ABSTRACT: Background. Enoxaparin is an established therapy for the treatment of patients with acute coronary syndrome (ACS), and bivalirudin is commonly used as the antithrombotic agent during percutaneous coronary intervention (PCI). This study was designed to examine the safety of switching from enoxaparin to bivalirudin in these patients. Methods. The Switching from Enoxaparin to Bivalirudin in Patients with Acute Coronary Syndromes without ST-segment Elevation Undergoing Percutaneous Coronary Intervention (SWITCH) trial was a prospective, open-label, multicenter study including 91 patients who presented with an ACS without ST-segment elevation, and who had received >/= 1 dose of enoxaparin (1 mg/kg SC) within the 12 hours prior to PCI. Patients were enrolled into 3 time categories: Group 1: 0–4; Group 2: 4–8; and Group 3: 8–12 hours from last enoxaparin dose to PCI. The primary endpoint of the study was major bleeding complications. Results. Baseline characteristics and average number of enoxaparin injections prior to PCI were similar in all 91 patients and among the groups. There was no occurrence of death, Q-wave myocardial infarction (MI), or acute revascularization in any group and no incidence of intracranial or retroperitoneal bleeding. The overall rate of major bleeding (7.7%) was comparable among groups (p = 0.39), as was the incidence of periprocedural non-Q-wave MI (overall 12%; p = 0.58), irrespective of the time interval between enoxaparin and bivalirudin administration. Conclusions. Switching from enoxaparin to bivalirudin for patients with ACS undergoing PCI appears to be clinically safe without increased risk of major bleeding complications, regardless of the time of enoxaparin administration, and is safe enough to warrant testing it in larger numbers.

       Recent randomized trials have established that patients who present with acute coronary syndrome (ACS) non-ST-elevation myocardial infarction (MI) may be managed with low-molecular weight heparin (LMWH) followed by early angiography and by appropriate medical management, percutaneous coronary intervention (PCI) or surgery.^1–3 Despite the common utilization of the LMWH enoxaparin for the early treatment of patients presenting with ACS, there is still insufficient information available regarding its efficacy and safety when combined with other antithrombotic agents, such as unfractionated heparin, in the context of an early invasive strategy. This is particularly due to the complexity of switching between subcutaneous and intravenous heparins and the lack of accurate bedside monitoring for anticoagulant levels after administration of a LMWH. The direct thrombin inhibitor bivalirudin has been successfully introduced as an antithrombotic agent during PCI⁴ and has several biological advantages over unfractionated heparin.⁵ Unlike heparins (unfractionated or low-molecular weight), bivalirudin inhibits both fluid-phase and clot-bound thrombin with similar potency, providing a distinct pharmacological advantage, particularly in ACS patients.⁶ Given the growing use of enoxaparin in the management of ACS patients and the known benefits of anticoagulation with bivalirudin for PCI, there is a need for safety data for ACS patients who have been pretreated with enoxaparin and who are then given bivalirudin during PCI. As patients are often referred to the catheterization laboratory without knowledge of their last enoxaparin administration, questions remain as to whether patients who are given full doses of enoxaparin (1mg/kg subcutaneously every 12 hours) can be given a full dose of bivalirudin (0.75 mg/kg bolus and 1.75 mg/kg/hour infusion) for PCI, regardless of the time the last dose of enoxaparin was administered, or whether there should be an enoxaparin washout or bivalirudin dose adjustment. The Switching from Enoxaparin to Bivalirudin in Patients with Acute Coronary Syndromes without ST-segment Elevation Undergoing Percutaneous Coronary Intervention (SWITCH) trial was designed to address these questions and to help establish a safe method of switching ACS patients being pretreated with enoxaparin to bivalirudin for PCI.

