MX2008002534A - Use of enoxaparin for performimg percutaneous coronary intervention - Google Patents

Abstract

Methods for performing percutaneous coronary intervention in a patient in need thereof comprising administering intravenously a bolus comprising an effective amount of enoxaparin sodium to the patient after sheath insertion and prior to the percutaneous coronary intervention are described. Also described are methods for preventing or treating thrombosis, such as thrombotic episodes, in a human percutaneous coronary intervention patient by treating that patient with enoxaparin.

Description

METHODS FOR CARRYING OUT A CORONARY INTERVENTION PERCUTANEA This application claims priority under section 1 19 (e) of title 35 of U.S.C. of provisional application n ° 60 / 713,329, filed on September 2, 2005, the entire contents of which are incorporated herein by reference. This invention relates to methods for performing percutaneous coronary intervention in a patient in need, comprising administering to the patient intravenously a bolus comprising an effective amount of enoxaparin sodium (sometimes referred to herein as "enoxaparin") after The invention also relates to methods for preventing or treating thrombosis, such as thrombotic events, in a human patient undergoing percutaneous coronary intervention by treatment of said patient with a percutaneous coronary intervention ("PCI"). Enoxaparin Enoxaparin sodium is available from Sanofi-aventis under the trademark Lovenox® (Clexane® in some other countries). The known dosage regimens of enoxaparin sodium include those shown below: Dosage regimen Indication Standard regimen Severe renal failure Prophylaxis in abdominal surgery 40 mg SC once to 30 mg SC once a day Prophylaxis in replacement surgery 30 mg SC every 12 30 mg SC once a knee hours day Prophylaxis in replacement surgery of 30 mg SC every 12 30 mg SC once at hip hours or 40 mg SC day once a day Prophylaxis in medical patients 40 mg SC once to 30 mg SC once a day general day Hospital treatment of DVT 1 mg / kg SC every 12 1 mg / kg SC once with or without embolism hours (with warfarin) pulmonary day Outpatient treatment 1, 5 mg / kg SC once 1 mg / kg SC once a day acute DVT without pulmonary embolus per day (with warfarin) day Prophylaxis of complications 1 mg / kg SC every 12 1 mg / kg SC once to ischemic unstable angina e hours (with aspirin) day myocardial infarction (MI) no wave Q Elderly: For treatment of MI in elderly patients > = 75 years of age, administration is started with 0.75 mg / kg SC every 12 hours. In the present specification, methods are provided for carrying out a percutaneous coronary intervention in a patient in need thereof. The uses comprise administering to the patient intravenously a bolus comprising an effective amount of enoxaparin after inserting the sheath and before percutaneous coronary intervention.

