The following activity is supported by an unrestricted educational grant from Cordis Corporation.
Topics:
Part I. Late Loss and Target Lesion Revascularization: The New Measurement Criteria;
Part II. Significance of Late Loss and Target Lesion Revascularization in Interpreting Drug-Eluting Stent Clinical Trial Results (Part Two)
Faculty/Credentials: Darrin Crosby, BS, RRT, Clinical Specialist Cordis Cardiology, Orlando, Florida; Marco A. Costa, MD, PhD, Assistant Professor of Medicine, Director of Research and Cardiovascular Image Core Laboratories, Division of Cardiology, University of Florida, Shands Hospital, Jacksonville, Florida
Learning Objectives.
At the conclusion of this activity, the participant should be able to:
1. Explain the pathophysiology and processes of restenosis.
2. Explain the differences in trial endpoints that describe restenosis (i.e. binary restenosis, target lesion revascularization, and late loss).
3. Explain why late loss is an important trial endpoint in the evaluation of the drug-eluting stent.
4. Critically evaluate drug-eluting stent trials by also looking at QCA methodology, whether routine angiographic follow-up was performed, and the time of follow-up.
Activity instructions. Successful completion of this activity entails reading the article, answering the test questions and obtaining a score of over 70%, and submitting the test and completed evaluation form to the address listed on the form. Tests will be accepted until the expiration date listed below. A certificate of completion will be mailed to you within 60 days. Estimated time to complete this activity: 1 hour
Initial release date: April 30, 2003
Expiration date: April 30, 2004.
Target audience. This educational activity is designed for physicians, nurses and cardiology technologists who treat patients with coronary artery disease.
Accreditation statements. This activity is sponsored by HMP Communications.
Physicians: HMP Communications, LLC is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
HMP Communications, LLC designates this continuing medical education activity for a maximum of 1 category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity.
This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies.
Nurses: Provider approved by the California Board of Registered Nursing, Provider Number 13255 for 1 contact hour.
Radiologic Technologists: Activities approved by the American Medical Association (AMA Category 1) are eligible for ARRT Category B credit as long as they are relevant to the radiologic sciences. Radiologic Technologists, registered by the ARRT, may claim up to 12 Category B credits per biennium.
SICP: Society of Invasive Cardiovascular Professionals (SICP) approved for 1 CEU.
Commercial support disclosure. This educational activity has been supported by an educational grant from Cordis Corporation.
Faculty disclosure information. All faculty participating in Continuing Education programs presented by HMP Communications are expected to disclose to the meeting audience any real or apparent conflict(s) of interest related to the content of their presentation.
Darrin Crosby, BS, RRT, has disclosed that he works for Cordis Corporation. Marcos A. Costa, MD, disclosed that he has received a research grant from Cordis and is a member of the speakers’ bureau for Cordis.
Late Loss and Target Lesion Revascularization:
The New Measurement Criteria
Part One of a CME/CEU Program
for Cath Lab Digest
Darrin Crosby, BS, RRT, Orlando, Florida
The process of restenosis, the renarrowing of a coronary artery lumen following a revascularization procedure, begins at the time of percutaneous coronary intervention (PCI). Restenosis has long been seen as the Achilles’ heel of interventional cardiology. Between 30-50% of patients treated with balloon angioplasty and 15-30% of patients treated with bare metal stents return with a repeat stenosis. Many require a repeat intervention.1
We know that the development of restenosis involves three major processes:
Elastic recoil is the acute renarrowing of an artery after balloon angioplasty.
Negative arterial remodeling affects the outermost vessel layer, the adventitia. 2,3 As the vessel begins to heal itself, the adventitial layer shrinks inward.
Both negative arterial remodeling and elastic recoil are considered to be mechanical causes of restenosis.
Neointimal hyperplasia is not a mechanical function of the anatomy, but rather a biological wound healing response to arterial injury caused by PCI. Neointimal hyperplasia involves smooth muscle cell (SMC) proliferation, migration, and production of extracellular matrix. 4
The introduction of stents has virtually eliminated the problems of elastic recoil and negative arterial remodeling, leaving neointimal hyperplasia as the primary cause of restenosis. The introduction of drug-eluting stents (DES) adds a new dimension to patient treatment. While stents address the mechanical causes of restenosis, the addition of a drug serves to prevent the development of neointimal hyperplasia.
Current Criteria To Evaluate Restenosis With Bare Metal Stents
Today restenosis is measured in two ways:
1. Angiographically (with binary restenosis);
2. Clinically (with target lesion revascularization).
The term binary restenosis is used interchangeably with angiographic restenosis, and it is defined as a 50% or more diameter stenosis (DS) at follow up. 5 It can be measured either by visual inspection or by quantitative coronary angiography (QCA). These patients may or may not present with symptoms. The percent of binary restenosis appears to correlate directly with three specific criteria:
Lesion length;
Vessel diameter
Presence of diabetes. 6
The longer the length of the lesion or the smaller the vessel diameter that is treated, the higher the risk of restenosis. Patients with diabetes also carry an additional risk of restenosis, regardless of lesion length or vessel diameter. This makes predicting binary restenosis rates in a clinical trial fairly accurate if the average lesion length, vessel diameter and percent of diabetic patients are known.
