Bivalirudin, a synthetic 20 amino acid polypeptide direct thrombin inhibitor, is a new class of hirudin that entered European markets and North American markets at the beginning of this century. This compound can block the action of thrombin by specifically binding directly to the catalytic site and peripheral anionic site of soluble thrombin and fibrin-bound thrombin. Currently, bivalirudin is extensively used before and during urgent or elective percutaneous coronary intervention (PCI) procedures for acute coronary syndrome (ACS) patients as an anticoagulant therapy in western countries.1-4 Compared with unfractionated heparin, bivalirudin was not inferior as an anticoagulant therapy to prevent ischemic events. The prime advantage of bivalirudin lies in its fewer bleeding side events.5,6 At present, the risk of bleeding during anticoagulant therapy has drawn great attention.7 Therefore, bivalirudin is increasingly used in clinical practice. However, this compound has not yet entered into the Chinese market. This article focuses on the clinical research results of the domestic bivalirudin as anticoagulation treatment in elective PCI.
Patients were eligible for enrollment if all of the following criteria were met: (1) Agreed to participate in this clinical trial and signed a written informed consent; (2) Age range from 18 to 70 years old, male or female; (3) Underwent elective PCI one week after myocardial infarction, including patients who received a thrombolytic therapy or not, with stable or unstable angina that proved to be suited for PCI by coronary angiography. Patients were excluded if one or more of the following criteria were met: (1) Age >70 or <18 years old; (2) Prior administration of unfractionated heparin 4 hours before PCI, subcutaneous injection of low molecular heparin (LMH) 12 hours before PCI, long-term use of warfarin; (3) Thrombolytic therapy within 48 hours before PCI; (4) Bleeding tendency: a history of gastrointestinal bleeding within 3 months, cerebral hemorrhage within 6 months, cerebral infarction within 3 months; (5) Serious agranulocytosis and thrombocytopenia patients who could not undergo PCI or heparin-induced thrombocytopenia (HIT) patients; (6) Refractory hypertension (>180/110 mmHg, 1 mmHg=0.133 kPa) that was not under control; (7) Liver or renal function parameters increased to 1.5 times of upper limits (except an increase in liver function parameter caused by myocardial infarction); (8) Patients who had bathystixis or major surgery within one month; (9) Patients had a history of allergy to heparin or biological products; (10) Pregnant, lactating, or female patients who plan to conceive.
This clinical trial was a randomized, single-blinding, parallel controlled, multicenter trial. The study protocol and informed consent had been approved by the ethics committee of Guangzhou General Hospital of Guangzhou Military Command and was executed by five clinical centers. Patients who met the inclusion criteria and did not have exclusion criteria were enrolled prior to coronary angiography. All patients provided written informed consent. A total of 218 elective PCI patients were randomly enrolled into our clinical trial. Those who were suitable for PCI after CAG were randomly assigned to be treated with bivalirudin or heparin. There were 110 patients in the bivalirudin group, one was excluded for improper enrollment and four were lost to follow-up because of poor compliance. There were 108 patients in heparin group; six patients were lost, five lost to follow-up because of poor compliance and one lost because of erroneous entry into the group. Totally 109 patients in the bivalirudin group and 108 patients in the heparin group were included for baseline analysis and 24 hour analysis, and the improper enrolled case who did not receive the study medicine in the bivalirudin group was excluded. Thirty day follow-up was completed by 105 patients in the bivalirudin group and 102 patients in the heparin group. Domestic bivalirudin was administrated as a 0.75 mg/kg iv bolus before the PCI procedure, followed by 1.75 mg·kg-1·h-1 for sustained treatment after PCI procedure. Domestic bivalirudin was provided by the Shenzhen Salubaris Parmaceuticals Co. LTD, China (specifications, 25 mg/vial, lot no. 060901). Activated coagulation time (ACT) was checked five minutes after administration, and if ACT was less than 225 seconds, an additional bolus of 0.3 mg/kg was added. In the heparin group, heparin sodium was administrated at 130 U/kg before PCI. Heparin sodium was provided by the Hebei Changshan Biomedicine Limited Liability Company, China (specifications 12 500 U/vial, lot no. 061101). ACT was determined five minutes after administration, and if ACT was less than 225 seconds, an additional intravenous bolus of 300 U heparin sodium was administrated, if the procedure lasts longer than one hour, an additional 1000 U/h of heparin was added.
