Pharmacy & Therapeutics - September 2008 - (Page CB5)

In the past, it had not been recommended that anticoagulation be given with streptokinase. Another question to be answered in this study was whether adding anticoagulation to streptokinase improves outcomes without unacceptably increasing bleeding risk. What was the primary efﬁcacy endpoint and what were the results? The primary end point of the study was death or nonfatal recurrent MI within 30 days. At 30 days, there was a signiﬁcant beneﬁt in the Lovenox® (enoxaparin sodium injection) group compared with UFH; as shown in Figure 1, 9.9% of patients in the Lovenox group died or suffered a nonfatal recurrent MI versus 12.0% of patients treated with UFH (RRR=17%; P<.001). Similar results were observed at day 8, where 7.2% of patients satisﬁed the primary endpoint in the Lovenox arm versus 9.3% in the UFH group (RRR=13%; P<.001), but even at 48 hours, Lovenox was statistically superior to UFH in the reduction of nonfatal MI (P<.001) as well as with the combined endpoint of death, nonfatal MI, or urgent revascularization (P<.001). The ﬁrst of the net clinical beneﬁt measures tested was death, nonfatal MI, or nonfatal disabling stroke. Disabling stroke is a very important safety outcome, and a reason that many physicians may hesitate when using ﬁbrinolytic therapy for STEMI. In the group treated with Lovenox, there was a statistically signiﬁcant reduction in this measure versus patients treated with UFH (18% RRR). The second net clinical beneﬁt measure was broader and included nonfatal major bleeding (including nonfatal disabling stroke as well as other major bleeding episodes). Again, a signiﬁcant beneﬁt was observed in the group treated with Lovenox versus UFH (RRR=14%). Finally, the third measure looked at nonfatal intracranial hemorrhage, which is the type of stroke that is most worrisome in patients receiving ﬁbrinolysis; again, a signiﬁcant beneﬁt was seen with Lovenox (RRR=17%). What were the results in terms of safety? There was more nonfatal major bleeding in the patients who received Lovenox. Although the difference was signiﬁcant because of the size of the study, the actual numbers were small. Out of over 20,000 patients, there was a 45-patient difference between the two study arms. Much more reassuring is the fact that at 48 hours, 8 days, and 30 days, there was no signiﬁcant difference between the treatment groups in terms of ICH. There is an increase in bleeding with Lovenox at all time points, but I believe that this risk is offset by the efﬁcacy advantages. Why did the researchers stop UFH after 48 hours but continue Lovenox? Did it affect the outcomes? The reason that 48 hours was established as the minimum time for UFH is that there are no data showing that more than 48 hours’ therapy is helpful in patients with STEMI who received a ﬁbrinolytic. When we look at the data, there was already a separation of the efﬁcacy endpoints at 48 hours. There is no reason to believe, based on previous data, that any additional beneﬁt with UFH would be seen beyond 48 hours, and we would in fact expect bleeding complications to be more common with UFH had it been continued. What was the secondary endpoint of this study and what was the result? The major secondary endpoint was a composite of death, nonfatal recurrent MI, or urgent revascularization within 30 days. Urgent revascularization measures the number of episodes of recurrent myocardial ischemia that required the clinician to perform PCI or CABG. On this endpoint, a signiﬁcant beneﬁt again was seen with Lovenox over UFH (11.7% vs. 14.5%, P<.001, RRR=19%). Did the researchers look at different patient It did not take long for these curves to diverge (they had already subgroups? What were the ﬁndings there? separated, favoring Lovenox, at 48 hours), and they continued The researchers looked at a number of prespeciﬁed subgroups. to improve over time. There was not a single endpoint for which a beneﬁt of Lovenox What is the basis and results of the “net clinical over UFH was not apparent. This is very reassuring. One beneﬁt” endpoints? interesting subgroup was the 23% of patients who proceeded Another objective of this study was to evaluate the safety to PCI within 30 days; these were generally elective, given that performance of the two arms of therapy. The concept of net only 2.8% required PCI as rescue therapy. Many were still on clinical beneﬁt combines efﬁcacy and safety outcomes to give a Lovenox, because the PCI was often done during their index clearer picture of the effect of using the therapy than is shown by hospitalization. In contemporary US practice, where it is common focusing only on efﬁcacy results. for patients who have undergone ﬁbrinolysis to have elective PCI, this study shows that Lovenox provides a durable beneﬁt over UFH. Please remember it’s important to interpret subgroup analyses with caution. Based on the results of this study, what role should Lovenox play for the hospital management of patients following STEMI? Emergency physicians and cardiologists should know that, despite the recent emphasis on primary PCI, ﬁbrinolysis is an effective treatment option for STEMI patients (unless speciﬁcally contraindicated), and should not be considered a second-class therapy. ExTRACT demonstrated that in this patient population, Lovenox was superior to UFH. Please see important safety information on back page. Please see accompanying full prescribing information for LOVENOX, including boxed WARNING. 5

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Pharmacy & Therapeutics - September 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/New Medical Devices Drug Forecast Effect of Prescription Copays on Adherence and Treatment Failure with Oral Antidiabetic Medications Vaccine Declinations Present New Challenges for Public Health Universal Health Care in America Digestive Disease Week and American Diabetes Association Pharmaceutical Approval Update

Pharmacy & Therapeutics - September 2008

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