Activated Clotting Time (ACT)-Guided Intravenous Dalteparin Dosing during Percutaneous Coronary Intervention

The superiority of low-molecular weight heparin (LMWH) over unfractionated heparin (UFH) in the management of acute coronary syndrome (ACS) patients was demonstrated in the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE)¹ and Thrombolysis in Myocardial Infarction (TIMI) 11B² trials, and since then, LMWH has become a mainstay of management for these patients. However, LMWH has not become a preferred anticoagulant in the context of percutaneous coronary intervention (PCI), in part because the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial³ did not show any difference in the primary efficacy outcome, but was associated with an elevated in-hospital major bleeding rate in patients who received LMWH compared to UFH. One of the limitations of the SYNERGY trial was that monitoring was performed for the UFH group, but not for the LMWH group. Although the Safety and Efficacy of Enoxaparin in Percutaneous Coronary Intervention Patients (STEEPLE) trial⁴ reported significant lower major bleeding complications in patients undergoing elective PCI without an increase in ischemic complications, many interventionalists are skeptical about using this strategy because of a perceived inability to monitor LMWH during PCI. The strategy of administration of LMWH without monitoring during PCI may become problematic in cases where the pharmacokinetic drug profile is unpredictable (e.g., renal failure) and cases where the implications of thrombosis can be life-threatening (e.g., left main coronary artery stenting). The perception that LMWH cannot be monitored is based on predominantly noninvasive studies5 in which LMWH was administered via a subcutaneous route. However, during PCI, LMWH is administered intravenously, resulting in higher peak plasma concentrations that we have shown to consistently raise the activated clotting time (ACT).^6,7 Based on our previous observations, we had proposed a minimum target ACT of 175 seconds for patients receiving LMWH with glycoprotein IIb/IIIa inhibitors (GPI) and a minimum of 200 seconds for patients receiving LMWH alone (i.e., no adjunctive GPI) during PCI (Figure 1).^6–8 These targets can be supported by the fact that patients treated with dalteparin 40 IU/kg achieved a maximum mean ACT of less than 175 seconds and experienced a higher rate of thrombotic complications compared with patients treated with 60 IU/kg who had achieved ACT levels above 175 seconds.⁹ Based on the above observations, the full-time faculty of our institution adopted an ACT-guided strategy of intravenous (IV) dalteparin administration during PCI. We now report a retrospective analysis of the first 104 patients who received ACT-guided dalteparin during PCI.

Methods

Patient population. This is a retrospective study of 104 consecutive patients who underwent PCI using IV dalteparin as the anticoagulant agent. Dosing of dalteparin was determined using an ACT-guided strategy (described below) from December 2005 to August 2006 at a single institution. The hospital’s Institutional Review Board approved the study. Demographic, periprocedural and laboratory data were collected by reviewing charts and hospital records. The in-hospital events and length of stay were also recorded. Periprocedural medication and ACT monitoring. Patients with non-ST segment elevation acute coronary syndrome (n = 49) were started on LMWH and patients with ST-segment elevation myocardial infarction (n = 2) were given unfractionated heparin at the time of diagnosis and continued until arrival to the cardiac catheterization laboratory. All patients were loaded with aspirin 325 mg and clopidogrel 300–600 mg prior to PCI. All patients received an initial IV bolus of 50 IU/kg of dalteparin. A GPI bolus at the beginning of the intervention was given at the discretion of the operator. No infusion of GPI was administered following the bolus dose, as per routine management at our institution.^10,11 The minimum target ACT was 175 seconds for patients who received GPI and 200 seconds for patients who were not given GPI.⁸ Patients who did not achieve the target ACT after the initial 50 IU/kg were given supplemental boluses of dalteparin with a rule-of-thumb that for every 10 IU/kg of dalteparin IV, the ACT will increase by approximately 10 seconds.⁸ The ACT was measured by using the Hemochron^®(ITC Technidyne Corp, Edison, New Jersey) device at baseline, post bolus of dalteparin (3–5 minutes), and at the end of procedure (14–20 minutes). Coronary intervention. Coronary interventional procedures were performed according to standard techniques, via a femoral approach. Balloon angioplasty, stents and rotational atherectomy were performed at the operator’s discretion. Femoral vascular closure devices (Angio-Seal [St. Jude Medical, Minnetonka, Minnesota] or Perclose [Perclose Inc., Redwood City, California]) were used unless contraindicated. Serial monitoring of cardiac biomarkers was performed every 8 hours for 24 hours after PCI, and hemoglobin levels were measured every 24 hours until the patient was discharged. An ACT value < 160 seconds was considered appropriate for sheath removal.⁸

