Managed Care - September 2008 - (Page C15)

outpatient because of geographic inaccessibility. Eligible patients could be treated in the hospital, but ONLY Lovenox patients were permitted to go home on therapy (72%). A total of 501 patients were randomized in the study and all patients were treated. Patients ranged in age from 19 to 96 years (mean age 57.8 years) with 60.5% men and 39.5% women. Patients were randomized to either Lovenox 1 mg/kg every 12 hours SC or heparin IV bolus (5000 IU) followed by a continuous infusion administered to achieve an aPTT of 60 to 85 seconds (in-patient treatment). All patients also received warfarin sodium as described in the previous study. Lovenox or standard heparin therapy was administered for a minimum of 5 days. Lovenox was equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism. The efficacy data are provided below [see Table 22]. Table 22 Efficacy of Lovenox in Treatment of Deep Vein Thrombosis Dosing Regimen1 Lovenox Heparin 1 mg/kg q12h SC aPTT Adjusted IV Therapy Indication n (%) n (%) All Treated DVT Patients 247 (100) 254 (100) Patient Outcome Total VTE2 (%) 13 (5.3) 3 17 (6.7) DVT Only (%) 11 (4.5) 14 (5.5) Proximal DVT (%) 10 (4.0) 12 (4.7) PE (%) 2 (0.8) 3 (1.2) 1 All patients were also treated with aspirin 100 to 325 mg per day. 2 Evaluation timepoints are after initiation of treatment. Therapy continued for up to 8 days (median duration of 2.6 days). In a survey one year following treatment, with information available for 92% of enrolled patients, the combined incidence of death, myocardial infarction, or recurrent angina remained lower for Lovenox versus heparin (32.0% vs 35.7%). Urgent revascularization procedures were performed less frequently in the Lovenox group as compared to the heparin group, 6.3% compared to 8.2% at 30 days (p = 0.047). 14.6 Treatment of acute ST-segment Elevation Myocardial Infarction (STEMI) In a multicenter, double-blind, double-dummy, parallel group study, patients with STEMI who were to be hospitalized within 6 hours of onset and were eligible to receive fibrinolytic therapy were randomized in a 1:1 ratio to receive either Lovenox or unfractionated heparin. Study medication was initiated between 15 minutes before and 30 minutes after the initiation of fibrinolytic therapy. Unfractionated heparin was administered beginning with an IV bolus of 60 U/kg (maximum 4000 U) and followed with an infusion of 12 U/kg per hour (initial maximum 1000 U per hour) that was adjusted to maintain an aPTT of 1.5 to 2 times the control value. The IV infusion was to be given for at least 48 hours. The enoxaparin dosing strategy was adjusted according to the patient’s age and renal function. For patients younger than 75 years of age, enoxaparin was given as a single 30-mg intravenous bolus plus a 1 mg/kg SC dose followed by an SC injection of 1 mg/kg every 12 hours. For patients at least 75 years of age, the IV bolus was not given and the SC dose was reduced to 0.75 mg/kg every 12 hours. For patients with severe renal insufficiency (estimated creatinine clearance of less than 30 mL per minute), the dose was to be modified to 1 mg/kg every 24 hours. The SC injections of enoxaparin were given until hospital discharge or for a maximum of eight days (whichever came first). The mean treatment duration for enoxaparin was 6.6 days. The mean treatment duration of unfractionated heparin was 54 hours. When percutaneous coronary intervention was performed during study medication period, patients received antithrombotic support with blinded study drug. For patients on enoxaparin, the PCI was to be performed on enoxaparin (no switch) using the regimen established in previous studies, i.e. no additional dosing, if the last SC administration was less than 8 hours before balloon inflation, IV bolus of 0.3 mg/kg enoxaparin if the last SC administration was more than 8 hours before balloon inflation. All patients were treated with aspirin for a minimum of 30 days. Eighty percent of patients received a fibrin-specific agent (19% tenecteplase, 5% reteplase and 55% alteplase) and 20% received streptokinase. Among 20,479 patients in the ITT population, the mean age was 60 years, and 76% were male. Racial distribution was: 87% Caucasian, 9.8% Asian, 0.2% Black, and 2.8% other. Medical history included previous MI (13%), hypertension (44%), diabetes (15%) and angiographic evidence of CAD (5%). Concomitant medication included aspirin (95%), betablockers (86%), ACE inhibitors (78%), statins (70%) and clopidogrel (27%). The MI at entry was anterior in 43%, non-anterior in 56%, and both in 1%. The primary efficacy end point was the composite of death from any cause or myocardial re-infarction in the first 30 days after randomization. Total follow-up was one year. The rate of the primary efficacy end point (death or myocardial re-infarction) was 9.9% in the enoxaparin group, and 12.0% in the unfractionated heparin group, a 17% reduction