Methods for preventing thrombosis in a human patient in need are also provided. The uses comprise administering to the patient intravenously a bolus comprising an effective amount of enoxaparin after inserting the sheath and before percutaneous coronary intervention. Methods for treating thrombosis are also provided in a human patient in need thereof. Uses include administering a bolus to the patient intravenously which comprises an effective amount of enoxaparin after inserting the sheath and before percutaneous coronary intervention. Figure 1 shows severe and minor hemorrhage unrelated to CABG at 48 hours in the STEEPLE study. The P values are the comparison of the enoxaparin groups with the UFH group (unfractionated heparin). 95% confidence interval for adjusted differences between the groups for major and minor non-CABG bleeding at 48 hours: enoxaparin 0.5 mg / kg and HNF, (-4.8 to -0.5%), enoxaparin 0 , 75 mg / kg and HNF, (-4.1% to 0.0%); non-inferiority margin of 2.6%. Figure 2 shows the odds ratio and the 95% confidence interval of risk factors for major and minor bleeding unrelated to CABG at 48 hours in the STEEPLE study (multivariate analysis). Figure 3 shows the Kaplan Meier curve for all-cause mortality and non-fatal myocardial infarction at 30 days in the STEEPLE study. Figure 4 shows the design of the STEEPLE study. TCA, activated clotting time; CABG, coronary artery bypass graft; GP, glycoprotein; IV, intravenous; IM, myocardial infarction; PCI, percutaneous coronary intervention; RUVT, urgent revascularization of the treated vessel. Figure 5 shows a subgroup analysis for the STEEPLE study of severe or minor bleeding unrelated to CABG at 48 hours, comparison of enoxaparin from 0.5 mg / kg (A) to 0.75 mg / kg (B) ) with HNF. As used herein, "enoxaparin sodium" refers to the low molecular weight heparin (LMWH) approved by the U.S. Food and Drug Administration (FDA), or any other regulatory agency outside the United States, such as Lovenox® (injectable enoxaparin sodium), Clexane® or Klexane®, and any LMWH approved by the FDA, or any other regulatory agency outside the United States , in accordance with an application citing Lovenox® (injectable enoxaparin sodium), Clexane® or Klexane® as the included drug. Enoxaparin sodium is available from Sanofi-aventis and is sold in the United States in the form of injectable enoxaparin sodium, with the trademark Lovenox® (Clexane® in some other countries). In general, enoxaparin sodium is obtained by the alkaline degradation of the benzyl ester of heparin obtained from the porcine intestinal mucosa. Its structure is characterized, for example, by a group of 2-0-sulfo-4-enopyranosuronic acid at the non-reducing end and a 2-N, 6-0-disulfo-D-glucosamine at the reducing end of the chain. The average molecular weight is approximately 4500 daltons. The molecular weight distribution is: < 2000 daltons < 20% 2000 to 8000 daltons > 68% > 8000 daltons 18% Injectable sodium enoxaparin is a sterile aqueous solution containing enoxaparin sodium. Enoxaparin sodium injection is available from Sanofi-aventis in pre-filled syringes of 100 mg / ml (pre-filled syringes of 30 mg / 0.3 ml, pre-filled syringes of 40 mg / 0.4 ml, pre-filled syringes of 60 mg / 0.6 ml, 80 mg / 0.8 ml pre-filled syringes, and 100 mg / 1, 0 ml pre-filled syringes), graduated pre-filled syringes, multi-dose vials (multi-dose vials of 300 mg / 3.0 ml), and ampoules (30 mg / 0.3 ml). Enoxaparin sodium for injection of 100 mg / ml concentration contains 10 mg of enoxaparin sodium (approximate anti-Factor Xa activity of 1000 IU [with respect to the first international reference standard of low molecular weight heparin of WHO]) by 0, 1 ml of water for injection. Enoxaparin sodium injection is also available in Sanofi-aventis in pre-filled 150 mg / ml pre-filled syringes (90 mg / 0.6 ml pre-filled syringes, 120 mg / 0.8 ml pre-filled syringes, and 150 mg pre-filled syringes / 1.0 ml). Enoxaparin sodium for injection of 150 mg / ml concentration contains 15 mg of enoxaparin sodium (approximate anti-Factor Xa activity of 1500 IU [with respect to the first international reference standard of low molecular weight heparin WHO]) by 0, 1 ml of water for injection. Pre-filled syringes and graduated injectable enoxaparin sodium syringes are preservative free and are intended for use as a single dose injection only. There are also multiple dose vials and these contain 15 mg / l, 0 ml of benzyl alcohol as a preservative. The pH of the injection is 5.5 to 7.5. Injectable sodium enoxaparin can also be administered in an arterial line for an indication of hemodialysis. As used herein, the reference to the administration of enoxaparin sodium once a day means, for example, administration every twenty-four hours, four hours or so. The terms "prevent" "preventing" and "prevention" refer to the administration of the therapy to an individual who may finally manifest at least one symptom of a disease or condition (eg, thrombosis) but who does not yet, to reduce the possibility of the individual developing the symptom of a illness or disorder during a given period of time. Said reduction can be reflected, for example, in the delayed appearance of at least one symptom of a disease or condition in the patient. As used herein, the terms "treat," "treat," or "treatment" refer to the administration of the therapy to an individual who already manifests at least one symptom of a disease or condition (e.g., thrombosis) , or that has previously manifested at least one symptom of a disease or condition. "Body weight" refers to the weight of a patient that is determined by actually weighing or estimating before the administration of enoxaparin sodium. In the event that the body weight of a patient is estimated before the first dose of enoxaparin sodium is administered, the patient's body weight can be subsequently determined by actually weighing it before any subsequent enoxaparin dose, and accordingly adjust the amount of enoxaparin of the next dose to be administered to the patient. "Kg" refers to the patient's body weight in kilograms. "Percutaneous coronary intervention" (PCI) encompasses a variety of procedures used to treat patients with diseased heart arteries, for example, chest pain caused by the deposit of fats, cholesterol and other substances in the blood (called plaque) that can reduce blood flow to almost a trickle, or heart attack caused by a large blood clot that completely blocks the artery. Usually, ICP is carried out by inserting a thin tube (catheter) with balloon at the end from an artery in the groin to the problem in an artery of the heart (this is called percutaneous transluminal coronary angioplasty, also known as PTCA, dilatation of the artery coronary balloon or balloon angioplasty). Afterwards, the balloon swells by compressing the plaque and dilating (widening) the narrowed coronary artery so that the blood can flow more easily. This is often accompanied by the insertion of an expandable metal stent. Endovascular prostheses are metal mesh tubes to keep arteries open after PTCA. A "pod" is a tube or other device that is inserted into an artery and used to guide a catheter to the site. A method for performing percutaneous coronary intervention in a patient in need is provided, which comprises administering to the patient intravenously a bolus comprising an effective amount of enoxaparin after inserting the sheath and before percutaneous coronary intervention. A method for preventing or treating thrombosis, such as thrombotic events, in a percutaneous coronary intervention in a human patient is also provided by treatment of said patient with enoxaparin. In some embodiments, enoxaparin is administered immediately before percutaneous coronary intervention. In some embodiments, removal of the sheath occurs immediately after percutaneous coronary intervention. In some embodiments, removal of the sheath takes place 4 to 6 hours after the percutaneous coronary intervention. In some embodiments, enoxaparin is administered in an amount such that the patient reaches an anti-Xa level of 0.5 to 1.8 IU / ml. In some embodiments, enoxaparin is administered in an amount such that the patient reaches an anti-Xa level from 0.5 to 1.2 IU / ml. In some embodiments, enoxaparin is administered in an amount sufficient to reduce the primary endpoint of any bleeding compared to an NFH regimen adjusted by TCA. In some embodiments, enoxaparin is administered with a dosage of 0.5 mg / kg. In some embodiments, enoxaparin is administered with a dosage of 0.75 mg / kg. The administration of enoxaparin sodium is made, for example, by intravenous injection directly with a syringe, and further, for example, by injection into an i.v. pre-established A bolus dose of enoxaparin can be administered, for example, in about 10 seconds or less, or from about 10 to about 20 seconds, or from about 15 to about 30 seconds, or from about 30 seconds to about 1 minute, or about 1 to about 5 minutes, or about 5 to about 10 minutes, or about 10 to about 30 minutes.

