Stent zurück
+++ Lotus-Effekt am Herzen +++
Bereits seit einigen Jahren nutzt die Technik den "Lotus-Effekt" für selbstreinigende Fensterscheiben, Dachziegel oder Kloschüsseln. Würzburger Wissenschaftler setzen diesen Effekt nun bei künstlichen Herzklappen und Gefäßstützen (Stents) ein. Entsprechend behandelte Implantate werden vom Körper besser akzeptiert.
Stents dehnen verengte oder verschlossenen Blutgefäße und halten sie offen. Ebenso wie künstliche Herzklappen liegen sie im Blutstrom. Da sie für den Körper Fremdkörper darstellen, können sie die Blutgerinnungskaskade auslösen, durch die Blutpfropfen entstehen. Ein weiteres Risiko ist, dass Blutzellen die künstlichen Klappen und Stents nach und nach zuwuchern. Forschungsarbeiten am Lehrstuhl für Funktionswerkstoffe der Medizin und Zahnheilkunde zeigten, dass entsprechend strukturierte Oberflächen dafür weniger Angriffspunkte bieten.
Der Lotus-Effekt ist nach der Wasserpflanze benannt, an der er erstmals untersucht wurde. Die Lotusblätter weisen eine fein strukturierte Oberfläche auf, an der sich Schmutz nicht dauerhaft festsetzen kann und von abperlendem Regenwasser abgewaschen wird. Die Würzburger Forscher untersuchen die Einflüsse der Oberflächentopografie und der physikalisch-chemischen Oberflächeneigenschaften auf die Reaktion mit Blut. Dabei berücksichtigen sie sowohl mit bloßem Auge erkennbare wie auch ultrakleine Strukturen.
Antihaftbeschichtung:
The New England Journal of Medicine -- December 23, 1999 -- Vol. 341, No.26
Coronary Stents -- Have They Fulfilled Their Promise?
Since the introduction of coronary stents into clinical practice in the early 1990s, the number of stent implantations has increased so rapidly that stents are currently used in 60 to 70 percent of all percutaneous interventional procedures. (1) Although stent implantation was initially limited to large vessels (greater than or equal to 3.0 mm in diameter) that had proximal, discrete lesions, improvements in stent design and technique now allow their deployment in vessels that are smaller and diffusely diseased, vessels with lesions at bifurcations, and vessels with thrombus in patients with acute myocardial infarction. This rapid growth in the use of stents has been attributed in part to the favorable results of early clinical trials, (2,3,4,5,6,7,8,9) but it also appears that interventionists and clinicians have been quick to embrace the immediate angiographic outcome of stenting -- a smoother, larger lumen -- and the potential for decreasing the risk of restenosis with seemingly little or no increased risk of complications. Since more than 500,000 coronary-stent procedures have been performed this year, it is both timely and appropriate to assess the influence of the increasing use of stents on patients' outcomes. Two studies in this issue of the Journal allow us to do so. (10,11) Although these studies differed in design, in size, in their patient populations, and in the characteristics of the stents used, their results are remarkably consistent.
In the study by Rankin and colleagues, (10) data were prospectively collected on all 9594 percutaneous coronary-revascularization procedures performed in residents of British Columbia, Canada, during a three-year period beginning in 1994. The data were linked to information from province-wide health care data bases, and the procedures were separated into sequential half-year groups. Although the overall prevalence of coexisting conditions and severity of disease remained constant, an increase in the use of stents, from 14.2 percent to 58.7 percent of all procedures, was associated with a significant decrease in the incidence of major cardiac events at one year. It is clear that this decrease was due entirely to the 30 percent reduction in target- vessel revascularization, from 24.4 percent to 17.0 percent, without significant changes in the rates of myocardial infarction or death.
Thoughtfully, the authors compared the results in consecutive patients over time rather than comparing the results between those treated with a stent and those not so treated, since the latter approach cannot distinguish a treatment effect from selection bias. Although the association between increased use of stents and improved outcomes does not necessarily prove the existence of a cause-and-effect relation, the decrease in the rate of target-vessel revascularization in the absence of a decrease in the clinical complexity of the patients' conditions suggests that the favorable results are due to the more widespread use of stents.
In the multicenter, randomized trial reported by Grines et al., (11) balloon angioplasty was compared with angioplasty combined with implantation of an intracoronary stent in patients who were undergoing mechanical reperfusion for acute myocardial infarction. Among patients who received a heparin- coated stent, the incidence of the combined primary end point of death, subsequent myocardial infarction, disabling stroke, or target-vessel revascularization because of ischemia at six months was significantly lower than in the group that received angioplasty alone. As in the study by Rankin et al., this effect was due entirely to the lower incidence of the single end point of target-vessel revascularization (17.0 percent in the angioplasty group vs. 7.7 percent in the stent group). As expected, stent implantation, as compared with angioplasty, resulted in a larger luminal diameter immediately after the procedure and a lower rate of restenosis on angiography at 6.5 months, although there was no significant difference in mortality at either 30 days or 6 months.
Both these studies support the findings of the initial trials in which the use of coronary stents resulted in increases in the immediate gain in vessel diameter and subsequent decreases in the rate of restenosis and, consequently, decreases in rates of target-vessel revascularization. In fact, both studies also extend the early observations to subgroups of patients with more complex lesions. To date, however, it is disappointing that no study has shown that stents favorably influence mortality; in fact, several trials, including the study by Grines et al., report higher rates of death and myocardial infarction among patients randomly assigned to stent implantation. (3,8,11) In all these trials, rates of death and myocardial infarction among patients who received stents were only slightly and not significantly higher than those among patients who did not, and none of the trials had sufficient power to detect a difference in mortality.