Methods
       The SWITCH trial was an open-label, multicenter, prospective phase IV study in high-risk patients who presented with non-ST ACS and were consequently managed with early invasive treatment. SWITCH was designed to evaluate the safety of switching from pretreatment with enoxaparin, administered with established guideline-based therapy including aspirin and clopidogrel, to bivalirudin for PCI.
       Patient population, recruitment and follow up. Patients were enrolled as they qualified with the objective of recruiting 30 patients in each of the following time windows from the last enoxaparin dose prior to PCI: 0–4 hours, 4–8 hours and 8–12 hours at 3 different centers (Appendix). Eligible patients had to meet the following inclusion criteria: 1) minimum age >/= 18 years at the time of enrollment; 2) have ACS without ST-elevation on electrocardiogram and with new or dynamic ST-segment deviation, or elevation of cardiac biomarkers (troponin-T, troponin-I or creatinine kinase-MB fraction) at the time of presentation; 3) be scheduled for PCI; and 4) have received enoxaparin 1 mg/kg subcutaneously within the last 12 hours.
       Patients were to be excluded if they: 1) had ST-segment elevation of ? 1 mm in 2 contiguous electrocardiogram leads lasting for > 30 minutes, or new left bundle branch block, or a clinical syndrome consistent with acute evolving transmural MI requiring immediate thrombolytic or interventional reperfusion therapy; 2) had cardiogenic shock (systolic blood pressure < 80 mmHg for > 30 minutes not responding to intravenous fluids, or requiring intravenous pressor agents or an intra-aortic balloon pump); 3) had bleeding diathesis or history of intracerebral mass, aneurysm, arteriovenous malformation, hemorrhagic stroke or gastrointestinal or genitourinary bleeding within the last 2 weeks; 4) had a platelet count < 100,000/mm3 at baseline, or a history of heparin-induced thrombocytopenia; 5)had received warfarin, unless warfarin could be safely discontinued and the baseline international ratio was </= 1.5 times control; 6) were started on bivalirudin in the 6 hours prior to enrollment; 7) received thrombolytic therapy or abciximab within the last 24 hours; 8) were taking fondaparinux; 9) had absolute contraindications or allergy that could not be premedicated to iodinated contrast, or to any of the study medications or to aspirin; 10) had contraindications to angiography, including but not limited to, severe peripheral vascular disease; 11) underwent gamma brachytherapy; 12) had angina from secondary causes; 13) were pregnant or nursing (women of child-bearing potential must have had a negative urine or serum pregnancy test prior to enrollment); 14) had a calculated serum creatinine clearance < 30 mL/minute (determined by the Cockcroft Gault formula: [(140 - age in years) x weight in kg]/[48,869 x creatinine in mmol/L) or /[72 x creatinine in mg/dL]; for women, multiply by 0.85]); 15) were previously enrolled in this study; or 16) were enrolled in another investigational drug study that had not completed the follow-up phase. All patients provided written informed consent. The protocol was approved by the institutional review board or ethics committee at each participating center.
       This study consisted of 3 periods: pretreatment before PCI, treatment during PCI with bivalirudin and follow-up after discontinuation of bivalirudin to hospital discharge. The pretreatment period comprised the time prior to PCI and consisted of eligibility confirmation, consent, patient enrollment and the collection of baseline assessments. The treatment period comprised the time during PCI for the duration of bivalirudin treatment, and the follow-up period comprised the time from bivalirudin discontinuation to hospital discharge. All clinical events, procedures, adverse events and concomitant medication were collected.
Patients were compared among each of the following time windows from the last enoxaparin dose (1 mg/kg subcutaneously) prior to PCI in 3 groups: Group 1: 0–4 hours; Group 2: 4–8 hours; and Group 3: 8–12 hours. All patients were then required to receive a full dose of bivalirudin (0.75 mg/kg bolus and 1.75 mg/kg/hour infusion) during PCI. All patients received aspirin in accordance with local practice (recommended 300–325 mg orally once a day), regardless of reported aspirin usage before hospital admission, and clopidogrel according to local practice. The timing and dosing of clopidogrel in this protocol were left to the discretion of the investigators and treating physicians. It was strongly recommended, however, that PCI patients in whom a total of < 300 mg clopidogrel had been administered in the preceding 4 days be given at least 300 mg of clopidogrel in the catheterization laboratory just prior to PCI, but in no case more than 2 hours following PCI. Patients previously treated with either eptifibatide or tirofiban for the present episode of ACS could be enrolled, and the glycoprotein (GP) IIb/IIIa inhibitor continued along with bivalirudin. Patients treated with abciximab within the last 24 hours were excluded. Other medications included as recommended treatments in the American College of Cardiology/American Heart Association Guideline for Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction were allowed to be used per current recommendations. These included nitrates, morphine sulphate, beta-adrenergic blockers, calcium antagonists and angiotensin-converting enzyme inhibitors.
