Safety of an Aspirin-Alone Regimen After Intracoronary Stenting With a Heparin-Coated Stent
Final Results of the HOPE (HEPACOAT and an Antithrombotic Regimen of Aspirin Alone) Study
Background— Stent thrombosis is an infrequent complication of intracoronary stenting that often has devastating clinical consequences. This study assesses the additional benefit of heparin coating with the BX VELOCITY Balloon-Expandable Stent with HEPACOAT, Carmeda end-point attached heparin (HEPACOAT) in patients with de novo or restenotic native coronary artery lesions treated with aspirin monotherapy after optimal stenting.
Methods and Results— This was a multicenter, prospective, nonrandomized, pilot study. Two hundred patients (69% men; mean age, 64.1±11.2 years) meeting the eligibility criteria were treated with the HEPACOAT stent and aspirin alone after stenting. Any other antiplatelet or anticoagulation therapy was not permitted. Procedural success was achieved in all patients. There were 3 postprocedural non–Q-wave myocardial infarctions. The primary end point of stent thrombosis at 30 days occurred in 2 of 200 patients (1%): in one after blunt chest trauma and in the other in the setting of essential thrombocytosis. Major adverse cardiac events (death, myocardial infarction, target lesion revascularization, and coronary artery bypass grafting) were observed at 30 days in 5 of 200 (2.5%) patients.
Conclusions— The BX VELOCITY stent with HEPACOAT and aspirin alone after the procedure was safe in select patients with de novo or restenotic lesions in native coronary arteries. Heparin coating provides additional protection against stent thrombosis.
Received November 8, 2002; de novo received April 29, 2003; revision received June 12, 2003; accepted June 12, 2003.
Stent-assisted percutaneous coronary intervention (PCI) is widely accepted for the treatment of coronary artery disease; up to 80% of all treated vessels are stented.1 To prevent stent thrombosis, a serious complication of stent implantation, dual-antiplatelet therapy with aspirin and ticlopidine has optimal efficacy.2 Recently, ticlopidine has almost entirely been replaced by clopidogrel, a newer potent platelet adenosine diphosphate receptor antagonist; clopidogrel has at least the same antiplatelet effect, faster onset of action, and better safety profile in terms of reduced risk of hematological complications.3–7 At present, the combination of aspirin and clopidogrel is standard therapy after coronary stent implantation. Although this therapy has substantially decreased stent thrombosis, it has not eliminated this catastrophic event.
Coating of the stent surface with an antithrombotic agent may further reduce stent thrombosis. The ability of heparin-coated stents to prevent stent thrombosis was first shown in experimental studies.8,9 Subsequent clinical trials demonstrated superiority of heparin-coated stents, used in combination with two antiplatelet drugs, over angioplasty in terms of safety and efficacy.10,11 The aim of the present study was to determine the safety and effectiveness of a heparin-coated stent (BX VELOCITY Balloon-Expandable Stent with HEPACOAT) (HEPACOAT) [Cordis Corporation] in patients with de novo or restenotic lesions in native coronary arteries treated with aspirin alone after the procedure in an attempt to evaluate the added benefit of a heparin-coated stent in low-risk patients.
Study Design and Ethical Considerations
The study was designed as a multicenter, prospective, nonrandomized safety trial. Twenty US centers enrolled patients between October 26, 2000, and October 1, 2001. The protocol was performed according to the principles of the Helsinki declaration and was approved by each site’s local institutional review board.
Given the concern that a recommended therapy was being withheld, the trial was designed in conjunction with the Food and Drug Administration to include frequent assessments of patient safety. The trial was conducted in 4 consecutive phases with 50 patients in each phase. As the end of each phase, trial enrollment was stopped, and 30-day clinical event rates were assessed by an independent Data Safety Monitoring Committee. It was prespecified that the trial would be stopped if (1) 4 or more of the first 50 patients had a documented subacute thrombosis or (2) the overall cumulative subacute thrombosis rate was >7.6% for all subsequent phases.
At any point during the procedure or follow-up, if the investigator felt that the angiographic results were suboptimal or that the clinical situation mandated, the patient was given the adenosine diphosphate receptor antagonist clopidogrel, according to standard procedures. These patients were removed from the primary analysis population, entered into a separate registry, and followed in a similar manner to patients in the primary study. All other treatments, including platelet glycoprotein (GP) IIb/IIIa receptor inhibitors, were at the discretion of the physicians, whether before, during, or after the procedure.