These findings are of prime importance to patients and physicians, and one can only speculate why the placement of an intracoronary stent would not result in a beneficial effect on mortality. Perhaps the lack of benefit is due to a lower incidence of grade 3 blood flow (i.e., normal flow, according to the classification of the Thrombolysis in Myocardial Infarction trial), as reported by Grines et al., (11) which may be due to the "no-reflow" phenomenon after implantation of the stent with use of a high-pressure balloon, or, alternatively, to an increased incidence of distal embolization during stent delivery. Accordingly, we should not use the results of the study by Grines et al. to fuel the ongoing debate between proponents of thrombolytic therapy and those who advocate primary angioplasty for the treatment of acute myocardial infarction, since that debate is about mortality and not about the need for repeated revascularization. Rather, since rigorously executed trials often lag behind clinical practice, we should acknowledge Grines and the other investigators of the Stent Primary Angioplasty in Myocardial Infarction Study (11) for once again having transformed a practical clinical question into a randomized trial in search of evidence to shape conventional wisdom.
Failure to show a difference in mortality between treatment groups does not necessarily mean that there is no difference. It is important to remember that the outcome of stenting has been studied in relatively small numbers of patients (a total of 3009 patients, in eight previous randomized trials (2,3,4,5,6,7,8,9)), who have been followed over comparatively short periods of time. In addition, percutaneous coronary interventions continue to be performed in patients who have predominantly single-vessel or double-vessel disease and who are at relatively low risk for death, in contrast to patients who undergo coronary bypass surgery, who have repeatedly been shown to be at higher risk at base line. (12)
Finally, the wider use of stents has been associated with improved outcomes in procedures that do not actually involve stent implantation, in part because of the security provided by the availability of stents and the knowledge that they can be used in cases of abrupt vessel closure or suboptimal results.
This relation is supported by the evidence in the present studies; Rankin et al. (10) have shown that procedures performed during more recent years had better outcomes, and Grines et al. (11) report outcomes in the angioplasty group that were more favorable than anticipated. Likewise, we can anticipate that outcomes after percutaneous coronary interventions will improve further as the use of adjunctive pharmacologic agents, such as platelet glycoprotein IIb/IIIa receptor antagonists, continues to increase. (13,14,15)
Stents will most assuredly be viewed as one of the most important advances in cardiovascular medicine in this decade. Although it has yet to be shown that they can save lives, it is likely that they will have a favorable, albeit moderate, influence on mortality. It is becoming increasingly clear that stents have fulfilled their promise to decrease the morbidity associated with angina and the need for repeated revascularization after the percutaneous coronary interventions and that they are safe to use in patients with acute myocardial infarction. Although restenosis within implanted stents and side-branch occlusion remain problems, it is likely that as technology continues to advance, the development of intravascular brachytherapy, techniques for local drug delivery, and novel stent coatings will allow these endovascular scaffolds to bridge the gap between molecular and clinical medicine.
Alice K. Jacobs, M.D.
Boston Medical Center
Boston, MA 02118
References
1. Faxon DP, Williams DO, Yeh W, Mehra A, Holubkov R, Detre K. Improved
inhospital outcome with expanded use of coronary stents: results from the
NHLBI Dynamic Registry. J Am Coll Cardiol 1999;33:Suppl A:91A. abstract.
Return to Text
2. Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of
coronary-stent placement and balloon angioplasty in the treatment of
coronary artery disease. N Engl J Med 1994;331:496-501.
Return to Text
3. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-
expandable-stent implantation with balloon angioplasty in patients with
coronary artery disease. N Engl J Med 1994;331:489-95.
Return to Text
4. Serruys PW, van Hout B, Bonnier H, et al. Randomised comparison of
implantation of heparin-coated stents with balloon angioplasty in selected
patients with coronary artery disease. Lancet 1998;352:673-81. [Erratum,
Lancet 1998;352:1478.]
Return to Text
5. Savage MP, Douglas JS Jr, Fischman DL, et al. Stent placement compared
with balloon angioplasty for obstructed coronary bypass grafts. N Engl J Med
1997;337:740-7.
Return to Text
6. Versaci F, Gaspardone A, Tomai F, Crea F, Chiariello L, Gioffre PA. A
comparison of coronary-artery stenting with angioplasty for isolated stenosis
of the proximal left anterior descending coronary artery. N Engl J Med
1997;336:817-22.
Return to Text
7. Sirnes PA, Golf S, Myreng Y, et al. Stenting in Chronic Coronary Occlusion
(SICCO): a randomized, controlled trial of adding stent implantation after
successful angioplasty. J Am Coll Cardiol 1996;28:1444-51.
Return to Text
8. Erbel R, Haude M, Hopp HW, et al. Coronary-artery stenting compared
with balloon angioplasty for restenosis after initial balloon angioplasty. N Engl
J Med 1998;339:1672-8.
Return to Text
9. Buller CE, Dzavik V, Carere RG, et al. Primary stenting versus balloon
angioplasty in occluded coronary arteries: the Total Occlusion Study of
Canada (TOSCA). Circulation 1999;100:236-42.
Return to Text
10. Rankin JM, Spinelli JJ, Carere RG, et al. Improved clinical outcome after
widespread use of coronary-artery stenting in Canada. N Engl J Med
1999;341:1957-65.
Return to Text
11. Grines CL, Cox DA, Stone GW, et al. Coronary angioplasty with or
without stent implantation for acute myocardial infarction. N Engl J Med
1999;341:1949-56.