       Endpoints. The primary endpoint of this trial was major bleeding. Secondary endpoints were: 1) composite ischemic endpoint including the occurrence of death, MI or unplanned revascularization for ischemia; 2) minor bleeding; and 3) thrombocytopenia. All endpoints were collected during the index hospitalization.
       Definition of endpoints. Major bleeding was defined as the occurrence of 1 of the following: a) transfusion of >/= 2 units of whole blood or packed red blood cells; b) intracranial bleeding; c) retroperitoneal bleeding; d) spontaneous hematuria or hematemesis; e) a drop in hemoglobin (HgB) > 4 g/dL (or 12% of hematocrit) with no bleeding site identified despite attempts to do so; or f) spontaneous or nonspontaneous blood loss associated with a HgB drop > 3g/dL (or 10% of hematocrit); 2) minor bleeding was defined as any observed bleeding event that did not meet the criteria for a major hemorrhage. Bleeding events were also analyzed by using the Thrombolysis In Myocardial Infarction (TIMI) criteria⁷ and the GUSTO criteria.⁸ Data on the incidence of transfusions were collected. For all bleeding endpoints, decreases in hemoglobin measurements were adjusted for any packed red blood cells or whole blood transfused between the baseline and post-treatment hemoglobin measurements according to the Landefeld Index.⁹ The number of units of packed red blood cells and whole blood combined were then added to the change in hemoglobin. All bleeding, however assessed, which met the protocol criteria for major and minor bleeding events, but which were judged to be due to blood loss associated with a coronary artery bypass surgery procedure, were considered separately from other bleeding.
       Composite ischemic endpoints comprised the occurrence of death, MI or unplanned revascularization for ischemia. All-cause mortality was recorded and all deaths were reported as serious adverse events. MI (after PCI) was defined as the occurrence of new Q-waves > 0.04 seconds in duration in >/= 2 contiguous leads or elevated creatinine kinase (CK)-MB fraction (CK in the absence of CK-MB fraction) > 3 times the upper normal limit in 1 sample. Unplanned revascularization for ischemia was defined as any revascularization that was not specifically planned but was considered a consequence of clinical ischemia; i.e., did not include staged procedures. Thrombocytopenia was defined as a platelet count of < 150,000 cells/mm3 in patients without thrombocytopenia at baseline. Thrombocytopenia was further classified as mild (100,000–149,999 cells/mm3), moderate (50,000–99,999 cells/mm3) or severe (< 50,000 cells/mm3).
       Statistics and analysis. Sample size. In the Randomized Evaluation in PCI Linking Bivalirudin to Reduced Clinical Events (REPLACE-2) study,4 the major bleeding rate was 2.4% for patients with bivalirudin. Based on the assumption that the SWITCH trial had a similar risk of major bleeding (definition of major bleeding in SWITCH included spontaneous hematuria or hematemesis in addition to the major bleeding criteria in REPLACE-2), under the null hypothesis, a sample size of 90 was calculated to give the trial an 80% power to detect whether the switch from enoxaparin increased the bleeding risk from null hypothesis of 3% to the alternative hypothesis of 10%.
       Primary analysis. Patients were enrolled in the order they qualified for the study. The data were analyzed for the 3 groups based on the time between the last dose of enoxaparin and PCI, as previously described. Event rates for the 3 groups were described and compared with the 8–12 hour group acting as the control group.
       Secondary analyses. Secondary analyses of death, MI, unplanned revascularization and thrombocytopenia were conducted for the 3 groups. Simple descriptive statistics and/or patient data listings were used to summarize most of the data collected on the case report form.
       Continuous variables were summarized using means, standard deviations, medians, interquartile ranges and minimum and maximum values. Categorical variables were described using frequencies and percentages. Statistical analyses were performed using the Statistical Analysis System, version 8.2 (SAS Institute Inc., Cary, North Carolina). Data are expressed as mean ± standard deviation for continuous variables and as percentages for categorical variables. The Student’s t-test was used to compare continuous variables and the Chi-square test or Fisher’s exact test was used to compare categorical variables. A p-value < 0.05 was considered to indicate statistical significance.
       Safety analyses. Adverse events. The incidences of in-hospital adverse events were summarized by body system and preferred terms by relationship with bivalirudin, severity and by treatment groups. The incidences of serious adverse events in-hospital were summarized by body system and preferred terms, by relationship with bivalirudin, severity and by treatment groups. Laboratory parameters and vital signs were summarized by treatment groups.