Patients were candidates for the study if they satisfied the following criteria: evidence of ischemia (angina pectoris or/and positive stress test), lesion >50% and ≤25 mm in length (visual estimate) in a native coronary artery in a vessel 3.0 to 4.0 mm in diameter (by visual estimate). Patients were excluded because of Q-wave myocardial infarction within preceding 72 hours; impaired renal function (creatinine >3.0 mg/dL); unprotected left main coronary artery disease with ≥50% stenosis; ostial lesion; bifurcation lesion; severe lesion calcification; diffuse distal disease, angiographic lesion thrombus; reduced left ventricle ejection fraction (≤30%); participation in any other investigational drug or device protocol; and pre-PCI or post-PCI treatment with ticlopidine or clopidogrel.
PCI was performed using standard techniques. All patients were treated with 325 mg aspirin ≥12 hours pre-PCI. Heparin was administered during the procedure to maintain an activated clotting time >250 seconds. After intracoronary injection of nitroglycerin (100 to 200 μg), baseline angiography of the lesion was performed in >2 near-orthogonal views. The angiograms included at least 2 cm of guiding catheter and minimized lesion foreshortening to allow for accurate quantitative coronary angiographic (QCA) measurements. Lesions were treated with the HEPACOAT stent. If a dissection occurred during predilation or stent implantation, additional HEPACOAT stent(s) were implanted to treat the dissection. An independent core laboratory (Angiographic Core Laboratory, Cardiovascular Research Foundation, New York, NY) analyzed all cineangiograms.
Creatinine kinase (CK) was measured at 8 and 16 hours post-procedure. If elevated, CK and CKMB were evaluated every 8 hours until returning to normal or hospital discharge. Electrocardiograms were obtained after the completion of the procedure, at 24 hours after PCI, for any suspicious ischemic episode, and at discharge.
Baseline data were collected on standardized case report forms. Clinical follow-up was mandated at 30 days (additional follow-up at 6 and 12 months is being collected). An independent clinical events committee adjudicated all primary and secondary end points. A data safety monitoring board met after each group of 50 patients reached the 30-day end point.
End Points and Definitions
The primary end point of the study was stent thrombosis at 30 days. Secondary end points included procedural success and major adverse cardiac events (MACE): cardiac death, Q-wave and non–Q-wave myocardial infarction (MI), target lesion revascularization (TLR), and CABG.
Stent thrombosis was angiographic thrombus or subacute closure of the stented vessel at the time of a clinically driven angiographic restudy for documented ischemia (chest pain and ECG changes). Also, any death attributed to a cardiac cause within the first 30 days was considered a surrogate for stent thrombosis in the absence of documented angiographic stent patency. Cardiac death was death due to MI, cardiac perforation, pericardial tamponade, arrhythmia or conduction abnormality, cerebrovascular accident within 30 days of the procedure (or suspected being as related to the procedure), death as the result of a complication of the procedure (including bleeding, vascular repair, transfusion reaction, or bypass surgery), and any death in which a cardiac cause could not be excluded. Q-wave MI was postprocedure CK or CKMB elevation above normal with new pathological Q-waves in ≥2 contiguous leads. Non–Q-wave MI was elevation of postprocedure CKMB >3× normal value or (if no CKMB assay was performed) elevation of CK to >2× normal value in the absence of pathological Q waves. Procedural success was a final diameter stenosis of <50% (by QCA) without in-hospital MACE.
The study was designed to estimate the subacute thrombosis rate in patients receiving the HEPACOAT stent and aspirin alone. The expected subacute thrombosis rate was assumed to be 0.001, that is, near zero. A one-group χ2 test with a 0.05 1-sided significance level and 80% power to detect the difference between the null hypothesis proportion, π0, of 0.02 and the alternative proportion, π1, of 0.001 yielded a sample size of 183.
Baseline characteristics and outcomes are reported with descriptive statistics. Categoric variables are reported as counts and percentages, and continuous variables are reported as mean±1 SD. All tests were 2-sided, and a value of P<0.05 was considered significant.
Two hundred patients (69% men; mean age, 64.1±11.2 years) were enrolled in the primary study. Baseline characteristics are detailed in Table 1. Most patients had single-vessel disease (115; 57.5%). Double- and triple-vessel disease was present in 58 (29%) and 27 (13.5%) patients, respectively. Angiographic variables and procedural characteristics are presented in Table 2. QCA data were available in 197 of 200 patients (98.5%). The majority of treated lesions were de novo (97.5%). Two or more stents were inserted in 21 vessels (10.5%), with a mean number of stents of 1.11±0.31 implanted at 14.9±3.4 atm. The left anterior descending artery was the most frequently treated vessel (39.5%). Baseline flow was disturbed (TIMI grade 1 to 2) in 9 vessels (4.5%). Intravenous platelet GPIIb/IIIa inhibitors were administered in 110 procedures (55%): abciximab in 33 (16.5%), eptifibatide in 57 (28.5%), and tirofiban in 20 (10%). Procedural success was achieved in all patients. Additional balloon dilation(s) after stent deployment were performed in 90 vessels (45%). Diameter stenosis decreased from 66±17% to 4±10%.
