Detection of coronary microembolization by Doppler ultrasound in patients with stable angina pectoris during percutaneous coronary interventions under an adjunctive antithrombotic therapy with abciximab: design and rationale of the High Intensity Transient Signals ReoPro (HITS-RP) study

The mouse monoclonal antibody abciximab against the platelet receptor glycoprotein IIb/IIIa (GPIIb/IIIa) is able to inhibit platelet aggregation by more than 80% [16]. In patients with acute myocardial infarction abciximab was able to improve myocardial microcirculation and reduce infarct size due to dissolution of thrombi and microemboli [17]. Therefore we hypothesize that abciximab is a possible agent to reduce coronary microembolization in patients with stable CAD undergoing elective PCI.

The HITS-RP study is a prospective, double-blinded, randomized, placebo controlled trial in patients with coronary artery disease (CAD) undergoing PCI. The study goal is to determine the efficacy of intravenous abciximab bolus application with subsequent 12-hour intravenous infusion in reducing high intensity transient signals (HITS) compared to placebo. The trial is registered under http://​www.​drks-neu.​uniklinik-freiburg.​de/​drks_​web/​:​DRKS00000603.

The primary study end point of the HITS-RP study is the incidence of HITS during PCI. Secondary endpoints are changes in CFVR, cardiac biomarkers (cTNI, CK, CK-MB) and hs-CRP in comparison to the initial values, ECG changes, bleeding complications due to the additional thrombocyte inhibiton, and any type of major adverse cardiac or vascular event during one month follow-up. Bleeding complications will be assessed according to the GUSTO criteria (a-severe or life-threatening; b-moderate; c-mild) [18].

The prospective study will include 60 consecutive patients with CAD and elective PCI. Recruitment will commence in may 2012. The Institutional Ethics Committee of University Hospital of Jena approved the study protocol.

Patient randomization is performed centrally with a randomization ratio of 1:1 (n = 30 patients per group). Patients will be randomized by blockwise randomization with a fixed block size of 6 using Datinf randList 1.2. The random number generator is based on the algorithm of Park and Miller with Bays-Durham correction. Allocation concealment is done in the pharmacy. Medication will be delivered in black syringes with a label only containing study name and patients number (Figure 1).

Based on the results of previous studies [7] we expect 27 HITS on average in the placebo group and 18 HITS in the treatment group. Assuming a standard deviation of 12 in both groups, we will need a sample size of 29 patients to detect the treatment effect with a power of 80% at a two-sided alpha-level of 0.05. To account for drop-outs we have chosen to include 30 patients per group in the study.

All patients receive 100 mg acetylsalicylic acid once daily before PCI and thereafter according to the standards of good clinical practice. Those patients not already taking clopidogrel medication will receive 600 mg immediately after PCI and afterwards 75 mg once daily. A heparin bolus of 70 IU Heparin/kg body weight is given following the insertion of the arterial sheath. All other medication is given at the discretion of the attending cardiologist. After diagnostic angiography with knowledge of the coronary anatomy patients are planned to undergo balloon dilatation with implantation of a stent for a single stenosis. The choice of stent (bare-metal or drug-eluting stent) is left to the discretion of the attending cardiologist. Patients will be randomly assigned to the glycoprotein IIb/IIIa receptor antagonist abciximab or placebo. The study drug will be given as an i.v. bolus of 0.25 mg/kg body weight 10 minutes before PCI followed by a continuous infusion at 0.125 μg/kg/min initiated immediately after the bolus and continued for 12 h. A Doppler guidewire is positioned 1 to 2 cm distal to the stenosis for PCI. At this position the average peak velocity (APV) is recorded. Before and after each interventional step CFVR is measured as the ratio of maximum APV and baseline APV. Maximum hyperemia will be induced by intracoronary injection of 30–40 μg adenosine. The number of HITS will be measured as previously described [7].

After PCI, removal of the sheath is performed according to local practice. Care must be taken to ensure adequate hemostasis.

After 12 and 24 h creatine kinase (CK), creatine kinase-MB (CK-MB), cardiac troponin I (cTNI), hemoglobin (Hb), hs-CRP will be determined and after 24 h also an ECG will be recorded. At 30-day follow-up all cause mortality, myocardial infarction, angina pectoris, new congestive heart failure, and bleeding complications will be assessed. This is the end of the trial.

The primary end point will be analyzed according to the intention-to-treat principle using the independent-samples t-test. In addition per-protocol analysis and to adjust for risk factors (such as diabetes, hypertension, smoking, cholesterol level, sex) multivariate regression analysis will be performed. The secondary endpoints are compared using Student’s t-test, Mann–Whitney U test, chi-square test and Fisher’s exact test as appropiate and by multivariate regression models.

All data will be collected independently in a blinded database by an external data management facility (2conduct clinical trials). A p-value of <0.05 will be considered as statistically significant. Data analysis will be performed using SAS 9.3 (SAS Institute Inc.).

Due to the small study size results will be interpreted with caution and in case of reduction of HITS a larger clinical trial will have to follow. Due to statistical reasons, we do not expect a difference in the composite major adverse cardiac event rate (death, reinfarction, target vessel revascularization, new congestive heart failure) between the two study arms.

Clinical findings suggest that coronary microembolization and pNSTEMI are frequent periprocedural complications. Relevant numbers of microemboli during cardiac interventions could also be detected in the cerebrovascular circulation [23].

Administration of abciximab could protect the myocardium and maybe also the cerebrovascular system. It may reduce the incidence of myocardial damage and also the inflammatory reaction associated with myocyte necrosis. Because of its ease administration and general availability this treatment approach could have a high potential in clinical practice.