Two hours after extubation, low molecular heparin was administrated as routine for three days, if necessary the administration could be extended. Clopidogrel 75 mg/d and aspirin 100-300 mg/d were administered for three days before PCI. Patients who did not take those medicines for three days took a loading dose of clopidogrel 300 mg and aspirin 300 mg as soon as possible. Patients took clopidogrel 75 mg/d and aspirin 100 mg/d as routine for at least 30 days after PCI. Application of glycoprotein IIb/IIIa inhibitors for patients with confirmed thrombus was initiated at 10 μg/kg iv before PCI, followed by 0.15 μg·kg-1·min-1 iv for 24-36 hours.
Efficacy evaluation criteria
Efficacy of anticoagulation: ACT was considered the criteria of anticoagulation and was tested in the catheterization lab. The ACT level was tested by HemochromR Jr bedside compact hemoglutination analyzer (IVC, Edison, USA) and a rapid test strip before PCI, five minutes after bivalirudin or heparin administration, five minutes after each additional doses of bivalirudin or heparin, at the end of the procdure, 30 minutes, 1 hour, then every hour after drug withdraw until 15 minutes before extubation. ACT was longer than 225 seconds during the procedure.
PCI success: The residual diameter of the target lesion stenosis was less than 20% after cardiovascular angiography, and no major adverse cardiovascular events (MACE) occurred within 24 hours after the operation, including death, acute myocardial infarction (AMI), coronary arterial perforation, pericardial tamponade, no-reflow phenomenon, branch occluding, or acute coronary artery bypass graft surgery.
Survival: Survival was defined as no cardiac events (death, myocardial infarction, target vessel revascularization) for 30 days after PCI procedure.
Safety evaluation criteria
Bleeding criteria were established according to REPLACE-2 study6 and divided into major bleeding or minor bleeding within 24 hours and within 30 days after PCI. Major bleeding was defined as massive bleeding or life-threatening hemorrhage; such as intracranial hemorrhage, retroperitoneal bleeding, clinically overt bleeding that resulted in a decrease in hemoglobin more than 30 g/L (or haematocrit (HCT) drop more than 10%), or transfusion of two or more units of packed red blood cells or whole blood. Minor bleeding was defined as obvious bleeding (e.g. macroscopic hematuria, spitting blood or brown vomitus with the occult blood test positive, tarry stool and occult blood test positive, hematoma at the site of puncture) resulting in a decrease in hemoglobin of 20-30 g/L, or HCT drop less than 10%.
The routine blood count, liver function, kidney function, electrolyte, fibrinogen were monitored before PCI and 24 hours after PCI.
SAS Statistical Software Version 9.0 (SAS Institute Inc., USA) and two-tailed tests were used. Measurement data were expressed as mean ± standard deviation (SD) for normal distribution or median (interquartile range) for skewed distribution. Paired t-tests or singed rank sum tests were used for the inner group comparison before and after administration. Student's t test and the Wilcoxon rank-sum test were used for inter group comparison. The chi-square test was used for enumeration data analysis. A level of P<0.05 was considered as having statistical significance.
General information of the two groups
The average ages of patients in the bivalirudin and heparin groups were 57 (50-63) and 59 (55-65) years, respectively (P<0.05). However, there were no statistically significant differences in gender, weight, indication for PCI, baseline systolic pressure and diastolic pressure, heart rate, red blood cell counts, white blood cell counts, blood platelet counts, and ACT before PCI between the two groups (P>0.05). The ratio of PCI accomplished via the percutaneous transfemoral access between the two groups was not statistically different (P>0.05, Table 1).
All patients in our trial took dual antiplatelet therapy. GP IIb/IIIa inhibitor was used after PCI in one patient (0.9%) of the bivalirudin group and four patients (3.7%) of the heparin group (P=0.2122).
Results of efficacy evaluation
Efficacy of anticoagulation
ACT was 225 seconds or longer at 5 minutes after bivalirudin administration in the bivalirudin group, which was required by the PCI procedure. Two patients in the heparin group did not reach the requirement and were given additional administration. During the PCI procedure ACT longer than 225 seconds was maintained in both groups, but the bivalirudin group showed a faster ACT recovery character. ACT values in the bivalirudin group were lower than in the heparin group at 30 minutes, 1 hour and 2 hours after drug withdraw (P<0.05). Changes in ACT over time are shown in Figure 1.
Procedural success rates
Procedural success rates were 100.0% (109/109) and 98.2% (106/108) in the bivalirudin and heparin groups, respectively. There was no statistically significant difference between the two groups (P>0.05). Two patients in the heparin group suffered AMI within 24 hours after PCI. One of them was due to heparin leaking to subcutaneous spaces.