In-hospital and 30-day events are presented in Table 3. The majority of the procedures (197; 98.5%) were uncomplicated. Five patients had residual dissections after initial stenting. In each of these cases, a second stent was successfully placed to cover the dissection. Three patients (1.5%) had non–Q-wave MI. There was a 2.5% rate of vascular access complications. All patients were receiving aspirin at the time of hospital discharge, and no patients received clopidogrel, ticlopidine, or warfarin.
Thirty-day follow-up was available for 198 of 200 patients (99%). Follow-up angiograms were performed in 39 patients. Nine MACE occurred in 5 patients (2.5%) (Table 3). Two patients (1%) had subacute stent thrombosis and subsequent Q-wave MI and TLR on the 10th and 11th days after PCI, respectively. The first patient had stent thrombosis after blunt chest trauma. The second patient had essential thrombocytosis with a chronically elevated platelet count of 500 to 700×109/L. On the day of the event, his platelet count was 752×109/L. There was one death adjudicated by an independent clinical events committee as due to a noncardiac cause; this was a 69-year-old man who died of respiratory failure 4 days after stenting of the middle portion of the LAD.
Thirty-five patients were followed in a separate registry. They were excluded from the primary analysis for the following reasons: 8 did not receive the study stent; 9 had long (>20 mm) or multiple lesions; 4 met major exclusion criteria (3 enrolled <72 hours after MI and 1 had planned elective abdominal surgery); 3 received other anticoagulants (bivalirudin or coumarin); and 11 received clopidogrel. Baseline demographics were similar to the patients in the primary analysis with the exception of more peripheral vascular disease in the registry (15.6% versus 5.1%, P=0.04).
Lesions in the registry were more often calcified (12.9% versus 2%, P=0.01) and had a greater preprocedural diameter stenosis (73±13 versus 66±17, P=0.04). Baseline angiographic and procedural characteristics are detailed in Table 4. Procedures appeared to be more complicated in the registry patients with more dissections and more frequent use of ≥2 stents. Only 82% had successful stent deployment; 90.6% had successful procedures. There was one intraprocedural abrupt closure that was successfully treated with balloon angioplasty and one emergency CABG for retrograde dissection into the proximal circumflex.
At 30 days, MACE occurred in 4 registry patients (11.4%) including 2 deaths, 1 as a consequence of stent thrombosis. In this patient, the initial procedure was successful. Twelve days after stenting, she underwent elective colon cancer resection (for which she was excluded from the primary analysis); the immediate postoperative course was complicated by hypotension, Q-wave MI, and cardiac arrest leading to death. The other death was from postprocedural renal failure and sepsis.
Stent thrombosis is a major complication of coronary stenting. During the evolution of antithrombotic pharmacotherapy to prevent this complication, various treatment regimens were proposed including aspirin, heparin, warfarin, and so forth. The data of 5 randomized trials showed that the dual treatment with aspirin and a thienopyridine was superior to other combinations.2,12–15 In STARS, the rate of 30-day stent thrombosis in patients treated with aspirin plus ticlopidine was 0.5%, with 5.5% hemorrhagic complications.
Ticlopidine has been largely replaced by clopidogrel; it is better tolerated with fewer hematological side effects.3–7 With the use of aspirin plus ticlopidine/clopidogrel, subacute stent thrombosis rates are extremely low in patients with simple lesions2; however, stent thrombosis rates are clearly higher in more complex patient/lesion subsets: acute coronary syndromes including acute MI, bifurcation lesions, long lesions, small vessels, and multivessel stenting. Several registries have reported subacute stent thombosis rates between 0.5% and 1.9%.16–18
Subacute thrombosis typically occurs early, within 2 days of the procedure, with mortality rates exceeding 20% and death/MI rates exceeding 70%.16–18 Patients who survive subacute thrombosis have poor outcomes at 6 months, with mortality rates of 20% to 25%.19 Therefore, this devastating event needs to be prevented in every way possible.
The idea of stenting with bare stents, with aspirin used as the only antiplatelet agent, has been examined in a number of studies.15,17,20–22 The prospective MUSIC trial22 showed that optimum IVUS-guided stenting (stent expansion ≥90% reference lumen and/or minimal lumen area ≥9 mm2) with aspirin as sole antiplatelet therapy can be performed with rates of 30-day stent thrombosis of 1.3%. The randomized study of Albiero et al21 reported a 1.9% rate of stent thrombosis at 30 days in patients treated with IVUS-guided stenting with aspirin alone. Despite the attractiveness of IVUS-guided stenting, optimal stent deployment cannot be achieved in all lesions.