Results

Tables 1 and 2

       Groups 1 and 2 each consisted of 30 patients and Group 3 consisted of 31 patients. Baseline characteristics and number of enoxaparin injections of the analyzed patients were comparable and are presented in Table 1 and Figure 1. GP IIb/IIIa inhibitors were started prior to PCI as well **Wakmsan16947.jpg**as provisionally during PCI in a comparable number of patients within the 3 groups (Table 2).
       Bleeding endpoints (primary and secondary) are presented in Table 3. Overall, 7 patients experienced major bleeding (4 patients in Group 1, 1 patient in Group 2, and 2 patients in Group 3; p = 0.39) and 4 patients required a blood transfusion of > 2 units (2 patients in Group 1 and 2 patients in Group 3; p = 1.0). We did not observe any intracranial or retroperitoneal bleed or drug-related thrombocytopenia. Spontaneous

Tables 3-5

hematuria/hematemsis occurred in 1 patient and minor bleeding in a total of 4 patients. Overall there was no difference in any of the bleeding events among the 3 groups, however there was a trend toward more TIMI minor and GUSTO mild bleeding in Group 1 (p = 0.067). Analysis of the bleeding endpoints according the TIMI⁷ and GUSTO⁸ criteria are presented in Tables 4 and 5. None of the patients experienced TIMI major bleeding, and a total of 3 patients (3%) presented with TIMI minor bleeding. All patients with TIMI minor bleeding were in Group 1 (10%). We did not observe any GUSTO severe bleeding, whereas GUSTO moderate bleeding occurred in a total of 4 patients (4%); 2 of these patients (7%) in Group 1 and 2 (7%) in Group 3 (p = ns), and GUSTO mild in a total of 3 patients (3%), all in Group 3 (10%) (p = ns between groups).
       We did not observe any deaths, unplanned revascularizations, procedural Q-wave MIs or recurrent chest pain. Furthermore, there was no incidence of a no-reflow phenomenon and no abrupt target vessel closure in any of our patients. Non-Q-wave MI occurred in 11 patients overall (12%). Again, there was no difference among groups (Group 1: 13%; Group 2: 7%; Group 3: 19%; p = 0.58).
       Six of the above-mentioned bleeding events were independently adjudicated to have been related to the administered drugs. We did not identify any other drug-related adverse events.