Return to Text
12. Hannan EL, Racz MJ, McCallister BD, et al. A comparison of three-year
survival after coronary artery bypass graft surgery and percutaneous
transluminal coronary angioplasty. J Am Coll Cardiol 1999;33:63-72.
Return to Text
13. The EPISTENT Investigators. Randomised placebo-controlled and
balloon-angioplasty-controlled trial to assess safety of coronary stenting with
use of platelet glycoprotein-IIb/IIIa blockade. Lancet 1998;352:87-92.
Return to Text
14. The EPIC Investigators. Use of a monoclonal antibody directed against
the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N
Engl J Med 1994;330:956-61.
Return to Text
15. The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade
and low-dose heparin during percutaneous coronary revascularization. N
Engl J Med 1997;336:1689-96.
The New England Journal of Medicine -- December 23, 1999 -- Vol. 341, No. 26
Coronary Angioplasty with or without Stent Implantation for Acute Myocardial Infarction
Cindy L. Grines, David A. Cox, Gregg W. Stone, Eulogio Garcia, Luiz A. Mattos, Alessandro Giambartolomei, Bruce R. Brodie, Olivier Madonna, Marcel Eijgelshoven, Alexandra J. Lansky, William W. O'Neill, Marie-Claude Morice, for the Stent Primary Angioplasty in Myocardial Infarction Study Group
--------------------------------------------------------------------------------
Abstract
Background. Coronary-stent implantation is frequently performed for treatment of acute myocardial infarction. However, few studies have compared stent implantation with primary angioplasty alone.
Methods. We designed a multicenter study to compare primary angioplasty with angioplasty accompanied by implantation of a heparin-coated Palmaz- Schatz stent. Patients with acute myocardial infarction underwent emergency catheterization and angioplasty. Those with vessels suitable for stenting were randomly assigned to undergo angioplasty with stenting (452 patients) or angioplasty alone (448 patients).
Results. The mean (±SD) minimal luminal diameter was larger after stenting than after angioplasty alone (2.56±0.44 mm vs. 2.12±0.45 mm, P<0.001), although fewer patients assigned to stenting had grade 3 blood flow (according to the classification of the Thrombolysis in Myocardial Infarction trial) (89.4 percent, vs. 92.7 percent in the angioplasty group; P=0.10). After six months, fewer patients in the stent group than in the angioplasty group had angina (11.3 percent vs. 16.9 percent, P=0.02) or needed target-vessel revascularization because of ischemia (7.7 percent vs. 17.0 percent, P<0.001). In addition, the combined primary end point of death, reinfarction, disabling stroke, or target-vessel revascularization because of ischemia occurred in fewer patients in the stent group than in the angioplasty group (12.6 percent vs. 20.1 percent, P<0.01). The decrease in the combined end point was due entirely to the decreased need for target-vessel revascularization. The six-month mortality rates were 4.2 percent in the stent group and 2.7 percent in the angioplasty group (P=0.27). Angiographic follow-up at 6.5 months demonstrated a lower incidence of restenosis in the stent group than in the angioplasty group (20.3 percent vs. 33.5 percent, P<0.001).
Conclusions. In patients with acute myocardial infarction, routine implantation of a stent has clinical benefits beyond those of primary coronary angioplasty alone. (N Engl J Med 1999;341:1949-56.)
Source Information
From the Division of Cardiology, William Beaumont Hospital, Royal Oak, Mich. (C.L.G., W.W.O.); Mid Carolina Cardiology, Charlotte, N.C. (D.A.C.); Washington Hospital Center, Washington, D.C. (G.W.S., A.J.L.); Hospital Gregorio Maranon, Madrid (E.G.); Instituto Dante Pazzanese de Cardiologia, Sao Paulo, Brazil (L.A.M.); St. Joseph's Hospital, Syracuse, N.Y. (A.G.); LeBauer Health Care, Greensboro, N.C. (B.R.B.); Cordis, Johnson & Johnson, Paris (O.M.); Cardialysis, Rotterdam, the Netherlands (M.E.); and Institut Cardiovasculaire Paris Sud, Antony, France (M.-C.M.). Address reprint requests to Dr. Grines at the Cardiac Catheterization Laboratories, William Beaumont Hospital, 3601 W. Thirteen Mile Rd., Royal Oak, MI 48073-6769.
The members of the Stent Primary Angioplasty in Myocardial Infarction study group are listed in the Appendix.
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The New England Journal of Medicine -- December 23, 1999 -- Vol. 341, No. 26
Improved Clinical Outcome after Widespread Use of Coronary-Artery Stenting in Canada
James M. Rankin, John J. Spinelli, Ronald G. Carere, Donald R. Ricci, Ian M. Penn, J. David Hilton, Mark A. Henderson, Robert I. Hayden, Christopher E. Buller
--------------------------------------------------------------------------------
Abstract
Background. The introduction and refinement of coronary-artery stenting dramatically changed the practice of percutaneous coronary revascularization in the mid-1990s. We analyzed one-year follow-up data for all percutaneous coronary interventions performed in a large, unselected population in Canada to determine whether the use of coronary stenting has been associated with improved outcomes.
Methods. Prospectively collected data on all percutaneous coronary interventions performed on residents of British Columbia, Canada, between April 1994 and June 1997 were linked to province-wide health care data bases to provide the date of the following end points: subsequent target- vessel revascularization, myocardial infarction, and death. Base-line characteristics and procedural variables were identified and Kaplan-Meier survival curves were generated for 9594 procedures divided into seven groups, one for each sequential half-year period.
