pharmacy, MO, said the blood-thinning agent is poised to challenge Plavix (clopidogrel) and Effient (prasugrel) and change the management of cardiovascular disease in patients with ACS. Stacy reviewed Brilinta’s prescribing information and clinical evidence supporting its use in ACS.
Approval was largely based on data from PLATO (Platelet Inhibition and Patient Outcomes), a multicenter, double-blind, randomized trial (N=18,624). The trial compared the effectiveness of Brilinta versus Plavix in preventing cardiovascular events in patients with ACS with or without ST-segment elevation. After 6 to 12 months, Brilinta reduced the rate of myocardial infarction and cardiovascular death (the composite endpoint) by 16%, which Stacy said was significant. No difference in stroke risk was found between the agents.
Patients were randomized to a 180-mg loading dose of Brilinta followed by a 90-mg maintenance dose twice daily or to a 300- to 600-mg loading dose of Plavix followed by a 75-mg maintenance dose. Patients able to tolerate aspirin also received a 75- to 100-mg dose of aspirin. Stacy said a subgroup analysis favored restricting the concomitant dose of aspirin to <100 mg to avoid diminishing the effectiveness of Brilinta. The rate of dyspnea was higher in the Brilinta group compared with the Plavix group (14% vs 8%, respectively), but she said few patients in either group discontinued the study because of dyspnea, which was generally mild to moderate in intensity and resolved with continued treatment.
PLATO researchers had excluded patients with an increased risk of bradycardic events because Brilinta has the potential to increase the occurrence of bradyarrhythmias, including ventricular pauses. A post hoc analysis of data for a subset of 3000 patients enrolled in PLATO found that patients taking Brilinta were more likely to have ventricular pauses than were patients randomized to Plavix in the trial’s acute phase (6% vs 3.5%, respectively); after 1 month of therapy, rates dropped to 2.2% and 1.6%, respectively.
Stacy said that, unlike its competitors, Brilinta and its major metabolite (AR-C124910XX) are equipotent and reversibly interact with the adenosine diphosphate platelet P2Y12 receptor to prevent signal transduction. Median time to peak plasma concentration can occur as early as 2 hours after dosing.
Like other antiplatelet agents, Brilinta is associated with an increased risk of minor and major bleeding events. However, PLATO researchers observed no statistically significant difference between Brilinta and Plavix on any of the secondary bleeding endpoints, including major life-threatening bleeding events (11.6% vs 11.2%, respectively). About half the bleeding events occurred within the first 30 days of starting therapy. A trend toward increased risk of bleeding during a noncoronary artery bypass graft (CABG) procedure was reported with Brilinta, but Stacy said this was not significant.
For patients with ACS initiating therapy with Brilinta, prescribing instructions recommend a 180-mg loading dose (two 90-mg tablets) followed by maintenance therapy of 90 mg twice daily. For aspirin-tolerant patients, a loading dose of 325 mg is recommended followed by a lower maintenance dose of 75 mg to 100 mg per day; Stacy emphasized that the daily dose of aspirin should not exceed 100 mg. She noted that patients with ACS who have already received a loading dose of Plavix can be treated with Brilinta. If a patient routinely taking Brilinta misses a dose, he or she should receive the next dose at the scheduled time. Brilinta can be administered with or without food.
Based on PLATO’s findings, the FDA has required black box warnings for Brilinta related to bleeding risk, especially when coronary artery bypass graft surgery is planned, there is concomitant use of aspirin, or dyspnea is present. Because Brilinta undergoes hepatic metabolism primarily by the CYP3A4/5 enzyme, the package insert warns against using Brilinta with CYP3A inhibitors and potent CYP3A inducers and with simvastatin or lovastatin doses >30 mg. Clinicians should also monitor patient’s digoxin levels when initiating or changing therapy with Brilinta, due to the risk of inhibition of the P-glycoprotein transporter.
—David Despain
This product theater was sponsored by Astra Zeneca.