In some embodiments, the patient exhibits a significant reduction in severe bleeding compared to a subject who has been given UFH before undergoing percutaneous coronary intervention. In some embodiments, the significant reduction of severe hemorrhage is at least 25%. In some embodiments, the significant reduction of severe hemorrhage is at least 40%. In some embodiments, the significant reduction of severe hemorrhage is at least 55%. In some embodiments, the patient achieves the target anticoagulation level at a significantly higher rate compared to the rate for a subject receiving UFH. In some embodiments, the patient achieves the target anticoagulation level at a rate at least 2 times faster than the rate for a subject receiving UFH. In some embodiments, the patient reaches the target anticoagulation level at a rate at least 3 times faster than the rate for a subject receiving UFH. In some embodiments, the patient reaches the target anticoagulation level at a rate at least 4 times faster than the rate for a subject receiving UFH. In some embodiments, the patient is given a second bolus of enoxaparin during percutaneous coronary intervention. In some embodiments, the amount of enoxaparin in the second bolus is less than the amount of enoxaparin initially administered. In some embodiments, the amount of enoxaparin in the second bolus is approximately half the amount of enoxaparin initially administered. In some embodiments, the patient is administered at least one additional therapeutic agent. Said "co-therapy" (or "combination therapy") may include the following examples: administration of each agent in a sequential manner in a regimen that provides the beneficial effects of the drug combination; and / or co-administering the aforementioned components in a substantially simultaneous manner (eg, in a single injection with a fixed ratio of these active agents or in multiple injections, separate for each agent, etc.). Therefore, the methods described herein are not limited in terms of the sequence of administration; Enoxaparin sodium can be administered before, at the same time or after the administration of the other agent. In addition, enoxaparin sodium may be administered alone or in combination with other treatments, for example, drug-eluting stent. In some embodiments, said at least one additional therapeutic agent is chosen from aspirin and thienopyridines. In some embodiments, said at least one additional therapeutic agent is chosen from clopidogrel and GP IIb / Illa inhibitors. In some embodiments, said at least one additional therapeutic agent is chosen from inhibitors of GP llb / llla. Inhibitors of GP llb / Illa include abciximab (marketed as ReoPro®), tirofiban (marketed as Aggrastat®) and eptifibatide (marketed as Integrelin®). In some embodiments, enoxaparin is administered in approximately the same amount as when the GP IIb / Illa inhibitor is not administered. Therefore, combination therapy methods are provided for the treatment of a human ICP patient, which comprises administering to the patient intravenously a bolus comprising an effective amount of enoxaparin after inserting the sheath and prior to the procedure; and at least one additional therapeutic agent. Methods for preventing or treating thrombosis in a human ICP patient are also provided, comprising administering to the patient intravenously a bolus comprising an effective amount of enoxaparin after inserting the sheath and prior to the procedure; and at least one additional therapeutic agent. Methods for performing percutaneous coronary intervention in a patient in need thereof are also provided, comprising administering to the patient intravenously a bolus comprising an effective amount of enoxaparin after inserting the sheath and prior to the procedure; and implanting in a patient's blood vessel a drug-eluting stent. In some embodiments, the prevention of thrombosis comprises the prevention of thrombotic events. In some embodiments, the treatment of thrombosis comprises the treatment of thrombotic events. When dosing regimens of enoxaparin sodium are provided, the dosage regimen for the administration of enoxaparin sodium is based on the particular indication. For each indication, methods that include methods for preventing and / or treating thrombotic events in a human ICP patient are provided herein. It will be readily apparent to those skilled in the relevant arts that other modifications and appropriate adaptations of the uses and applications described herein are suitable and can be carried out without departing from the scope of the invention or any embodiment thereof. Having described the present invention in detail, it will be understood more clearly by reference to the following examples of the invention which are included herein for purposes of illustration only and which are not intended to limit the invention. Example 1: Patient treatment A patient is identified as a candidate for PCI. After inserting the sheath but before the ICP, the patient is administered a dosage of 0.5 mg of enoxaparin sodium per kg of body weight of the patient per intravenous bolus over a period of about 20 seconds. The level of anti-Xa experienced by the patients is analyzed centrally and it is determined that the patient has reached an anti-Xa level of 1 IU / ml. Example 2: Patient treatment A patient is identified as a candidate for PCI. After inserting the sheath but before the ICP, the patient is administered a dosage of 0.75 mg of enoxaparin sodium per kg of body weight of the patient per intravenous bolus over a period of about 20 seconds. The level of anti-Xa experienced by the patients is analyzed centrally and it is determined that the patient has reached an anti-Xa level of 1 IU / ml. Example 3: The STEEPLE study The guidelines of the American College of Cardiology / American Cardiac Association (ACC / AHA) and the European Society of Cardiology (ESC) recommend the use of intravenous unfractionated heparin (FNH) adjusted by coagulation time activated (TCA) during the ICP. However, there is an interest in improving anticoagulation regimens during PCI, especially given the limitations of UFH such as its unpredictable effect on coagulation, the need for repeated monitoring of coagulation, the narrow therapeutic window, the induction of the activation of platelets, and the risk of thrombocytopenia. Low molecular weight heparins (LMWH), such as enoxaparin, are used as anticoagulants most frequently during PCI in patients with acute coronary syndrome (ACS) and also during elective procedures. They have a response to the dose of anticoagulants more stable and predictable, obviating the need for monitoring of coagulation; a longer half-life; and an anti-factor Xa: major activity, which results in lower thrombin generation and activation. LMWHs are associated with reduced platelet activation, release of the factor of Willebrand, and inflammation. Small and / or non-comparative trials have shown the viability of a single intravenous bolus of enoxaparin of 1 mg / kg, 0.75 mg / kg, and 0.5 mg / kg in patients undergoing PCI with or without administration