Results. The overall burden of coexisting illnesses remained stable throughout the study period. A large increase in the rate of coronary stenting (from 14.2 percent in the period from April to June 1994 to 58.7 percent in the period from January to June 1997) was associated with a significant reduction in the rate of adverse cardiac events at one year (from 28.8 percent to 22.8 percent; adjusted relative risk, 0.79; 95 percent confidence interval, 0.69 to 0.90; P<0.001). This reduction in adverse events was exclusively due to a large reduction in subsequent target-vessel revascularization (from 24.4 percent to 17.0 percent; adjusted relative risk, 0.72; 95 percent confidence interval, 0.62 to 0.83; P<0.001) without significant changes in the overall rates of myocardial infarction (5.4 percent, P=0.28) or death (3.9 percent, P=0.65).
Conclusions. The need for target-vessel revascularization during one year of follow-up after percutaneous coronary intervention decreased during the mid- 1990s. The reduction was coincident with the introduction and subsequent widespread use of coronary stenting. (N Engl J Med 1999;341:1957-65.)
Source Information
From Vancouver General Hospital, Vancouver (J.M.R., D.R.R., I.M.P., C.E.B.); the British Columbian Cardiac Registries, Vancouver (J.J.S.); St. Paul's Hospital, Vancouver (R.G.C.); Royal Jubilee Hospital, Victoria (J.D.H.); and Royal Columbian Hospital, New Westminster (M.A.H., R.I.H.) -- all in British Columbia, Canada. Address reprint requests to Dr. Buller at Interventional Cardiology Research, 865 W. 10th Ave., Vancouver, BC V5Z 1L7, Canada, or at chbuller@interchange.ubc.ca.
The New England Journal of Medicine -- December 3, 1998 -- Volume 339, Number 23
Coronary-Artery Stents -- Gauging, Gorging, and Gouging
( Messen , Fressen , Meisseln)
Coronary stenting is now the predominant form of nonsurgical myocardial
revascularization and accounts for well over 60 percent of the percutaneous
coronary-revascularization procedures performed in the United States. The
number of patients undergoing stenting in 1998 is estimated at 500,000, with
an average of 1.7 stents implanted per patient. (1) Since coronary stenting
was first approved for elective implantation in late 1994, the growth in use of
the procedure has been explosive. At the time of its approval, there were
important drawbacks, including bleeding complications, a prolonged hospital
stay, high cost, and a very restricted indication for patients with a new, focal
lesion involving a large native coronary artery. (2) In the span of just a few
years, the problems of bleeding complications and prolonged hospital stays
have faded into the background, but the problems of cost and appropriate
indications remain.
The results of two randomized trials designed to gauge the benefits and risks
of stenting are reported in this issue of the Journal. In both cases, the results
emphasize the progress that has been made in two directions in this field.
(3,4)
The trial reported by Erbel et al. (3) demonstrated a significant benefit of
stenting for patients in whom there was renarrowing of a coronary vessel
after balloon angioplasty. A trial of stenting for stenosis in saphenous-vein
bypass grafts (5) and a large randomized trial of stenting compared with
balloon angioplasty, which showed a 43 percent reduction in the need for
repeated procedures in a diverse patient population, (6,7) further support the
expansion of indications for stenting.
The other major advance involves the use of adjunctive drug therapy to
prevent thrombosis of stents, one of the important problems limiting their use.
As previously demonstrated by Schomig et al. in the Intracoronary Stenting
and Antithrombotic Regimen trial, (8) dual antiplatelet therapy with aspirin
and ticlopidine was superior to a regimen of aspirin, prolonged heparin, and
warfarin in patients with stents. The trial by Leon et al. (4) extends these
findings by showing the benefit of dual antiplatelet therapy as compared with
aspirin alone.
By coincidence, Erbel et al. used the outmoded anticoagulation regimen and
confirmed a 4 percent rate of subacute thrombosis, a dreaded complication
that is frequently associated with large myocardial infarctions or even death.
In the trial by Leon et al., the rate of this complication was only 0.5 percent in
the group of patients treated with aspirin and ticlopidine. Even though one of
the selection criteria in this study was a successful stent procedure, the low
rate of subacute thrombosis is a meaningful step forward.
Cognizant of the findings of the Intracoronary Stenting and Antithrombotic
Regimen trial, cardiologists had largely abandoned the prolonged use of
heparin and warfarin and adopted dual antiplatelet therapy by early 1996. In
addition, the use of high-pressure balloon inflation inside the stent,
introduced by Colombo et al., led to reduced rates of stent thrombosis (9) and
helped make stenting a practical therapeutic approach. This led to marked
reductions in length of hospitalization, bleeding complications, and cost. But
high-pressure inflation and adjunctive antiplatelet therapy cannot, by
themselves, account for the phenomenal increase in the use of coronary
revascularization -- from essentially zero to half a million procedures in 3 1/2
years (Figure 1).