Survival rates without cardiac events at 30 days
The 30 days survival rates without a cardiac event were 100.0% (105/105) and 98.0% (100/102) in the bivalirudin and heparin groups, respectively (P>0.05). Two patients in the heparin group suffered AMI within 24 hours after PCI. One of them died within 30 days after the procedure.
Bleeding events at 24 hours after PCI included a minor bleeding rate in the bivalirudin group of 0.9% (1/109), and 6.5% (7/108) in the heparin group. There was a statistically significant difference between the two groups (P<0.05). Major bleeding event did not occur in either group.
Bleeding events at 30 days after PCI included a 1.9% (2/105) minor bleeding rate in the bivalirudin group and a minor bleeding rate in the heparin group of 8.8% (9/102) (P<0.05). One patient suffered gastrointestinal hemorrhage in the heparin group (1.0%) while no major bleeding events occurred in the bivalirudin group. No other serious adverse events were reported in either group.
The tests of hematology values, liver function, renal function, electrolyte and fibrinogen levels showed no statistically significant differences before PCI and 24 hours after PCI in the two groups (P>0.05). No other adverse reactions were reported in either group.
Bivalirudin mediates its anticoagulant effect by blocking factor IIa. Bivalirudin has a short half-life and its anticoagulant effect fades quickly after withdrawal of the drug. So it is appropriate for short-term intensive anticoagulation therapy. In early clinical trials, bivalirudin has already been used in acute PCI as anticoagulation treatment. Its clinical application has been extended to both urgent and elective PCI procedures,1-4,8 peripheral vascular intervention, and dialysis.9-11 Compared with unfractionated heparin/low molecular heparin, bivalirudin treatment has a decreased risk of bleeding. So it is more suitable for the patients who have a high risk of bleeding, especially those in need of anticoagulation treatment.12 With an ageing population, patients with thromboembolic disease usually have an accompanying high risk of bleeding, especially those taking interventional therapies. Multiple antiplatelet treatments lead to a propensity for a greater risk of bleeding. Therefore, more attention should be paid to the risk of bleeding in interventional procedures. Bivalirudin had already shown significant advantages in numerous clinical trials and in clinical practice for decreasing the risk of bleeding.12 Unfortunately, bivalirudin has not come into the Chinese market yet, so changing the dose of unfractionated heparin/low molecular heparin was the only choice for decreasing the risk of bleeding. However in clinical practice, it is very hard to handle the issue of doses for different populations. Therefore, clinical research on domestic bivalirudin is important.
Our study chose patients who will undergo elective PCI as study participants. The anticoagulation and clinical end point events of domestic bivalirudin treatment were compared with heparin treatment. Our results demonstrated that domestic bivalirudin was not inferior, or even superior, to heparin in anticoagulation, procedure success rate, and 30 days survival rate without cardiac event, at the same time it was associated with less hemorrhaging, all of which are in line with the foreign research results.5,6,12-15 This may suggest that domestic bivalirudin can provide effective and safe anticoagulation, which is similar to the western agent.
Figure 1 shows a faster ACT recovery with bivalirudin treatment, which may be the reason that the bleeding rate with bivalirudin is lower than with heparin. Once severe bleeding occurs, the coagulation function recovered faster after discontinuing the administration. Therefore, bivalirudin is much safer and more suitable for patients with a relatively high risk of bleeding. Moreover, this advantage may facilitate early extubation after an interventional procedure or reduce complications at the site of puncture, especially in those who undergo transfemoral access.9 In our study, three cases of puncture hematoma were reported in the heparin group, while none was seen in the bivalirudin group, which demonstrated that bivalirudin could decrease puncture hematoma.
As the tendency toward a faster fading of the anti-coagulation effect, bivalirudin may increase the early thrombosis rate after PCI.16 However, because of our small sample size, we did not find any trend of bivalirudin adding to the risk of acute or subacute coronary thrombosis. Actually, anticoagulant therapy only inhibits thrombosis induced by interventional apparatus in vascular or vascular mechanical injuries. Thrombosis after stent implantation is usually associated with insufficient antiplatelet treatment. Thus, once the operation is over, there is no need to maintain anticoagulation treatment if there is no complication.
In summary, our study demonstrated that compared with heparin in elective PCI, domestic bivalirudin is not inferior in efficiency and safety, and has fewer associated hemorrhage events. Domestic bivalirudin can meet the requirements of perioperative anticoagulant therapy. The rate of bleeding with bivalirudin is much lower than with heparin.
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