Definitions. Post-PCI myocardial infarction (MI) was defined according to the Thrombolysis In Myocardial Infarction (TIMI) criteria.¹² A new MI was defined by biochemical or electrocardiographic criteria: the MB isoform of creatine kinase (CK-MB) at least three times the upper limit of the normal range in at least one blood sample, or the finding of abnormal Q-waves in two or more contiguous leads. For patients with a recent MI who had an elevated CK-MB level before the procedure, a value of > 3 times the upper limit of normal and at least 50% above the baseline value was required to meet the definition. Bleeding was defined according to the Randomized Evaluation in the PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) criteria.¹³ Major bleeding was defined as either any intracranial, intraocular or retroperitoneal, or clinically overt bleeding with a drop in hemoglobin by 3 g/dl, or any drop in hemoglobin by 4 g/dl, or the transfusion of two or more units of packed red blood cells. Minor bleeding was defined as clinically overt bleeding not meeting the above criteria. We chose to define and compare our bleeding complications using the REPLACE-2 trial definitions and outcomes, as this trial uses a sensitive definition of bleeding and has reported the lowest rates of bleeding in the context of modern PCI. Thrombocytopenia was defined as a fall in the platelet count below 100,000/µl, or a decrease by 25% below baseline values, in the event the initial platelet count was < 100,000/µl. Statistical analysis. Continuous variables are presented as mean ± standard deviation and categorical variables are presented as percentages using SPSS software version 13.0 (SPSS, Inc., Chicago, Illinois). Microsoft Excel software was used in constructing the graphs. The mean ACT at specified time points was used to construct the graphs. The standard error of the mean is depicted as an error bar in the graph.

Results

Baseline characteristics. A total of 104 patients underwent ACT-guided dalteparin administration during PCI during the study period. Baseline characteristics and procedural data are shown in Tables 1 and 2, respectively. Most of our patients were African-American (80%) and had a high prevalence of hypertension (88%) and diabetes (57%). Over half of the patients had a history of previous PCI (53%). The most common indication for the procedure was stable angina (50%), followed by unstable angina (34%). Left anterior descending artery (LAD, 37%) followed by right coronary artery (RCA, 33%) and left circumflex (LCX, 27%) were the most common vessels to undergo intervention. Drug-eluting stents were used in 73% of the patients. The mean number of stents used per patient was 1.6, and the mean length and diameter of stents used were 17.3 mm and 2.9 mm, respectively. Closure devices were used in 89% of the patients. Activated clotting time (ACT). The mean baseline ACT was 138 ± 41 seconds; after the initial bolus of dalteparin 50 IU/kg, this value rose to 231 ± 78 seconds. In the 68 patients who achieved the target ACT after the initial bolus of dalteparin, the mean ACT was 261 ± 76 (Figure 2). In the 36 patients who required a supplemental bolus to achieve the target ACT, the mean initial post dalteparin bolus ACT value was 188 ± 59 seconds. The mean supplemental dose administered was 14 ± 6 IU/kg of dalteparin. The mean ACT after the supplemental dose was 239 ± 79 (Figure 3). In-hospital outcomes. The in-hospital outcomes are summarized in Table 3. There were no in-hospital deaths or target vessel revascularizations in our study group. The composite endpoint of in-hospital death, target vessel revascularization (TVR), and MI was 5.8%. The incidence of bleeding complications (both major and minor) was 2%. One patient had a 4.1 gm drop in hemoglobin without any overt bleeding which was counted as major bleeding and one patient had a groin hematoma, which was counted as minor bleeding. One patient had a drop in platelet count from 112K to 94K, which was counted as thrombocytopenia.