The widespread use of stents by cardiologists predates the strong evidence
provided by the recent trials and probably reflects a response to angiographic
gratification -- the x-ray image of a large, smooth arterial lumen -- which a
colleague and I have called the "oculostentotic reflex." (10) Cardiologists
have mistakenly believed that stenting reduced the incidence of death and
myocardial infarction. However, careful examination of the results of
randomized trials comparing stenting with balloon angioplasty, including the
results of the trial by Erbel et al., shows an excess number of deaths and
myocardial infarctions among patients assigned to stents. (3,11,12)
Overall, however, these outcomes are infrequent, and the trials lacked the
statistical power to detect a harmful effect. This is an important point,
because death and myocardial infarction represent "hard," irrevocable end
points. In contrast, for the end point of repeated revascularization, trials
comparing balloon angioplasty with stenting by necessity involve a study
design without blinding, in which the cardiologist may forgo a repeated
procedure (a "softer" end point) because he or she knows that the patient
has already received a stent. To date, the only clinical benefit that has been
shown for stenting, as compared with balloon angioplasty, is a reduced need
for repeated target-vessel revascularization. (3,11,12,13) The excess risk of
death or myocardial infarction associated with stenting as compared with
balloon angioplasty was confirmed in a recent large trial, (6) and the excess
risk was averted with the adjunctive use of platelet glycoprotein IIb/IIIa receptor blockade.
It is disappointing to reflect on how quickly stenting was fully embraced by the
cardiology community for the wrong reasons. This is epitomized by a recent
review article on stenting in which the authors stated, "Stents clearly have a
great future -- they give excellent predictive results in angiography, are
clinically safe, and, most of all, calm the interventional cardiologist." (14)
Even with the broader, validated indications for stenting, there are still
important limitations to our knowledge. Unfortunately, in hospitals throughout
the United States today, patients with lesions in small arteries,
bifurcations, and extensive, diffuse atherosclerotic disease undergo
stenting even though there are no data to support these applications.
Furthermore, in the case of excellent results with balloon angioplasty,
there are no data to show that adding a stent to the dilated segment is
necessary or beneficial. (15)
Beyond overreaching the established indications on the part of cardiologists,
the largest concern at the moment lies in price gouging by the manufacturers
of stents. Even with the demonstrated benefit of stenting in reducing the need
for subsequent revascularization, the tradeoff, as shown in a randomized trial
in1994, is over $1,000 in excess cost per patient. (11) In the United States,
coronary stenting is a $1.5 billion industry, with an average unit price of over
$1,500 and well over 800,000 stents implanted in 1998. (1) An oligopoly of
four manufacturers controls the market, and the profit margin per stent is
estimated to be between 85 and 90 percent. (16) It is eye-opening to
compare the unit price of stents in Canada, where the same models cost
$650 (in U.S. dollars) -- 60 percent less than what patients in the United
States are charged. Competition among manufacturers led to an immediate,
substantial reduction in prices in Canada two years ago, but in the highly
profitable U.S. market, the companies scheme to maintain very high prices.
Coronary stenting is clearly one of the most important advances in
cardiovascular medicine of the past decade. Although technological
innovation should be rewarded, the profit margins do not need to be out of
line with those for all other biomedical devices. On the other hand,
interventional cardiologists have been appropriately characterized as
"medical-technology junkies who thrive on the latest and best
products." (16) Ideally, the use of these devices will be driven by
the latest and best data. Gorging on stents and price gouging appear to be
interdependent. With respect to coronary stenting in the late 1990s, we would
do well to remember what Plautus said: "In everything the middle road is the
best; all things in excess bring trouble to men."
Eric J. Topol, M.D.
Cleveland Clinic Foundation
Cleveland, OH 44195
1. Wohl V. Boston Scientific Corporation. Merrill Lynch & Company
Health-Medical Technology Report. October 6, 1998.
2. Topol EJ. Caveats about elective coronary stenting. N Engl J Med
1994;331:539-41.
3. Erbel R, Haude M, Hopp HW, et al. Coronary-artery stenting compared
with
balloon angioplasty for restenosis after initial balloon angioplasty. N Engl J
Med
1998;339:1672-8.
4. Leon MB, Baim DS, Popma JJ, et al. A clinical trial comparing three
antithrombotic-drug regimens after coronary-artery stenting. N Engl J Med
1998;339:1665-71.
5. Savage MP, Douglas JS Jr, Fischman DL, et al. Stent placement compared
with
balloon angioplasty for obstructed coronary bypass grafts. N Engl J Med
1997;337:740-7.
6. The EPISTENT Investigators. Randomised placebo-controlled and
balloon-angioplasty-controlled trial to assess safety of coronary stenting with
use
of platelet glycoprotein-IIb/IIIa blockade. Lancet 1998;352:87-92.
7. Topol EJ. Adjunctive therapy with coronary stenting: EPILOG-Stent 6
months
results. Presented at the 20th Congress of the European Society of
Cardiology
(ESC), Vienna, Austria, August 22-25, 1998. abstract.
8. Schomig A, Neumann F-J, Kastrati A, et al. A randomized comparison of
antiplatelet and anticoagulant therapy after the placement of coronary-artery
stents. N Engl J Med 1996;334:1084-9.
9. Colombo A, Hall P, Nakamura S, et al. Intracoronary stenting without
anticoagulation accomplished with intravascular ultrasound guidance.
Circulation
1995;91:1676-88.
10. Topol EJ, Nissen SE. Our preoccupation with coronary luminology: the
dissociation between clinical and angiographic findings in ischemic heart
disease.
Circulation 1995;92:2333-42.
11. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of
balloon-expandable-stent implantation with balloon angioplasty in patients
with
coronary artery disease. N Engl J Med 1994;331:489-95.
12. Serruys PW, van Hout B, Bonnier H, et al. Randomised comparison of
implantation of heparin-coated stents with balloon angioplasty in selected
patients
with coronary artery disease (Benestent II). Lancet 1998;352:673-81.