in the relative risk, (P=0.000003). [see Table 25] Table 25 Efficacy of Lovenox Injection in the treatment of acute ST-segment Elevation Myocardial Infarction Enoxaparin UFH Relative Risk P Value (N=10,256) (N=10,223) (95% CI) Outcome at 48 hours n (%) n (%) Death or Myocardial 478 (4.7) 531 (5.2) 0.90 (0.80 to 1.01) 0.08 Re-infarction Death 383 (3.7) 390 (3.8) 0.98 (0.85 to 1.12) 0.76 Myocardial Re-infarction 102 (1.0) 156 (1.5) 0.65 (0.51 to 0.84) <0.001 Urgent Revascularization 74 (0.7) 96 (0.9) 0.77 (0.57 to 1.04) 0.09 Death or Myocardial 548 (5.3) 622 (6.1) 0.88 (0.79 to 0.98) 0.02 Re-infarction or Urgent Revascularization Outcome at 8 Days Death or Myocardial 740 (7.2) 954 (9.3) 0.77 (0.71 to 0.85) <0.001 Re-infarction Death 559 (5.5) 605 (5.9) 0.92 (0.82 to 1.03) 0.15 Myocardial Re-infarction 204 (2.0) 379 (3.7) 0.54 (0.45 to 0.63) <0.001 Urgent Revascularization 145 (1.4) 247 (2.4) 0.59 (0.48 to 0.72) <0.001 Death or Myocardial 874 (8.5) 1181 (11.6) 0.74 (0.68 to 0.80) <0.001 Re-infarction or Urgent Revascularization Outcome at 30 Days Primary efficacy endpoint (Death or Myocardial 1017 (9.9) 1223 (12.0) 0.83 (0.77 to 0.90) 0.000003 Re-infarction) Death 708 (6.9) 765 (7.5) 0.92 (0.84 to 1.02) 0.11 Myocardial Re-infarction 352 (3.4) 508 (5.0) 0.69 (0.60 to 0.79) <0.001 Urgent Revascularization 213 (2.1) 286 (2.8) 0.74 (0.62 to 0.88) <0.001 Death or Myocardial 1199 (11.7) 1479 (14.5) 0.81 (0.75 to 0.87) <0.001 Re-infarction or Urgent Revascularization Note: Urgent revascularization denotes episodes of recurrent myocardial ischemia (without infarction) leading to the clinical decision to perform coronary revascularization during the same hospitalization. CI denotes confidence intervals. All patients were also treated with warfarin sodium commencing on the evening of the second day of Lovenox Injection or standard heparin therapy. 2 VTE = venous thromboembolic event (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]). 3 The 95% Confidence Intervals for the treatment difference for total VTE was: Lovenox versus heparin (-5.6 to 2.7). 14.5 Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction In a multicenter, double-blind, parallel group study, patients who recently experienced unstable angina or non-Q-wave myocardial infarction were randomized to either Lovenox 1 mg/kg every 12 hours SC or heparin IV bolus (5000 U) followed by a continuous infusion (adjusted to achieve an aPTT of 55 to 85 seconds). A total of 3171 patients were enrolled in the study, and 3107 patients were treated. Patients ranged in age from 25-94 years (median age 64 years), with 33.4% of patients female and 66.6% male. Race was distributed as follows: 89.8% Caucasian, 4.8% Black, 2.0% Asian, and 3.5% other. All patients were also treated with aspirin 100 to 325 mg per day. Treatment was initiated within 24 hours of the event and continued until clinical stabilization, revascularization procedures, or hospital discharge, with a maximal duration of 8 days of therapy. The combined incidence of the triple endpoint of death, myocardial infarction, or recurrent angina was lower for Lovenox compared with heparin therapy at 14 days after initiation of treatment. The lower incidence of the triple endpoint was sustained up to 30 days after initiation of treatment. These results were observed in an analysis of both all-randomized and alltreated patients. The efficacy data are provided below [see Table 23]. Table 23 Efficacy of Lovenox in the Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction (Combined Endpoint of Death, Myocardial Infarction, or Recurrent Angina) Dosing Regimen1 Lovenox Heparin Reduction p Value 1 mg/kg q12h SC aPTT Adjusted (%) IV Therapy Indication n (%) n (%) All Treated Unstable 1578 (100) 1529 (100) Angina and Non-Q-Wave MI Patients Timepoint2 48 Hours 96 (6.1) 112 (7.3) 1.2 0.120 14 Days 261 (16.5) 303 (19.8) 3.3 0.017 30 Days 313 (19.8) 358 (23.4) 3.6 0.014 1 2 All patients were also treated with aspirin 100 to 325 mg per day. Evaluation timepoints are after initiation of treatment. Therapy continued for up to 8 days (median duration of 2.6 days). The combined incidence of death or myocardial infarction at all time points was lower for Lovenox compared to standard heparin therapy, but did not achieve statistical significance. The efficacy data are provided below [see Table 24]. Table 24 Efficacy of Lovenox in the Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction (Combined Endpoint of Death or Myocardial Infarction) Dosing Regimen1 Lovenox Heparin Reduction p Value 1 mg/kg q12h SC aPTT Adjusted (%) IV Therapy Indication n (%) n (%) All Treated Unstable 1578 (100) 1529 (100) Angina and Non-Q-Wave MI Patients Timepoint2 48 Hours 16 (1.0) 20 (1.3) 0.3 0.126 14 Days 76 (4.8) 93 (6.1) 1.3 0.115 30 Days 96 (6.1) 118 (7.7) 1.6 0.069

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Managed Care - September 2008

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