A Randomized Trial of the Low-Molecular-Weight Heparin Certoparin to Prevent Restenosis Following Coronary Angioplasty

Coronary angioplasty has become a successful and widely used treatment for patients with coronary artery disease since its first clinical application in 1977. However, late (36 month) restenosis rates (20–30%) continue to be the most important clinical problem after successful coronary angioplasty.1–3 Chronic restenosis involves the development of fibrocellular intimal hyperplasia resulting from vascular injury, platelet activation, thrombin generation, release of multiple mitogens, and some other still unknown chemotactic and growth factors. The antithrombotic properties of heparin are the basis for its routine use in angioplasty procedures. Small mural thrombosis is a common occurrence during angioplasty. It appears that organization of mural thrombus and its incorporation into the coronary plaque may contribute significantly to post-angioplasty restenosis. Infusion experiments in vivo and in cell culture assays in vitro have demonstrated that low-molecular-weight heparin (LMWH) inhibits smooth muscle cell proliferation and migration. Castellot et al.4 reported that LMWH binds to the surface of the smooth muscle cell and is internalized. Once inside the smooth muscle cell, heparin either blocks the transition to or acts very early in the S phase, interfering with smooth muscle cell proliferation. LMWHs were shown to reduce restenosis after balloon angioplasty in a hypercholesterolemic rabbit iliac artery model.5 In a small, uncontrolled study, the LMWH reviparin reduced the incidence of peripheral in-stent stenosis.6 Several investigators7,8 have shown that the antiproliferation effects of LMWH are distinct from its anticoagulant effects. LMWH, by virtue of the small fragments, contains a high percentage of this non-anticoagulant fraction. Given the importance of platelet deposition and mural thrombosis in the pathogenesis of both acute coronary thrombosis and post-angioplasty restenosis, it appeared plausible in 1993 that appropriate, properly dosed, chronically administered antithrombotic therapy might be successful in reducing and controlling the risk of post-angioplasty restenosis. Since there is no good animal model for studying the restenosis process after coronary angioplasty, we hypothesized that immediate (within 24 hours) together with chronic (3 months) administration of LMWH would reduce restenosis after angioplasty. The study is entitled the Prophylaxis Against Restenosis Angioplasty Trial (PARAT). There have been several trials of drugs and devices to prevent restenosis following coronary angioplasty reported after this present trial began. Some of these are summarized in Table 1. The most promising treatment has been coronary brachytherapy with either gamma or beta radiation. Not all hospitals, however, have the capability of administering radiation in the coronary arteries. Although fish oil produced a reduction in restenosis, the results have not been duplicated in other trials. Probucol treatment resulted in less restenosis, but the drug has been removed from the market. None of the trials of LMWH resulted in a significant reduction of restenosis. The present PARAT trial used 8,000 anti-Xa U/day for 3 months, a more intense regimen than other trials. The dated nature of this study was due to delays in the sponsoring pharmaceutical company transcribing the case report forms into databases suitable for statistical analysis. These delays were caused by major changes in the personnel and organizational structure of the company that occurred near the end of the study. METHODS Study design and population. The PARAT study was a double-blind, placebo-controlled, randomized trial with 2 study groups conducted at 4 medical centers. The protocol was approved by the institutional review boards of each institution. Patients referred for elective balloon angioplasty from April, 1993 to December, 1994 were asked to participate and to provide written informed consent. Only balloon angioplasty was specified in order to avoid confounding treatment methods. The main criteria to evaluate the efficacy of long-term LMWH administration to prevent post-PTCA restenosis is the angiographically determined degree of vessel restenosis. The LMWH used in the study was certoparin, and was provided by Novartis Pharmaceuticals, the sponsoring pharmaceutical company. Repeat angiography at the end of a 6-month observation period was performed to evaluate the endpoint of the study. The degree of angiographically determined restenosis was documented by calculation of relative loss (RL) and is the endpoint of this study. Hermans et al.9 found RL values in the range of 0.10–0.12 at reference vessel sizes of 2.0–3.5 mm in patients without anti-restenosis therapy. Assuming a decrease in RL from 0.11 ± 0.15 (mean ± standard deviation) to 0.05 (A = 0.05; B = 0.20) under chronic LMWH administration, seventy-eight available patients in each study group would be needed to achieve a statistically significant