of glycoprotein (GP) inhibitors llb / llla. However, these uncontrolled studies do not allow definitive conclusions to be drawn in comparison with standard anticoagulation with UFH, and the optimal intravenous bolus dose remains unchanged during PCI. A meta-analysis of the data from randomized studies comparing the use of intravenous LMWH and intravenous UFH in patients undergoing PCI found no difference in the incidence of ischemic events and found a nonsignificant trend towards a reduction in severe haemorrhage with LMWH Methods Patients The STEEPLE study is a parallel, open-label, randomized, prospective trial that evaluates the safety and efficacy of enoxaparin at 0.5 mg / kg and 0.75 mg / kg intravenously versus an HNF regimen. intravenously adjusted by means of the TCA in patients undergoing non-urgent PCI. Between January 2004 and December 2004, 3528 patients were randomly distributed across 124 sites in 9 countries in Australasia, Europe and North America. Patients could be chosen to enter the study if they were scheduled to undergo a non-urgent one-vessel or multi-vessel PCI with a femoral approach and did not meet any of the exclusion criteria, including recent thrombolysis, step-by-step procedure, increased risk of bleeding, treatment with a parenteral antithrombotic before the procedure, or a known hypersensitivity to the study drugs. This study was carried out in accordance with the Declaration of Helsinki (Tokyo, 2004) and in accordance with local regulations. All patients gave informed consent and approval for the study was obtained from institutional review boards at each site. Study protocol Eligible patients were randomly assigned to receive an intravenous bolus of UFH adjusted by the ACT in accordance with the current norm or enoxaparin of 0.5 mg / kg or 0.75 mg / kg intravenously without follow-up of the coagulation. The patients were randomly distributed in a 1: 1: 1 ratio and classified according to the planned use of GP inhibitor llb / llla. All patients received aspirin (75 to 500 mg / day) and thienopyridines according to local practice. The use of all concurrent medications was consistent with local standards of care. Patients randomly assigned to any of the enoxaparin groups received a single intravenous bolus of enoxaparin after insertion of the sheath and immediately before the procedure. Randomly distributed dosing was used regardless of whether the investigator had chosen to start concomitant treatment with GP IIb / Illa inhibitor. Patients randomized to the UFH group who were not receiving concurrent treatment with GP IIb / Illa inhibitor were given an initial UFH bolus of 70 to 100 IU / kg, based on standard operator practice, to achieve a Target TCA from 300 to 350 seconds. Likewise, patients who received simultaneous treatment with GP IIb / Illa inhibitor were given an initial intravenous bolus of 50 to 70 IU / kg, to reach a target TCA of 200 to 300 seconds. Additional boluses of UFH were given before starting PCI only to patients who did not reach the lower limit of the target TCA. HFN was re-administered during the procedure when TCA measurements decreased below the recommended range. In all centers, the ACT was measured with a standardized Hemochron device. When the procedures were longer than 2 hours in patients assigned to enoxaparin, an additional bolus (half of the original dose) was recommended. Closure devices were allowed according to local practice. The withdrawal of the sheath with the TCA was authorized between 150 and 180 seconds in the UFH group, from 4 to 6 hours after the end of the PCI in the enoxaparin group of 0.75 mg / kg, and immediately after the end of the PCI in the enoxaparin group of 0.5 mg / kg. It is important that the monitoring or verification of anticoagulation was not necessary before removing the sheath in patients receiving enoxaparin. Criteria for assessment The primary endpoint of the trial was the incidence of major and minor bleeding unrelated to coronary artery bypass graft (non-CABG) 48 hours after PCI. Severe hemorrhage was defined as a hemorrhagic event resulting in death; which was retroperitoneal, intracranial or intraocular; that resulted in hemodynamic compromise that required specific treatment; required intervention (surgical or endoscopic) or decompression of a closed space to stop or control the event; was clinically significant with transfusion of at least 1 unit of packed red blood cells or whole blood; or was clinically significant with a decrease in hemoglobin ≤ g / dl (or a decrease in hematocrit ≤ 0%). Minor hemorrhage was defined as all bleeding events that did not meet the criteria for severe bleeding, but with at least one of the following characteristics: gross hemature not associated with trauma; epistaxis that was prolonged or that required intervention; gastrointestinal hemorrhage; hemoptysis; subconjunctive hemorrhage; hematoma > 5 cm or leading to prolonged hospitalization or new hospitalization; which is clinically significant with a decrease in hemoglobin ^ a < 3 g / dl; any decrease in hemoglobin? S g / dl with any transfusion of at least 1 unit of packed red blood cells or whole blood; or protamine sulfate administered for uncontrolled bleeding. The main secondary criterion of efficacy assessment was to achieve therapeutic anticoagulation at the beginning and end of the procedure. The proportion of enoxaparin patients achieving target anti-Xa levels (analyzed centrally) from 0.5 to 1.8 IU / ml was compared with the proportion of UFH patients reaching the target TCA (200 to 300 seconds with inhibitors). of GP llb / llla or 300 to 350 seconds without them), both at the beginning and at the end of the procedure. Other measures of secondary consequences were: 1. The combined endpoint of severe hemorrhage unrelated to CABG up to 48 hours after the index ICP, all-cause mortality, non-fatal myocardial infarction (defined as significant new Q wave in the derivations); Elevation of total creatine kinase or MB fraction 2 times the upper limit of the urgent or normal revascularization of the treated vessel at 30 days. 2. The combined endpoints of all-cause mortality or non-fatal myocardial infarctions, and all-cause mortality, non-fatal myocardial infarction, or urgent revascularization of the treated vessel, whichever comes first. All events were adjudicated by an independent blind clinical event committee. Statistical Analysis Initially a sample size of 2700 patients was calculated based on an incidence of all bleeding of up to 48 hours of 7.0% for the UFH group and a corresponding incidence of up to 3.7% in the enoxaparin group ( 47% risk reduction); the use of a bilateral type I error rate of 2.5% for each comparison of the enoxaparin group versus the HNF group, giving a global alpha level of 5%; the use of uncorrected chi-square tests; a power of 80%; and the assumption that approximately 2% of patients can not be treated. In a planned interim evaluation, the sample size was re-evaluated and because the total rate (3.5%) of bleeding was less than the expected 4.8%, it was adjusted to a final number of 3690 