Target Lesion Revascularization (TLR) is defined as the need for a repeat intervention (PTCA or CABG) at the site of the lesion due to the recurrence of symptoms. It is a clinical way to measure restenosis, although it can occur for reasons other than restenosis, such as disease progression or a new lesion adjacent to the original treated area.
The TLR rate will typically be approximately half that of the binary restenosis rate, meaning that binary restenosis can be asymptomatic. Often, an approximate 70% diameter vessel stenosis is needed for a patient to have ischemic symptoms. Since binary restenosis is defined as at least a 50% diameter stenosis, there are patients who have binary restenosis but do not need a repeat intervention since they are still asymptomatic. TLR continues to be one of the strongest endpoints for understanding restenosis clinically. 5,7,8
A New Method to Evaluate Restenosis: Late Loss
Patients and physicians can now expect restenosis rates as low as 2-4% with DES, compared to the previous rate of 15-30% with bare metal stents. It is now reasonable to expect that a single intervention for stenosis could also be the last intervention for that lesion. Drug-eluting stents will improve patient outcomes even for higher risk patients. 5
The ability of drug-eluting stents to inhibit neointimal hyperplasia calls for the use of a more sensitive measure of vessel patency. Late lumen loss, the angiographic representation of neointimal hyperplasia, is a precise and effective method of measurement.9 Not a new concept, late loss has been utilized for several years as a representation of the extent of neointimal hyperplasia. Clinical trials have demonstrated that late loss is independent of vessel size. 1 Calculation of ate loss allows the level of restenosis to be accounted for in all vessels, regardless of size. Unlike binary restenosis, late loss does not allow a narrowed vessel of any magnitude to go undetected.
Late loss is measured in millimeters. The equation in the QCA lab for this process is:
Minimum Lumen Diameter (MLD) Post Procedure minus (-)
MLD Follow-up = Late Loss
Currently, most bare metal stents have a late loss of about 0.8-1.0 mm at 8-9 months follow up.
So, how should one evaluate which stent will provide the best outcome for their patients? With the recent release of DES clinical data, there have been comparisons of binary restenosis rates for bare metal stents that appear to be very similar to the restenosis rates of the drug-eluting stents. How can a bare metal stent that was previously demonstrated to have a 25% restenosis rate now have a 10% restenosis rate? If one stent is evaluated with a patient population that has very few diabetics, short lesion lengths and large vessel diameters and the other stent is evaluated in a group of patients with many diabetics, long lesions and small vessel diameters, it’s easy to see how similar restenosis rates may be generated and give the appearance of equivalent effectiveness. This biological concept will hold true for any bare metal stent trial, regardless of the stent design or strut thickness.
The only true measure of equivalent performance is late loss. Late loss remains relatively constant, regardless of the vessel diameter or lesion length, and allows for a more reliable caparison of effectiveness between stents. Late loss is not only an objective way of comparing stents, but is also a more sensitive method to assess the effectiveness of drug-eluting stents in inhibiting neointimal hyperplasia.
TLR: An Important Partner to Late Loss
Measuring angiographic or binary restenosis does not provide a true picture of what is occurring within the vessel. TLR, however, remains an important tool for assessing clinical restenosis because it relates directly to patient symptoms. Taken together, measurement of late loss and TLR will provide a more accurate and complete understanding of patient outcomes. 5,8
At the end of the day, our job is patient welfare, and patients deserve not only the best technology available, but the best possible care in relation to that technology. Current methods for measuring restenosis were sufficient when our technology was limited to bare metal stents. However, with the addition of drug-eluting stents, our current standards must be updated. As cardiac cath lab professionals, it is our responsibility to hold the line when it comes to patient care and take the initiative to educate ourselves on new technologies that can impact the quality of a patient’s life.
______________________PART II___________________________
Significance of Late Loss and Target Lesion Revascularization in Interpreting Drug-Eluting Stent Clinical Trial Results
Part Two of a CME/CEU Program for Cath Lab Digest
Marco A. Costa, MD, PhD, Assistant Professor of Medicine, Director of Research and Cardiovascular Image Core Laboratories, Division of Cardiology, University of Florida, Shands Hospital, Jacksonville, Florida
The field of drug-eluting stents is rapidly evolving. The lack of a standard format to report study findings, however, limits comparisons across clinical trials. This article will review the concepts of angiographic late loss and target lesion revascularization and their value in evaluating the anti-restenotic effects of drug-eluting stents.