difference (one-sided testing). A goal of 170 patients (85 in each treatment arm) was set for the study. Secondary endpoints were safety evaluation and analysis of restenosis using the binary definition. The latter defines restenosis as the percentage of lesions with minimum lumen diameter (MLD) greater than 50% of the reference diameter. Inclusion and exclusion criteria. The patients were required to be between 21 and 80 years of age, have significant coronary artery disease (CAD, defined as stenosis > 50%), and be able to give informed consent. Excluding conditions were congestive heart failure, other major illnesses (i.e., cancer, liver disease, renal failure, etc.), severe hypertension, child bearing potential, coronary artery bypass surgery (CABG) within 6 weeks, oral anticoagulation therapy, active ulcer or gastrointestinal bleeding, thrombocytopenia, coagulopathy, severe osteoporosis, any cerebral vascular accident (CVA) or transischemic attack, severe diabetic retinopathy, hypersensitivity to heparin or LMWH, or participation in a clinical drug trial within the last 4 weeks. Randomization and drug regimens. At the time of angioplasty, patients were randomly assigned to treatment with twice-daily subcutaneous injections of LMWH (certoparin 80 mg, 8,000 anti XaU) or placebo for 3 months. All patients received aspirin (325 mg) daily for the entire study period. The study nurse coordinator administrated the first injection and then supervised the self-administered injections until the patient was discharged. The patients received a detailed medical history with special emphasis on history of bleeding disorders, neurologic disorders, alcohol abuse, and liver dysfunction. Baseline laboratory. Baseline laboratory studies included chest x-ray, electrocardiogram, bone density scan, urinalysis, stool for occult blood, complete blood count, electrolytes (including BUN and creatinine) liver function tests, PT, aPTT, lipid profile, lipoprotein, lipase, alpha-lipoprotein A and B, and several other investigational measurements relating to thrombosis. Angiography. Baseline, immediate post-PTCA, and 6-month angiograms were performed with 7 or 8 French (Fr) PTCA guiding catheters, to demonstrate the lesion in the 2 best orthogonal views after the patient was given 100–200 µg of intracoronary nitroglycerin. Follow-up angiograms were performed in the original catheterization lab, with the same catheters used at baseline, and using the same projections, table height, and image intensifier height. Follow-up evaluation. Patients were seen by the study coordinators at 2 weeks, 4–6 weeks, 3 months, and 6 months after the angioplasty. History, physical examination of injection areas, repeat baseline blood work, and electrocardiogram were done at these intervals. A repeat bone density scan was performed at 6 months. A stress thallium test was performed at 4–6 weeks and at 6 months. Quantitative coronary angiography (QCA). QCA was performed using the Heart Track® Quantitative Coronary Angiography Software System, Version 1.1 (Heart Ware, Inc., Durham, North Carolina). Images for computer analysis were acquired from a Sony Cine Video System SME-3500 using Image View® Coronary Angiography Display and Acquisition system (Heart Ware, Inc.). Images of the coronary arteries in diastole were digitized and saved to a database. Calibration was performed on the known diameter of the guide catheters. The latter was determined by ex vivo measurement of the contrast-filled catheters against a known grid using the QCA system. The measurements made were reference vessel diameter just proximal to the lesion, MLD, and lesion length. In some cases, the coronary anatomy was more suitable for the reference vessels to be measured just distal to the lesion. Calculated measurements were percent stenosis, acute gain, net gain at 6 months, and relative loss. The quantitative measurements were made by a cardiologist blinded to the patient’s identity and repeated independently by an experienced catheterization lab technician. If the reference vessel diameter or MLD differed between these two operators by more than 10%, the images were re-analyzed. When the measurements were less than 10%, the two operators’ evaluations were averaged. To further ensure accuracy and assess compatibility with other outside operators, the cine films from 20 random patients (24 lesions) were sent to an outside institution for QCA. Correlation coefficients for reference diameters between the 2 laboratories were 0.80 (p Statistical methods. Interval measurements were compared using the student’s t-test, and nominal data were compared with Chi-square analysis. In addition, cumulative frequency distribution plots were made on vessel measurements. RESULTS One hundred and eighteen patients with 158 lesions treated with PTCA were enrolled in the trial. One hundred and two patients completed the study and had follow-up QCA. Seven patients withdrew and refused to continue. Three patients were withdrawn by their physicians because of new medical conditions which developed. Two