patients Analysis was carried out in the population with intention to treat, and adjusted for the time of randomization. For analyzes of haemorrhage, anti-Xa target and TCA, adjustments were also made for the use of GP IIb / Illa inhibitors. The results for the population per protocol were similar to the population with intention to treat. The analyzes were carried out using SAS statistical software version 8.2 (SAS Institute Inc., Cary, NC, USA). The incidence of the primary endpoint between the enoxaparin and UFH groups was compared using logistic regression analysis. If enoxaparin was not superior to UFH, the non-inferiority of enoxaparin versus UFH was tested using a bilateral adjusted confidence interval of the differences in the planned event rates; the noninferiority margin was set at 30% of the bleeding rates observed in the UFH group. The endpoint of objective anti-Xa or TCA was analyzed using a logistic regression model. The objective of the combined quadruple endpoint was to show the non-inferiority of enoxaparin doses, using a bilateral confidence interval of the difference in event rates; the non-inferiority margin was set at 39% of the rates observed in the UFH group. The analysis of the time elapsed until an event for the other secondary endpoints until day 30 was carried out using Cox models of proportional risk. For the primary and secondary analyzes, each dose of enoxaparin was compared with that of UFH. The Simes adjustment for the multiplicity was applied to ensure a global type-1 error of 0.05: if both values of P are = D, 05, both are significant; if the highest P value is > 0.05, the other value of P has to be .30,025 to be significant. An independent data monitoring committee (DMC) followed the progress of the trial and ensured that patient safety was not compromised. After reviewing all the serious adverse events described in 3216 randomly distributed patients, the DMC recommended that the random distribution to the enoxaparin group of 0.5 mg / kg be stopped. Even though the numbers were small, the data at that time suggested that mortality from all causes in the enoxaparin group of 0.5 mg / kg tended to be higher than in the UFH group or the enoxaparin group of 0.75 mg / kg. However, there was no significant difference between the 0.5 mg / kg group and the UFH group. There was also no significant difference when the two enoxaparin groups were analyzed together and compared with the UFH group. Although the steering committee did not agree with the recommendations of the DMC, a conservative strategy was followed and recruitment in the enoxaparin group of 0.5 mg / kg was suspended shortly before the completion of the entire study. Results Characteristics of patients Between January 2004 and December 2004, 3528 patients were randomized to receive enoxaparin 0.5 mg / kg intravenously (1070 patients), enoxaparin 0.75 mg / kg intravenously (1228 patients) , or intravenous UFH (1230 patients). The characteristics of the initial values were well balanced between the 3 treatment groups (Table 1). The possibility of evaluation of patients was similar among the 3 groups: The main endpoint could be evaluated in 98.2% of the subjects, the anti-Xa or ACT measurements in 92.1% and the quadruple endpoint. combined in 97.0%, and the analysis of time elapsed until an event at 30 days in all subjects randomly distributed. Characteristics of the procedure The three groups were comparable for all the characteristics of the procedure (Table 1). Of the patients receiving UFH, 16.5% received at least one additional bolus due to low TCA. At least one additional bolus of enoxaparin was administered for prolonged procedures (> 2 hours) to 0.6% of patients receiving enoxaparin 0.5 mg / kg and 0.2% of patients receiving enoxaparin 0.75 mg / kg. The mean TCA at the beginning and end of the PCI was 336 and 292 seconds for patients receiving only HNF and 300 and 255 seconds for patients receiving UFH with GP IIb / Illa inhibitors. Main endpoint Severe and minor bleeding unrelated to CABG occurred at 48 hours in 6.0% of patients in the enoxaparin group of 0.5 mg / kg, 6.6% of patients in the enoxaparin group of 0.75 mg / kg and 8.7% of patients in the UFH group ( Figure 1 ). This represents a significant reduction of 31% in the main endpoint with enoxaparin 0.5 mg / kg compared to UFH, fulfilling the criteria of superiority against UFH (P = 0.014). A non-significant trend was observed in favor of enoxaparin 0.75 mg / kg compared to UFH (24% reduction, P = 0.052), fulfilling the criteria previously specified for noninferiority (95% confidence interval of the difference of -4.1% to 0.0%, excluding the non-inferiority margin of 2.6%). This beneficial effect was driven mainly by the reduction of severe bleeding unrelated to CABG, which was significantly reduced in both the enoxaparin group of 0.5 mg / kg (1.2% vs. 2.8%, P = 0.005). ) as in the group of 0.75 mg / kg (1.2% vs. 2.8%, P = 0.007), compared to UFH (Figure 1). There was no significant difference in the lower bleeding rate between any of the enoxaparin and UFH groups. Transfusion rates up to 48 hours were extremely low at 0.5%, 0.8% and 1.0% for the enoxaparin groups of 0.5 mg / kg, 0.75 mg / kg, and HNF, respectively . Consistent results were found throughout all the subgroups important for the primary endpoint. By means of multivariate analysis, significant independent correlates of the main endpoint included treatment with enoxaparin 0.5 mg / kg (Figure 2). Secondary endpoints It is significant that previously specified target anticoagulation levels (secondary endpoint) more patients receiving enoxaparin compared to patients receiving adjusted UFH through ACT. . When a narrower anti-Xa interval (0.5 to 1.2 IU / ml) was selected than that corresponding to the appropriate anticoagulation levels in the treatment of ACS, 75.5% and 59.4% of patients reached the goal of anti-Xa with enoxaparin 0.5 mg / kg and 0.75 mg / kg, respectively, maintaining a significant difference with UFH (P <; 0.001 for both comparisons). At the start of PCI the median anti-Xa levels were 0.81 and 1.09 U / ml for the enoxaparin groups of 0.5 and 0.75 mg / kg, respectively; at the end of the ICP these values were 0.68 and 0.93 Ul / ml, respectively. The four-fold combined endpoint occurred in 7.2% of patients receiving enoxaparin 0.5 mg / kg and in 7.9% of patients receiving enoxaparin 0.75 mg / kg, compared with 8.4% of patients receiving UFH, meeting the previously specified criteria for noninferiority for both doses of enoxaparin (Table 2). The incidence of all-cause mortality or non-fatal myocardial infarction at 30 days was similar among patients receiving either enoxaparin or UFH doses (Figure 3). The combination of all-cause mortality, non-fatal myocardial infarction, or urgent revascularization of the 30-day treated vessel and individual components are described in Table 2. Analysis The STEEPLE study is the first large, randomized, controlled trial for demonstrate the superior safety of intravenous enoxaparin versus unfractionated heparin in the modern era of PCI, which includes the use