Angiographically detected lesions of 50% or greater diameter stenosis (DS) at follow-up have been historically considered as representing restenosis. The classical binary definition based on percentage diameter stenosis does not accurately depict the degree of deterioration of the vessel post angioplasty and does not convey a measure of the vessel response to injury. The use of the term percentage diameter stenosis itself carries with it the assumption of normal-appearing reference segments, which is known from IVUS studies to be an erroneous assumption. 2 Furthermore, the binary definition of restenosis assumes that a patient with 51%DS lesion and a patient with 49%DS have different intimal hyperplasia responses and clinical outcomes. A disparity between binary angiographic restenosis and clinical outcomes has been documented in a recent retrospective analysis of multiple stent trials. 3 In this study, only 45% of the patients with binary angiographic restenosis required repeat revascularization. Nearly half of the patients that met binary criteria for angiographic restenosis had follow-up lesions with 4 Late loss is calculated as minimal lumen diameter post-procedure (MLD) minus MLD at follow-up. Late loss represents an angiographic surrogate for neointimal proliferation because stents eliminate the elastic recoil and remodeling components of restenosis.
In the era of mechanical prevention of restenosis, there were essentially no differences in angiographic late loss between devices (average of 1.0mm late loss). 5 Angiographic outcomes were mainly determined by the immediate luminal gains, the bigger is better adage.5 This strategy has been proven ineffective to eliminate restenosis.
Recently, the anti-restenosis paradigm has undergone a tremendous shift. Anti-proliferative strategies targeting the cell cycle have finally been able to inhibit neointimal proliferation and consequently decrease angiographic late loss. 6-11 The significance of the late loss parameter for drug-eluting stent trials is remarkable, as it represents the only angiographic criteria to determine whether the agent under investigation had restraining or inhibitory effect on neointimal proliferation. In other words, late loss is a major determinant of drug-eluting stent effectiveness. In the RAVEL trial10, a zero late loss observed at 6-month angiographic follow-up was associated with the absence of repeat revascularization after implantation of sirolimus-eluting stents (Figure 2).
In clinical trials testing the effect of a given therapy on restenosis, objective angiographic criteria have been preferred. As per the above discussion, late loss represents the best angiographic determinant of device effectiveness. That being said, clinical outcomes, particularly target lesion revascularization (TLR), must be regarded as the true measure of success for anti-restenosis therapies. 12 The incidence of target lesion revascularization may closer resemble our clinical practice, in which repeat coronary angiography is not performed routinely. Target lesion revascularization (TLR) is defined as any repeat revascularization procedure (percutaneous or surgical) of the original target lesion site, which includes the stented plus edge (typically 5 mm proximal and distal to the stent) segments. Thus, TLR is perceived to be the best clinical surrogate for angiographic restenosis. TLR is typically driven by clinical evidence of ischemic symptoms or positive stress-induced ischemia test, because asymptomatic patients with non-functional angiographic stenosis experience a benign course without reintervention. 13 While other clinical endpoints, such as incidence of mortality, myocardial infraction, or any type of repeat revascularization, are essential to determine safety of a new treatment strategy and the ultimate outcome for the patient, they do not contribute much to the assessment of clinical restenosis.
Pitfalls
Any careful interpretation of restenosis studies must consider the timepoint at which the data are reported. There is approximately a 70% increase in target lesion revascularization rates between 6- and 12-month follow-up. 3 The delay between the biological process and symptomatic presentation of restenosis may explain these findings.
Furthermore, additional reductions in lumen dimensions are observed beyond the six-month follow-up window. In the SCRIPPS trial14, additional 0.37mm of late loss was observed at 3-year follow-up compared to 6 months in the radiation arm. There was a 34% increase in TLR rates during the same period. Thus comparison between clinical restenosis studies with different timepoints is inappropriate. Drug-eluting stent studies have reported angiographic and clinical data at different timepoints (4, 6, 8, 9 or 12 months) 7-11, which greatly limits any valid comparisons across current trials.
The oculo-stenotic reflex is another important factor that should be considered when interpreting the results of drug-eluting stent studies. 15 This term derives from the observation that routine angiographic follow-up leads to a higher rate of repeat revascularization, most likely because of unnecessary interventions triggered by the visual appearance of the coronary obstruction. As a result, trials with routine angiographic follow-up tend to have higher TLR rates and should not be compared with clinical follow-up studies. 3,15
Finally, quantitative coronary angiography (QCA) results are highly dependable on the site of the measurements. 16 The QCA methodology of drug-eluting stents should always include the stented and edge segments, commonly defined as the stent plus at least 5mm proximal and distal to the stent borders. Data should be reported for both in-stent and in-lesion (stent plus margins) segments. This recommendation derives from the observation of a deleterious effect of brachytherapy and some pharmacological agents on the segments adjacent to the stent borders, so-called edge effect. 17
In conclusion, both late loss and TLR are key indicators of drug-eluting stent effectiveness to prevent restenosis. However, one should take into account the QCA methodology, whether routine angiographic follow-up was performed, and the time of follow-up.
(Part One)
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(Part Two)
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