Discussion
       The results of this prospective clinical trial suggest that in patients with ACS who received enoxaparin pretreatment, switching to full-dose bivalirudin during subsequent PCI is clinically safe and feasible, regardless of when the last enoxaparin dose was administered.
       The increase of any bleeding from 3–13% between Groups 2 and 1, and almost a doubling in bleeding complications in comparison to Group 3, which served as a control, although not statistically different, could be explained by the proximity of the bivalirudin to the enoxaparin or to the actual timing of the enoxaparin not related to the administration of bivalirudin, but may be confounded by subjects whose activity curves were on the upswing.
       Assessment of previous clinical trials evaluating the efficacy of enoxaparin versus unfractionated heparin in ACS patients, such as the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial,⁸ have shown a 6.7% incidence of major bleeding. This trial suggested that especially patients pretreated with enoxaparin and consequently receiving unfractionated heparin during the treatment course were at increased risk to develop bleeding.⁸ However, a direct comparison appears to be difficult, as only 66% of the SYNERGY patients had received a thienopyridine, and only 47% were treated with PCI, whereas approximately 57% of patients had received additional GP IIb/IIIa inhibitors.⁸ Furthermore, the SYNERGY trial and other trials did not evaluate the combination of enoxaparin and bivalirudin, and were primarily designed to investigate ischemic endpoints.^8,10–14
       A total of 7 patients (7.7%) from the SWITCH trial met the primary endpoint of major bleeding according to our definition. It has to be taken into consideration, however, that 2 of these 7 patients had received additional post-procedural enoxaparin and/or heparin, and that in contrast to the REPLACE-2 trial, 100% of our patients were, apart from being all high-risk ACS patients, treated with aspirin and clopidogrel according to current clinical practice. When analyzed by the TIMI and GUSTO criteria, no patient experienced TIMI major or GUSTO severe bleeding, which appears to be comparable to the 2.4% observed in the bivalirudin arm of the REPLACE-2 trial⁴ and the results from the SYNERGY trial.⁸
We observed minor bleeding, again equally distributed among the 3 groups, in 4 of our patients (4%) according to the SWITCH criteria, in 3 patients (3%) according to the TIMI criteria for minor bleeding, and in 4 patients (4%) according to the GUSTO criteria for moderate bleeding, and in 3 (3%) patients according to the criteria for mild bleeding. The lack of TIMI major bleeding in any of the groups was encouraging and suggests a safety profile of the SWITCH patients. Although bivalirudin dosage was comparable between the REPLACE-2 trial and our analysis, and additional GP IIb/IIIa inhibitors were used slightly more often in our trial, minor bleeding occurred significantly more often (13%) in REPLACE-2.⁴ A possible explanation for the observed difference in minor bleeding might be attributable to the combination of bivalirudin and enoxaparin, and also to the fact that about half the patients in REPLACE-2 in whom bivalirudin plus provisional GP IIb/IIIa inhibitors were administered had received abciximab, which was not used at all in our trial. In addition, the much larger number of patients included in REPLACE-2 may have further contributed to the different results observed.
       Bivalirudin directly and specifically inhibits thrombin, and unlike heparins, inhibits both fluid-phase and clot-bound thrombin.⁶ Furthermore, its effects are transient, with a plasma half-life of approximately 25 minutes. Thus our results suggest that bivalirudin, via its specific mode of action, may especially in the context of ACS, add to the anticoagulatory properties of enoxaparin, but unlike unfractionated heparin, may not increase the bleeding risk. This effect appears to be independent of the time and bioavailability of the last enoxaparin dose, which, due to the difficulty of determining when the last dose of enoxaparin is given in typical clinical practice, might be of specific clinical relevance.
       We did not observe any deaths, unplanned revascularizations or Q-wave MIs up to 30 days post-procedure in our patients. Post-procedural non-Q-wave MI occurred in 11 patients (12%), and like the bleeding endpoints, all outcomes were comparable among the 3 time groups.

       Study limitations. This study was performed as a nonrandomized trial which included a relatively small number of patients. The study is not powered to detect intergroup differences. The study does advocate the strategy of switching early after enoxaparin administration, and suggests that if switched to bivalirudin at that early time point — 0 to 4 hours — it is still safe and free of major TIMI bleeding. Larger, randomized trials are warranted to establish the thesis that timing of the switch does not matter, as suggested in our study.

Conclusion
       The data from this prospective, multicenter trial suggest that patients with ACS who received enoxaparin pretreatment within the last 12 hours can be safely switched to full-dose bivalirudin during subsequent PCI. This regimen appears to be associated with acceptable and comparable incidences of bleeding and low rates of ischemic events, and does not require complex periprocedural rheological measurements. The results from this relatively small patient population further suggest that switching between the two regimens may be safely performed no matter when the last dose of enoxaparin was administered and in combination with full-dose clopidogrel and aspirin therapy according to current ACS management standards.

Appendix

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