of drug-eluting endovascular prostheses, clopidogrel, and GP IIb / Illa inhibitors. Enoxaparin (0.5 mg / kg) significantly reduced the primary endpoint of any bleeding compared to an adjusted UFH regimen by means of ACT. It is important that both groups of enoxaparin showed a significantly greater reduction, of 57%, in severe hemorrhage versus UFH. In terms of efficacy, both doses of enoxaparin provided similar protection from day 30 of the ischemic events compared to UFH. These findings translate into non-significant reductions with enoxaparin of the four-fold endpoint; none of the enoxaparin groups met the non-inferiority trial. The clinical benefit observed with enoxaparin came with greater ease of use compared with UFH; Enoxaparin is used as a single intravenous bolus before starting PCI, without monitoring anticoagulation, a similar dose is used with or without GP IIb / III inhibitors, and there is the possibility of immediate removal of the sheath after the ICP with enoxaparin 0.5 mg / kg. The heparin dosage used in the STEEPLE trial, based on the ACC / AHA and ESC guidelines, resulted in the lowest rates of hemorrhage complications published to date. However, the enoxaparin strategies used in this study resulted in serious and minor bleeding complications compared to UFH. Enoxaparin results in a significant 4-fold increase in the rate at which patients achieve the target anticoagulation levels compared to UFH. This highlights the better bioavailability of enoxaparin versus UFH, which requires careful and meticulous monitoring of coagulation. Despite the strict monitoring imposed by the controlled nature of the trial, 80% of the Patients who were administered UFH were not in the target range of anticoagulation during the time of the procedure, a percentage that is likely to be even greater in "real world" practice. It is not clear if these patients who are outside the target range have worse consequences than those who fall within the target range. Studies have shown a poor relationship between ACT and ischemic or haemorrhagic events, and therefore question the value of systematic measurements of ACT in patients with UFH. In contrast, in a large population of unselected patients with unstable angina or myocardial infarction without ST segment elevation, it has been shown that anti-Xa levels were independently associated with 30-day mortality. However, the optimal level of anti-Xa with enoxaparin in patients undergoing PCI is not yet known and will be explored in further analyzes of the STEEPLE trial data. Even when the target was a narrower anti-Xa interval (0.5 to 1.2 IU / ml), enoxaparin remained significantly more predictable and stable than anticoagulation with HNF: more patients reached the target with the enoxaparin dose of 0.5 mg / kg. The important safety benefit seen with enoxaparin does not occur at the expense of an increase in the number of ischemic events. The double criterion of mortality for all causes and myocardial infarction, an indicator of serious clinical consequences, was similar among the three treatment groups. Among patients treated with enoxaparin and UFH, there were no significant differences in the triple ischemic endpoint or in any individual component of the combined endpoint, including mortality. The mortality rate in the trials was low and comparable to other recent PCI trials (n = 18; 0.5%). The premature termination of the low-dose enoxaparin group was a conservative stage in response to a request from the DMC and was based on an apparent but not significant increase in all-cause mortality versus the UFH group. The subsequent evaluation of causes of death, as well as of other adverse events not collected as study endpoints, did not suggest a relationship between the dose of enoxaparin and ischemic events. Since all components of the combined efficacy endpoint were lower in the enoxaparin group of 0.5 mg / kg than in the other two groups (except all-cause mortality, which was a very rare event), this suggested that the non-significant trend observed for mortality is due to the chance. Despite the premature interruption of the enoxaparin group of 0.5 mg / kg, 1,070 patients had already been randomized and therefore represents a well-balanced group to compare with the other treatment groups. According to the results of the STEEPLE study, it appears that enoxaparin, with or without GP IIb / III inhibitors, is a favorable alternative to UFH in non-urgent PCI. The REPLACE-2 trial showed that bivalirudin plus GP IIb / Illa inhibitors were not inferior to UFH plus GP IIb / Illa inhibitors planned for the primary endpoint of death, myocardial infarction, urgent revascularization and major bleeding. However, bivalirudin is given as a bolus followed by intravenous infusion. Unlike this, enoxaparin is administered in the form of a single bolus. In summary, the STEEPLE trial has confirmed that intravenous enoxaparin for the simple treatment of patients scheduled to undergo elective PCI is an attractive alternative to anticoagulation with UFH in the practice of catheterization. Table 1. Patient and procedure characteristics. Characteristic Enoxaparin Enoxaparin HNF 0.5 mg / kg 0.75 mg / kg (n = 1230) (n = 1070) (n = 1228) Age, years (mean ± SD) 63.4 ± 10.5 63.0 ± 10.2 63.5 ± 10.2 Age = 75 years,% 16.7 14.7 15.0 Men,% 74.7 76.1 74.0 Weight, kg (mean ± SD) 84.0 ± 16.9 84.2 ± 16.7 83.3 ± 16.0 Creatinine removal,% > 30 a = SO ml / min 17.4 18.5 18.0 ..30 ml / min 1, 3 0.5 1, 6 Diabetes,% 30.3 29.2 30.9 Previous myocardial infarction,% > 48 hours to -3 days 1.5 2.0 2.0: _48 hours 0.4 0.7 0.2 Previous unstable angina,% > 48 hours a. = 7 days 6.7 7.0 6.7 __48 hours 5.1 5.9 4.9 previous ICP,% 34.7 36.5 38.9 Previous CABG,% 14.4 12.7 15.1 Platelet count < 80,000 / mm3, 0.1 0.1 0.0% Hemoglobin < 10 g / dl,% 1.7 3.2 3.2 Concomitant medications Before PCI: Chronic treatment with 510 (47.7) 538 (43.8) 590 (48.0) thienopyridine Chronic treatment with aspirin 891 (83 , 3) 1056 (86) 1063 (86.4) ICP Day: Inhibitor of GP llb / llla used 433 (40.5) 499 (40.6) 491 (39.9) Thienopyridine 1007 (94.2) 1158 (94.5) 1170 (95.1) Aspirin 986 (92.3) 1147 (93.7) 1159 (94.4) Thrombolytics 7 (0.7) 7 (0.6) 8 (0.7) ICP ICP variables performed 1035 (96.7) 1205 (98.1) 1205 (98.0) Procedure with prosthesis 974 (94,1) 1126 (93,4) 1133 (94,0) endovascular Endovascular stent releasing 608 (58,7) 669 (55,5) 675 (56,0) drug Target vessel LAD 486 ( 47.0) 564 (46.8) 546 (45.3) LCX 329 (31.8) 362 (30.0) 375 (31.1) RCA 376 (36.3) 456 (37.8) 484 (40.2) LMA 13 (1,3) 17 (1,4) 12 (1,0) Saphene or artery graft 43 (4.2) 49 (4.1) 43 (3.6) Multi-vessel intervention (á> 161 (15.6) 184 (15.3) 207 (17.2) vessels) Closing device used 408 (39.5) 470 (39.1) 478 (39.7) Average time since the end of the 0:54 3:14 2:24 ICP upon removal of the sheath, (0: 01.4: 19) (0: 01.4: 55) (0: 01.4: 14) hours: min (IQR) GP, glycoprotein; LAD, left anterior descending; LCX, left circumflex; AML, left main artery; PCI, percutaneous coronary intervention; RCA, right coronary artery; DT, standard deviation; IQR, interquartile ranges; HNF, unfractionated heparin.