13. Fischman DL, Leon MB, Baim DS, et al. A randomized comparison of
coronary-stent placement and balloon angioplasty in the treatment of
coronary
artery disease. N Engl J Med 1994;331:496-501.
14. Goy JJ, Eeckhout E. Intracoronary stenting. Lancet 1998;351:1943-9.
15. Narins CR, Holmes DR Jr, Topol EJ. A call for provisional stenting: the
balloon is back. Circulation 1998;97:1298-305.
16. Winslow R. Missing a beat: how a breakthrough quickly broke down for
Johnson & Johnson. Wall Street Journal. September 18, 1998:1.
Coronary Stent
The History
the origin of the word "stent" :
Charles Stent (1845-1901), an English dentist who lent his name to a mold ( = Form ) with which to form an impression of the teeth and oral cavity
Alexis Carrel (Nobel prize laureate in 1912) : experiments with glass and metal tubes covered with paraffin that were introduced into canine thoracic aorta
Charles Dotter in 1964 : the concept of using an implantable prosthetic device to maintain the luminal integrity of diseased vessels (Circulation 1964;30:654-670)
Charles Dotter in 1969 : report of the nonsurgical endarterial placement of spiral springs (Invest Radiol 1969;4:329-332)
Charles Dotter in 1983 : nitinol ("memory metal") coil stent (Radiology 1983;147:259-260)
JC Palmaz in 1985 : stent mounted on a balloon (Radiology 1985;156:73- 77)
RA Schatz in 1987 : report of successful implantation of balloon- expandable stents in canine coronary arteries (Circulation 1987;76:450-457)
J Puel & U Sigwart in 1986 : the 1st stent in human coronary artery (N Engl J Med 1987; 316:701-706)
Radioaktive Drahtgitter gegen den Herzinfarkt
Bisher hatte man im Forschungszentrum Karlsruhe die Methode der Aktivierung von Metallen nur bei der Korrosionsdiagnostik von Maschinenteilen eingesetzt. Heidelberger Ärzte fanden ein originelleres Anwendungsgebiet. Sie ließen im dortigen Zyklotron ÆGefäßstützen“, sogenannte Stents, radioaktiv verändern. ÆStents“ dienen dazu, verengte Herzkranzgefäße für den Blutstrom offen zu halten, nachdem die Arterie mit Hilfe eines Ballons wiedereröffnet wurde. Der Erfolg dieser Ballondilatation ist zwar durchschlagend, doch bisher leider häufig nicht von Dauer. Bei 30 bis 50 Prozent der Patienten verengt sich das Herzkranzgefäß meist innerhalb von drei bis sechs Monaten erneut, so daß der Eingriff wiederholt werden muß. Christoph Hehrlein in der Abteilung für Kardiologie der Ludolf-Krehl-Klinik hat einen Weg gefunden, um den Wiederverschluß der Blutgefäße zu verhindern.
Herz-Kreislauf-Erkrankungen stellen die bei weitem häufigste Todesursache
in den
westlichen Industrienationen dar. In Deutschland verstarben im Jahre 1993
etwa 20 000
Menschen an einem Herzinfarkt, bedingt durch einen akuten Verschluß einer
Herzkranzarterie. Bei Patienten mit koronaren Durchblutungsstörungen
werden zwar
häufig die Beschwerden, zum Beispiel Brustschmerzen bei körperlicher
Anstrengung, durch
Medikamente gelindert, das Grundproblem, nämlich die Verengung eines
oder mehrerer
Herzkranzgefäße, aber nicht beseitigt. Als kausale Therapie kommen neben
der koronaren
Bypass-Operation zunehmend spezielle Kathetertechniken zum Einsatz, wie
die Æperkutane
transluminale Koronarangioplastie“ (PTCA) oder Ballondilatation, mit deren
Hilfe es
möglich ist, verengte Herzkranzgefäße wieder zu eröffnen. Im Jahr 1993
wurden in
Deutschland 69 804 Ballondilatationen durchgeführt. Die Zahl der
Interventionen stieg in
den vergangenen zwei Jahren weiter an. Zu den Vorteilen einer Dilatation
gehört unter
anderem, daß bei sehr hohem Primärerfolg, etwa 95 Prozent, für den Eingriff
weder eine
Vollnarkose noch eine Herz-Lungenmaschine oder eine Eröffnung des
Brustkorbes
erforderlich sind. Der Erfolg ist bisher aber oft nicht von Dauer, bei 30 bis 50
Prozent der
Patienten verengt sich das Herzkranzgefäß meist innerhalb von drei bis
sechs Monaten
erneut, so daß der Eingriff wiederholt werden muß. Auch durch die
Verwendung von
alternativen Verfahren, zum Beispiel der ÆAtherektomie“, bei der
arteriosklerotische
Plaques ausgeschnitten und anschließend entfernt werden, oder bei der
ÆRotablation“, bei
der arteriosklerotische Wandauflagerungen durch einen turbinengetriebenen
und mit
Diamanten besetzten Bohrkopf abgelöst werden, läßt sich die Zahl der
Wiederverschlüsse
nicht senken. Die Wiederverschlußrate ist auch von volkswirtschaftlicher
Relevanz: Nimmt
man die Gesamtkosten von zirka 6000 Mark für eine PTCA, so wären durch
eine
Halbierung der Wiederverschlußrate allein im Bereich des
Krankenkassenhaushalts
Einsparungen von zirka 100 Millionen Mark zu erzielen.