patients were discontinued because of hematuria. Four patients were lost to follow-up. The study was terminated by the sponsor before the target goal of 170 patients were enrolled. The reason for the termination was declining enrollment for simple balloon angioplasty in the face of the introduction of coronary atherectomy and stents. Table 2 shows the overall demographics of the patients enrolled in the study. The distribution of vessels treated during angioplasty showed that the LAD was more frequently treated in the LMWH group. This was probably due to chance occurrence. There was no significant difference in bone density either between the two groups, or from baseline to the 6-month point in the LMWH group. There was one death. The patient had withdrawn from the study for personal reasons. Approximately 3 months later, he died of unknown cause. The nurse coordinator learned of his death several weeks after he died. Figure 1 shows the clinical status of the patients at 6 months. There was no significant difference in the percent of patients having angina for the two groups. Table 3 shows the results of QCA performed during the study. There was no significant difference in the primary endpoint, relative loss, at six months. There is, however, considerable variability in the relative loss calculations. This appears to be due to the higher variability of the MLD measurements made at the 6-month point. This may have been due to uncontrollable differences in vessel projection from the day of PTCA to the 6-month angiogram. Variations in vascular remodeling and elastic recoil may also have had an effect. There was also no significant change in the MLD between placebo and the LMWH. This is reflected in the cumulative percentage graph of MLD shown in Figure 2. Table 3 also shows the results of binary restenosis between the placebo and LMWH. Binary restenosis refers to the percent of lesions with greater than 50% luminal narrowing at the 6-month point. The binary restenosis rate was significantly lower for the lesions treated with LMWH. This may be due to the reference vessel diameter, which was smaller for the LMWH group at the 6-month point. This would seem to imply that there was some interaction with LMWH and the reference vessel measured near the lesions. Attempts to explain this are shown in measurements in Table 4. Twenty-five untreated vessels had diameter measurements made before angioplasty and at the 6-month point. There was no significant difference in their diameters over 6 months for either the placebo or the LMWH group. From these data, it appears that there is no beneficial effect on restenosis using internal measurements of late loss and MLD. Using the binary definition of restenosis, there is a significant beneficial effect of the drug. DISCUSSION The low rates of hematuria and stool occult blood indicate that the administration of LMWH for 3 months did not produce significant hemorrhagic complications. Only 2 patients were withdrawn from the study because of hematuria. The safety of 3 month administration of LMWH is also confirmed by bone density analysis. The percentage of patients who were asymptomatic after a 6-month period was substantially greater than prior to the angioplasty. The clinical restenosis rate, i.e., the percentage of patients having angina, was less than the angiographic restenosis rate. This parallels the findings of many other restenosis trials. The primary endpoint of the trial, relative loss, was no different for LMWH compared to placebo. Although the binary restenosis rate was less for the LMWH group, the measurement of RL and MLD would indicate that LMWH has no significant beneficial effect. The binary restenosis rate of 31% for LMWH compared to 49% for placebo is probably a chance artifact. It seems to be the result of the fact that the reference vessel diameter for the LMWH group was significantly less at 6 months than at baseline for the LMWH group. Since this did not happen for other untreated vessels, this is probably a chance occurrence. It appears that similar to other trials using LMWH, certoparin has no significant beneficial effect in reducing restenosis following balloon angioplasty. The results of this trial, like the results of other trials, are also clouded by the mechanisms that are known to be involved in the development of restenosis. Without intravascular ultrasound (IVUS), it is impossible to sort out the contributions of elastic recoil, negative remodeling, and smooth muscle cell proliferation. These mechanisms could easily be sorted out in this area of stents with IVUS. Stents would eliminate elastic recoil and negative remodeling, allowing IVUS to quite precisely measure the effect of LMWH on the mechanism of smooth muscle cell proliferation in producing restenosis. The results of this trial are also limited by the failure to recruit the number of patients calculated to power the statistics of relative loss. There may have been beneficial effect had the full 170 patients been recruited.

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