Table 2. Secondary endpoints of the STEEPLE trial. A. Enoxaparin E criteria noxaparin HNF valuation 0.5 mg / kg (3.75 mg / kg (n = 1230) (n = 1070) (n = 1228) n / N (%) Difference Value n / N (% ) Difference Value n (%) versus P * versus P * HNF, (HFN IC, (95% CI 95%) Combination 74/1032 -0.8 (-3.2, 0.477 94/1 191 -0 , 5 (-2,7, 0,636 101/1198 of hemorrhage (7,2) 1, 5) (7,9) 1, 6) (8,4) severe not related to CABG up to 48 hours, mortality by all causes, non-fatal MI, or RUVT tn / N (%) Value Rate n / N (%) Value Rate n (%) risk, P * risk, IC P * (95% CI) 95% Combination 66/1070 1.12 0.513 84/1228 1.18 0.298 72/1230 mortality (6.2) (0.79- (6.8) (0, 86- (5.8) for all 1.60) 1.62) causes, non-fatal MI or RUVT at 30 days * Combination 59/1070 1.02 0.914 79/1228 1.14 0.419 70/1230 of mortality (5.6) (0.71, (6.4) (0.83, (5.6) for all 1.47) 1.58) causes, non-fatal MI at 30 days * Mortality for 10 / 1070 3.35 0.066 3/1228 0.61 0.495 5/1230 all (1.0) (0.92, (0.2) (0.15, (0.4) causes at 30 12.19 ) 2.54) days * IM non-fatal to 50/1070 0.91 0.636 76/1228 1.18 0.322 65/1230 the 30 days * (4.7) (0.62, (6.1) (0, 85, (5.2) 1.34) 1.65) RUVT at 30 8/1070 1.35 0.582 14/1228 1.77 0.199 8/1230 days * (0.8) (0.47, (1 , 1) (0.74, (0.7) 3.88) 4.21) Within 771/978 < 1045/1139 < 223/1134 interval (78.8) 0.001 (91.7) 0.001 (19.7) goal of anticoagulation during the procedure5 CABG, coronary artery bypass graft; IM, myocardial infarction; HNF, unfractionated heparin; RUVT, urgent revascularization of the treated vessel. * The P values are for the comparison of the enoxaparin groups with the UFH group. observed frequencies; 95% confidence interval for adjusted differences between groups for the rate of combined events of severe non-bleeding CABG up to 48 hours, all-cause mortality, non-fatal MI or RUVT at 30 days: enoxaparin 0.5 mg / kg and HNF, (-3.2 to 1.5%), enoxaparin 0.75 mg / kg and HNF, (-2.7% to 1, 6%); non-inferiority margin of 3.3%. * Described as risk rates § Anti-Xa levels of 0.5 to 1, 8 IU / ml for enoxaparin, TCA of 200 to 300 seconds with GP IIb / Illa inhibitors or 300 to 350 seconds without GP inhibitors llb / llla for the UFH. Although the administration of enoxaparin sodium has been described in connection with certain embodiments, it is not intended to limit the invention to the particular forms indicated, but on the contrary, it is intended to cover as many alternatives, modifications and equivalents as may be included within the spirit and scope of the invention as defined by the following claims.