The Clopidogrel for the Reduction of Events During Observation (CREDO) and the PCI-CURE (PCI Clopidogrel in Unstable angina to prevent Recurrent Events) studies both indicated benefits of long-term clopidogrel therapy beyond prevention of subacute stent thrombosis.23,24 With relative risk reductions in death and nonfatal MI of 24% to 25%, the evidence for long-term use of clopidogrel is substantial. However, clopidogrel is not universally available to all patients for economic and other (ie, geographic) reasons. Complications after CABG or post-noncardiac surgery in clopidogrel-treated patients are substantial25–27; judicious use is mandated to limit potential clinical risks, especially bleeding.
Heparin-coated stents prevent stent thrombosis in experimental studies.8,9 Subsequent clinical trials demonstrated the safety and efficacy of heparin-coated stents in combination with dual antiplatelet therapy (aspirin and ticlopidine) versus balloon angioplasty alone. Angiographically documented 30-day stent thrombosis occurred in only 0.2% of patients treated with a heparin-coated stent versus 1.7% of patients in the balloon angioplasty group.10 This study extends previous evidence that heparin coating may provide additional protection from thrombosis.
Our study is the first to use heparin-coated stents and sole aspirin antiplatelet therapy without IVUS guidance. The rate of 30-day stent thrombosis (1%) is comparable to standard antithrombotic regimens. The two patients with stent thrombosis in our study had exceptional circumstances (chest trauma in one and essential thrombocytosis in another) that may have contributed to this complication.
In STARS, 557 patients were randomly assigned to aspirin alone.2 The subacute stent thrombosis rate in sole-aspirin–treated patients was 3.6% (20 patients). The observed rate of stent thrombosis in the current study (1%) suggests that heparin coating provides additional protection. In the current study, the upper bound of the 95% confidence interval for the estimate of subacute stent thrombosis is <3.6%, the reported rate in STARS. However, the HOPE study was not designed or powered for formal comparison with this historic control.
The nonrandomized character of the study does not exclude selection bias similar to a randomized trial. The primary aim of the study was not to demonstrate the superiority of stenting without clopidogrel/ticlopidine but to evaluate the feasibility and safety of an aspirin alone regimen in uncomplicated patients. In this way, it was similar to many nonrandomized phase II trials. To adequately power a trial to evaluate the relatively rare event of subacute thrombosis, a sample of >2700 patients would be needed to demonstrate noninferiority.
When compared with the registry patients, the main study sample represents patients with less complicated procedures. However, almost half of the patients (43.1%) had complex lesions (type B2/C), and the majority of lesions (70.1%) were eccentric. Given the significant number of protocol deviations and the number of patients who received clopidogrel, it is impossible to estimate the effect of sole aspirin antiplatelet therapy in combination with heparin coating in the registry patients.
This study has demonstrated an acceptable stent thrombosis rate of the BX VELOCITY Balloon-Expandable Stent with HEPACOAT in patients with de novo and restenotic coronary artery lesions treated with aspirin alone after the procedure. The potential benefits of heparin coating for the prevention of stent thrombosis should be further evaluated in a large-scale, randomized, controlled trial.
This research was funded by Cordis Corporation, Warren, NJ. The following people contributed significantly to study enrollment: Barry George, Midwest Cardiology Research Foundation, Columbus, Ohio; Sheldon Goldberg, Cooper Health System, Camden, NJ; Steven Jones, Brookwood Medical Center, Birmingham, Ala; Jerry Kennett, Missouri Cardiovascular Specialists, Columbia, Mo; Francis Kiernan, Hartford Hospital, Hartford, Conn; Charles Lambert, Heart First Heart Institute, Melbourne, Fla; Khoi Le, Desert Cardiology Center, Rancho Mirage, Calif; William O’Neill, William Beaumont Hospital, Royal Oak, Mich; Charles O’Shaughnessy, EMH Regional Medical Center, Elyria, Ohio; Albert Raizner, Methodist Hospital, Houston, Tex; David Roberts, Sutter Memorial General Hospital, Sacramento, Calif; Ronald Rubinstein, Premier Cardiology Research, Neptune, NJ; David Williams, Rhode Island Hospital, Providence, RI; and Dale Wortham, Volunteer Research Group, Knoxville, Tenn. We also thank Martin Fahy, Gary Mintz, Manuela Negoita, and Eugenia Nikolsky from the Cardiovascular Research Foundation, New York, NY, for their contributions to the manuscript review and preparation.
Dr Fischell is a shareholder of Johnson & Johnson, serves as a consultant and investigator to Cordis Corp, is a coinventor of the BX VELOCITY Stent, serves as a consultant to Boston Scientific Corp, and receives research grants and royalties from Cordis. Dr Whitworth serves on the medical advisory board of Cordis and holds limited stock in Johnson & Johnson. Dr Wong serves as a consultant and member of the advisory board of Cordis. Dr Leon owns equity and stock in, and receives speaking honoraria and research grants from, Johnson & Johnson.
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