Für die Dilatation wird zunächst ein sehr dünner Führungsdraht durch die
verengte Stelle in
der Koronararterie geführt. Anschließend wird ein gefalteter Ballon in die
Engstelle
eingeführt und mit einem Druck bis zu 16 atm (das Achtfache des Drucks in
einem
Autoreifen) entfaltet. Es entstehen kleine Einrisse im arteriosklerotischen
Plaque und in der
nahegelegenen Gefäßwand, wodurch die Koronararterie gedehnt wird.
Außerdem wird der
Plaque in die Gefäßwand gedrückt. Beide Mechanismen tragen zur
Beseitigung der
Engstelle bei. Die Komplikationen der Ballondilatation sind neben dem
seltenen akuten
Gefäßverschluß im wesentlichen der chronische Wiederverschluß, das heißt
die Restenose
der Koronararterie. Bei einem Patientenkollektiv mit singulären Stenosen
liegt die
Restenoserate bei etwa 30 Prozent, nach der Wiedereröffnung eines
chronisch
verschlossenen Gefäßes verschließt sich dieses in etwa 50 Prozent der Fälle
ein drittes Mal
und die Behandlung eines stenosierten Venenbypasses durch die PTCA
kann sogar bei 80
Prozent der Patienten zu einem Wiederverschluß führen. Langstreckig
eingeengte und stark
verkalkte Gefäße bergen ebenfalls ein erhöhtes Risiko einer Restenosierung.
Es gibt einige
Patienten, bei denen eine PTCA mehrmals wiederholt werden muß, ehe
langfristig
Beschwerdefreiheit besteht. Die entscheidenden pathophysiologischen
Prozesse, die dem
Wiederverschluß nach Ballondilatation zu Grunde liegen, sind akute und
chronische
Rückstellmechanismen der Gefäßüberdehnung (im Englischen ÆRecoil“) und
die
Intimahyperplasie. Eingriffe am Gefäßsystem, wie die Dehnung mit einem
Ballon, führen
langfristig zur Gefäßeinengung durch Umbauvorgänge in der äußersten
Arterienschicht, der
Adventitia. Einrisse in die innerste und mittlere Arterienschicht – in Intima und
Media –
durch einen Ballonkatheter setzen als Heilungsvorgang eine Proliferation von
Zellen der
Gefäßwand in Gang. Das Ausmaß des Gefäßwandschadens und multiple
weitere Faktoren
wie die lokale Anlagerung von Thrombozyten, der Blutfluß und die
Expression von
Wachstumsfaktoren beeinflußen die Entwicklung der Intimahyperplasie.
Häufig ist die
Zellproliferation überschießend, das heißt die ungebremsten Interaktionen
zwischen
Wachstumsstimulatoren und zellulären Bestandteilen von Blut und
Gefäßwand bilden
letztlich die Grundlage für die erneute Einengung des Gefäßes.
Um Koronarstenosen zu beseitigen und das Rezidivrisiko zu senken, werden
immer
häufiger Gefäßstützen, sogenannte ÆStents“ implantiert. Der Radiologe
Charles Dotter ist
der eigentliche Begründer der Stent-Implantation. Dotter stellte bereits in
seiner 1964
veröffentlichten Arbeit ÆTransluminal treatment of arteriosclerotic obstruction“
das
Konzept vor, verengte Gefäße durch das Einbringen von Röhren zu dehnen,
um den
Blutfluß zu verbessern. Mitte der 80er Jahre gelang es Julio Palmaz, eine
röhrenförmige
Gefäßstütze aus dünnem Metall zu entwickeln, welche mittels Ballonkatheter
an die
Gefäßwand gedrückt und dadurch anmodelliert werden kann. Ein Stent
besteht aus einem
speziell gefalteten und tubulär angeordneten Draht, der sich ausdehnt und
dennoch einer
Kompression von außen mechanischen Widerstand entgegensetzt. Der
Ballon dehnt das
Gitter auf, der Innendurchmesser des Stents wird um ein Vielfaches
vergrößert. Der Einbau
des rigiden, wenig komprimierbaren Stents bewirkt, daß der
Gefäßdurchmesser auf einem
festgelegten Niveau verbleibt und die erneute Gefäßeinengung durch
Rückstellkräfte
verhindert wird. Neueste multizentrische Studien zeigen, daß die
Langzeitergebnisse bei
Patienten mit symptomatischen Koronarstenosen nach Implantation eines
Stents besser sind
als nach Dilatation alleine. Durch Verwendung von Stents konnte die
Wiederverschlußrate
nach PTCA im Mittel von 40 Prozent auf 30 Prozent gesenkt werden.
Obwohl die Restenoserate nach Stent-Implantation verglichen mit der PTCA
geringer ist,
bleibt sie auch bei der Stent-Implantation das vorrangige Problem. Die
wesentlichen
pathophysiologischen Vorgänge sind dabei die Proliferation von glatten
Muskelzellen und
die Intimahyperplasie. Es lag daher nahe, Stents zu entwickeln, die die
Zellwucherung vor
Ort verhindern, die eine lokale antiproliferative Wirkung ausüben. Seit
langem ist bekannt,
daß die Strahlentherapie das Wachstum von Tumoren hemmt.
Überschießende
Narbenbildungen nach Operationen, sogenannte Keloide, lassen sich durch
eine
niedrigdosierte Bestrahlung behandeln. Radioaktive Substanzen werden
heutzutage in der
Medizin in vielen therapeutischen Bereichen verwendet.