Claims (29)

CLAIMS:

1. Use of enoxaparin to manufacture a medicament for carrying out a percutaneous coronary intervention in a patient in need thereof, which comprises administering to the patient intravenously a bolus comprising an effective amount of enoxaparin after inserting the sheath and before the coronary intervention percutaneous

2. Use of claim 1, wherein the removal of the sheath occurs immediately after percutaneous coronary intervention.

3. The use of claim 1, wherein the sheath is removed from 4 to 6 hours after the percutaneous coronary intervention.

4. The use of claim 1, further comprising administering a second bolus of enoxaparin during percutaneous coronary intervention.

5. The use of claim 4, wherein the amount of enoxaparin in the second bolus is less than the amount of enoxaparin initially administered and preferably about half the amount of enoxaparin initially administered.

6. The use of claim 1, wherein the enoxaparin is administered in an amount such that the patient reaches an anti-Xa level of 0.5 to 1.8 IU / ml, more preferably 0.5 to 1.2 IU. / ml.

7. The use of claim 1, wherein enoxaparin is administered in an amount sufficient to reduce the primary endpoint of any bleeding compared to an NFH regimen adjusted for TCA.

8. Use of claim 1, wherein the enoxaparin is administered with a dosage of 0.5 mg / kg.

9. The use of claim 1, wherein enoxaparin is administered at a dosage of 0.75 mg / kg.

10. Use of claim 1, wherein the patient exhibits a significant reduction of severe bleeding compared to a subject who has been administered UFH before undergoing percutaneous coronary intervention, preferably significant reduction of severe bleeding is at least 25%, and more preferably from at least 40% to 55%.

11. The use of claim 1, further comprising administering at least one additional therapeutic agent.

12. The use of claim 11, wherein said at least one additional therapeutic agent is selected from aspirin, thienopyridines, clopidogrel and GP IIb / III inhibitors.

13. The use of claim 12, wherein the enoxaparin is administered in approximately the same amount as when the GP IIb / Illa inhibitor is not administered.

14. The use of claim 1, further comprising implanting a drug-eluting stent into a patient's blood vessel.

15. Use of claim 1, wherein the patient reaches the target level of anticoagulation at a significantly higher rate compared to the rate for a subject receiving UFH.

16. Use of claim 15, wherein the patient reaches the target level of anticoagulation at a rate at least 2 times faster than the rate for a subject receiving UFH and preferably at a rate at least 3 times to 4 times faster than the speed for a subject receiving HNF.

17. Use of enoxaparin to treat or prevent thrombosis in a human patient in need, which comprises administering to the patient intravenously a bolus comprising an effective amount of enoxaparin after inserting the sheath and before percutaneous coronary intervention.

18. The use of claim 17, wherein the sheath is removed immediately after percutaneous coronary intervention, preferably 4 to 6 hours after percutaneous coronary intervention.

19. Use of claim 17, further comprising administering a second bolus of enoxaparin during percutaneous coronary intervention.

20. The use of claim 19, wherein the amount of enoxaparin in the second bolus is less than the amount of enoxaparin initially administered and is preferably about half the amount of enoxaparin initially administered.

21. The use of claim 17, wherein the enoxaparin is administered in an amount such that the patient reaches an anti-Xa level of 0.5 to 1.8 IU / ml, preferably 0.5 to 1.2 IU / ml.

22. The use of claim 17, in which enoxaparin is administered in an amount sufficient to reduce the primary endpoint of any bleeding compared to an NFH regimen adjusted for TCA.

23. The use of claim 17, wherein the enoxaparin is administered at a dosage of 0.5 mg / kg, preferably 0.75 mg / kg.

24. Use of claim 17, in which the patient exhibits a significant reduction in severe bleeding compared to a subject who has been administered UFH before undergoing percutaneous coronary intervention, preferably the significant reduction of severe bleeding is at least from 25% to 55%.

25. Use of claim 17, further comprising administering at least one additional therapeutic agent.

26. The use of claim 24, wherein said at least one therapeutic agent additional is selected from aspirin, thienopyridines, clopidogrel and GP IIb / Illa inhibitors.

27. The use of claim 25, wherein the enoxaparin is administered in approximately the same amount as when the GP IIb / Illa inhibitor is not administered.

28. Use of claim 17, further comprising implanting a drug-eluting stent into a patient's blood vessel.

29. The use of claim 17, wherein the patient reaches the target level of anticoagulation at a significantly higher rate compared to the rate for a subject receiving UFH, preferably at a rate at least 2 times to 4 times faster than the rate for a subject receiving UFH. SUMMARY Methods for performing a percutaneous coronary intervention in a patient in need thereof, comprising administering to the patient intravenously a bolus comprising an effective amount of enoxaparin sodium after inserting the sheath and before percutaneous coronary intervention. Methods for preventing or treating thrombosis, such as thrombotic events, in a percutaneous coronary intervention in a human patient by treatment of said patient with enoxaparin are also described.