Discussion

Our study suggests that the dose of dalteparin administered intravenously during PCI can be safely adjusted by monitoring the ACT. Our previous observations that a minimum target ACT of 175 seconds for patients receiving LMWH with GPI and a minimum of 200 seconds for patients receiving LMWH alone (i.e., no adjunctive GPI) appears to be a safe and effective. The incidence of ischemic end points in our study is comparable to the ischemic end points reported in the SYNERGY³ and STEEPLE⁴ trials. However, bleeding complications in our study appear to be fewer than those reported in these trials. In the SYNERGY trial the reported non-CABG TIMI major bleeding was 2.4% and the total minor bleeding was 12.5% in the enoxaparin arm. The STEEPLE trial, which used a lower dose of enoxaparin, had fewer bleeding complications compared to the SYNERGY trial (non-CABG related major bleeding was 1.2% in the enoxaparin 0.5 mg and 0.75 mg arms and minor bleeding was 4.8% in enoxaparin 0.5 mg arm and 5.3% in enoxaparin 0.75 mg arm during the first 48 hours). The lower incidence of bleeding complications in our study could be due to ACT monitoring to adjust the dose of dalteparin. However, various other reasons might have contributed to lower bleeding complications in our study. First, fewer patients in our study received GPI compared to SYNERGY and STEEPLE trials (6.7% in our study compared to 30.7% in the enoxaparin arm of SYNERGY trial and about 40% in the two enoxaparin arms of STEEPLE trial). The reason for the lower rate of GPI use is that the majority of our patient population (85%) did not have elevated cardiac biomarkers. The withholding of GPI in our troponin negative patients was in part based on the observations from the Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT) study¹⁴ which did not show any benefit of GPI therapy in patients with no elevation in cardiac biomarker levels. Second, the patients who did receive GPI in our study received only GPI bolus without an infusion, which has been shown to reduce bleeding complications without increasing the ischemic endpoints.^10,11,15 Third, our target ACT was 200 seconds for those who did not receive GPI and 175 seconds for those who received GPI, which corresponds to 300 seconds and 200 seconds of ACT when UFH was administered.⁸ These ACT targets are lower than those used in the STEEPLE trial (target ACT was 300–350 seconds for patients who did not receive GPI and 200–300 seconds for those who received GPI). It is our contention that the anticoagulant effect of LMWH administered during PCI can and should be monitored and that algorithms based on the timing from the last administered subcutaneous dose, such as those used in the SYNERGY trial, are inadequate.³ First, it is not always possible to determine the timing of the last dose of LMWH; frequently, there is inadequate documentation in the chart, particularly in the case of patients who may have had therapies initiated in one institution and then are transferred to a tertiary care center for interventional services. Second, the timing approach is based on a presumption that the pharmacokinetics of LMWH is predictable. This may not be true in patients presenting with a variety of conditions, such as obesity and renal dysfunction — conditions associated with an ever-increasing proportion of patients undergoing PCI. Thus, LMWH-treated patients most in need of accurate levels of anticoagulation are likely to be the most at risk for inaccurate dosing and excessive bleeding. It has been previously reported that although UFH induces a greater increase in the ACT compared with dalteparin, there was a corresponding greater degree of variability in the response of the ACT to UFH compared with dalteparin.⁶ The tighter distribution of dalteparin-induced (in comparison to UFH-induced) peak ACT values has been confirmed in a recent randomized trial of PCI.¹⁶ These observations suggest that once a target ACT is reached using LMWH, the corresponding blood levels of anticoagulant may be more reliably predicted than had UFH been administered.
Study limitations. This study is a retrospective analysis and has all the inherent limitations of a retrospective study. There is no control group and the results are compared to historical controls. The definitions used for bleeding complications in our study are different from those used in the SYNERGY trial³ and the STEEPLE trial.⁴ However, we used REPLACE-213 definitions, which were sensitive compared to TIMI definitions.¹² The sample size is not large and there are no deaths or repeat revascularization. The outcomes studied are only in-hospital and there is no long-term follow-up data. Conclusions ACT-guided dosing of intravenously administered dalteparin appears to constitute a safe and effective strategy during PCI. Double-blind, randomized, prospective studies are required to confirm these preliminary findings.

1. Cohen M, Demers C, Gurfinkel EP, et al, for the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events Study Group. A comparison of low-molecular weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997;337:447.
2. Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction: Results of the Thrombolysis In Myocardial Infarction (TIMI) 11B trial. Circulation 1999;100:1593.
3. Ferguson JJ, Califf RM, Antman EM, et al. Enoxaparin vs. unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: Primary results of the SYNERGY randomized trial. JAMA 2004;292:45.
4. Montalescot G, White HD, Gallo R, et al. Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention. N Engl J Med 2006;355:1006–1017.
5. Henry TD, Satran D, Knoxx LL, et al. Are activated clotting times helpful in the management of anticoagulation with subcutaneous low-molecular-weight heparin? Am Heart J 2001;142:590–593.
6. Marmur JD, Anand SX, Bagga RS, et al. The activated clotting time can be used to monitor the low molecular weight heparin dalteparin after intravenous administration. J Am Coll Cardiol 2003;41:394– 402.
7. Cavusoglu E, Lakhani M, Marmur JD. The activated clotting time (ACT) can be used to monitor enoxaparin and dalteparin after intravenous administration. J Invasive Cardiol 2005;17: 416– 421.
8. Marmur JD, Bullock-Palmer RP, Lakhani MJ, Cavusoglu E. Strategies for the safe and rational use of dalteparin or enoxaparin during percutaneous coronary intervention. J Invasive Cardiol 2006;18(Suppl E):1E–13E.
9. Kereiakes DJ, Kleiman NS, Fry E, et al. Dalteparin in combination with abciximab during percutaneous coronary intervention. Am Heart J 2001;141:348– 352.
10. Marmur JD, Mitre CA, Barnathan E, et al. Benefit of bolus-only platelet glycoprotein IIb/IIIa inhibition during percutaneous coronary intervention: Insights from the very early outcomes in the EPIC trial. Am Heart J 2006;152:876–881.
11. Marmur JD, Poludasu S, Agarwal A, et al. Bolus-only platelet glycoprotein IIb-IIIa inhibition during percutaneous coronary intervention. J Invasive Cardiol 2006;18:521–526.
12. Bovill EG, Terrin ML, Stump DC, et al. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI), Phase II Trial. Ann Intern Med 1991;115:256–265.
13. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853–863.
14. Kastrati A, Mehilli J, Schuhlen H, et al. for the Intracoronary Stenting and Antithrombotic Regimen — Rapid Early Action for Coronary Treatment study Investigators. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004; 350: 232–238.
15. Fischell TA, Attia T, Rane S, Salman W. High-dose, single-bolus eptifibatide: A safe and cost-effective alternative to conventional glycoprotein IIb/IIIa inhibitor use for elective coronary interventions. J Invasive Cardiol 2006;18:487–491.
16. Natarajan MK, Velianou JL, Turpie AG, et al. A randomized pilot study of dalteparin versus unfractionated heparin during percutaneous coronary interventions. Am Heart J 2006;151:175.