In einer Kooperation mit dem Forschungszentrum Karlsruhe wurden
herkömmliche Stents
im Zyklotron radioaktiv verändert. Die Aktivierung von Metallen war in
Karlsruhe bisher
nur bei der Korrosionsdiagnostik von Maschinenteilen eingesetzt worden. Die
Umwandlung von herkömmlichen Stents in radioaktive Stents beinhaltet den
Beschuß mit
einer geringen Anzahl an Protonen, die in das Metall eindringen und
Metallpartikel in
Radionuklide transformieren. Bei diesem Protonenbeschuß entstehen
mehrere
Radionuklide (Co-55, -56, -57 sowie Mn-52 und Fe-55), die hauptsächlich
Beta-Strahlung,
weiche Röntgenstrahlung sowie einen sehr geringen Teil an harter Gamma-
Strahlung
produzieren. Ziel der ersten Pilotversuche war es, Stents mit einer so
niedrigen Aktivität
herzustellen, daß sie eine kurzfristige manuelle Handhabung erlauben und
ausgedehnte
Strahlenschutzmaßnahmen überflüssig machen. Intensive
Strahlenschutzmaßnahmen
würden den Gebrauch solcher Stents zum Beispiel in einem
Herzkatheterlabor erheblich
erschweren und verteuern. Nach den ersten Dosismessungen zeigte sich,
daß mehr als 99
Prozent der emittierten Strahlung dieser radioaktiven Stents in einer Distanz
von einem
Zentimeter im Gewebe absorbiert wird, das heißt, hauptsächlich eine lokale
Wirkung von
ihnen ausgeht. Die höchsten Strahlendosen wurden in unmittelbarer Nähe
um den Stent
gemessen, und mit jedem Millimeter Entfernung fiel die Strahlendosis
drastisch ab. In der
ersten Serie von Versuchen wurden Stents verwendet, die Radionuklide mit
kurzer und
auch relativ langer Halbwertszeit (HWZ) enthielten (Fe-55, HWZ 2,7 Jahre).
In einer
zweiten Serie von Experimenten untersuchten wir radioaktive Stents, deren
Aktivität nach
drei Monaten drastisch abgefallen und nach fünf Monaten vollständig
abgeklungen war.
Derartige Stents wurden durch die Verwendung von P-32 (HWZ 14,3 Tage)
hergestellt.
Stents mit einer Aktivität im Bereich der gesetzlich festgelegten ÆFreigrenze
für radioaktive
Stoffe“ wurden sodann im Tierversuch getestet.
Die radioaktiven Stents wurden in die Beckenarterien von Kaninchen
implantiert und die
Tiere für eine, vier, zwölf und 52 Wochen beobachtet. Danach wurden die
Arterien
eingehend histologisch untersucht. Die Wucherung der glatten Muskelzellen
in der
Gefäßwand war praktisch vollständig gehemmt worden, ebenso die
Intimahyperplasie,
während die beiden Prozesse bei den herkömmlichen Stents ungehemmt
abliefen. Auch ein
Jahr nach der Implantation war die Intimahyperplasie in der Beckenarterie
des Kaninchens
noch deutlich reduziert. Das Ausmaß der Reduktion war dosisabhängig.
Stents, die
innerhalb der ersten 10 Tage eine integrierte Strahlendosis von 20 Gray in
einem Millimeter
Abstand vom Stent produzierten – 70 Prozent der Gesamtdosis über den
Zeitraum eines
Jahres –, bewirkten eine mehr als 80prozentige Reduktion der
Intimahyperplasie im
Vergleich zu den Kontrollstents, solche, die innerhalb der ersten 10 Tage
eine
Gesamt-Strahlendosis von 10 Gray produzierten, eine etwa 40prozentige. In
dem
Beobachtungszeitraum von bis zu einem Jahr nach der Implantation von
radioaktiven Stents
im Kaninchen waren keine systemischen Nebenwirkungen der Behandlung
erkennbar. Auch
Stents mit einer Radioaktivität von kurzer Halbwertszeit verhinderten die
Intimahyperplasie
in der Kaninchenarterie, dieser Effekt ließ sich allerdings nur durch die
Verwendung etwas
höherer Strahlendosen erzielen. Die elektronenmikroskopische
Untersuchung zeigte, daß
die Gefäßzellen in der Nachbarschaft von radioaktiven Stents ultrastrukturell
keine Schäden
aufweisen. Das ÆEinwachsen“ eines solchen Stents in die Gefäßwand findet
wie beim
herkömmlichen Stent statt, allerdings zeitlich etwas verzögert. Ein
wesentlicher Parameter
für den uneingeschränkten Heilungsprozeß ist die Auskleidung der Stents mit
Endothel, das
heißt, die Neubildung einer Endothelzellschicht. Die zeitliche Verzögerung
der
Endothelialisierung verglichen mit den herkömmlichen Stents betrug je nach
Radioaktivität
in unseren Studien ein bis drei Wochen. Bei den geringen Strahlendosen, die
diese Stents
produzieren, sind bösartige Entartungen nicht zu erwarten. Mehr als 500 000
Patienten mit
Tumorleiden haben in den letzten 30 Jahren eine Bestrahlung des Brustkorbs
erhalten und
keine einzige maligne Entartung der Koronararterien entstand. Erste
klinische Studien mit
niederenergetischen radioaktiven Stents werden in Kürze begonnen.
Autoren: Dr. Christoph Hehrlein, Prof. Dr. Wolfgang Kübler, Medizinische
Universitätsklinik und Poliklinik, Abteilung Innere Medizin III, Kardiologie,
Bergheimer
Str. 58, 69115 Heidelberg, Telefon (06221) 56 88 71
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Created: 28.11.96 Updated: 28.11.96
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