The Centre For Women’s Reproductive Care Harvey Ward MB ChB, BSc(Med), FCOG (SA), MMed (O&G), FRANZCOG Obstetrician & Gynaecologist WHEN YOUR DOCTOR PRESCRIBES CLOMID You have been advised to take Clomid (Clomiphene by thickening mucus in the cervix and impairing citrate) also sold as Serophene. This is a mild sperm penetration. Recent studies suggest a fertility drug,
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Iags 1998_jan99_linnemeier.qxdCoronary Stenting Challenges: Technique,Design and Pharmacology Coronary artery stenting has changed the face of of early coronary stenting was subacute stent thrombosis interventional cardiology. In the USA what started as a and bleeding complications. Subacute stent thrombosis niche device in the form of the Gianturco-Roubin® s t e n t rates were reported to be 15.8% by Sigwart with the (Cook, Inc., Bloomington, Indiana) for acute and threat- M e d i n v e n t® stent in 1987,4 16% with the Palmaz-Schatz ened closure in the late 1980s evolved into an approved stent by Schatz in 1989,5 7.6% with the Gianturco- anti-restenosis device in the form of the Palmaz-Schatz® Roubin stent by Roubin in 1992,6 and 10% with the stent (Cordis, Miami Lakes, Florida) which was W i k t o r® stent by de Jaegere in 1992.7 An editorial in approved by the FDA in August 1994. Early reports 1989 by Serruys criticized these complications and from STRESS1 and BENESTENT2 proved beyond a questioned “…are we the sorcerer’s apprentice?…”8 shadow of a doubt that better initial minimum lumen Early stent techniques usually consisted of pre- diameters (MLD), achieved with the Palmaz-Schatz dilatation with a balloon catheter followed by low stent, correlated with less restenosis 6 months later com- pressure stent implantation with the stent delivery bal- pared to balloon angioplasty, in accordance with the the- loon only. A great contribution to stent technique was ories of Kuntz and Baim.3 BENESTENT quoted a made by Colombo and his colleagues from Milan, 13.5% rate of bleeding complications and a 3.5% rate of I t a l y .9 Prior intracoronary ultrasound (ICUS) data subacute stent thrombosis. Bleeding complications of showed that over 80% of Palmaz-Schatz coronary 7.3% and subacute stent thrombosis rates of 3.4% in stents were underdeployed. Colombo theorized that STRESS did not hamper the explosive growth of coro- stent thrombosis may be secondary to incomplete stent nary stenting. Interventionalists were reluctantly content apposition rather than the inherent thrombogenicity or to accept these complications in order to achieve the the stent, and that if adequate stent expansion was long-term benefit of reduced restenosis. Restenosis rates achieved the systemic anticoagulation with coumadin and complications have improved since these early stent may not be necessary. Colombo concluded that if high experiences, and in order for these to be further reduced pressure (> 16 atm) non-compliant balloon dilatations or eliminated, efforts must continue in three directions: were used post-Palmaz-Schatz stent implantation that 1) better stent technique; 2) refined stent design; and 3) patients could safely be released on a combination of improved pharmacologic regimens and agents.
ASA + ticlopidine with a subacute stent thrombosis Stent technique. If the Achilles’ heel of early coro-
rate of 0.8%. He also concluded that stent use could be nary angioplasty was restenosis, then the Achilles’ heel expanded to achieve the benefit of reduced restenosis.
Stone et al. studied the Palmaz-Schatz stent using From Northside Cardiology, Indianapolis, Indiana.
serial ICUS measurements post-stent delivery at 12, 15 Presented at the Fifth Biennial International Andreas Gruentzig and 18 atm pressure to determine the ideal pressure at Society Meeting, Punta del Este, Uruguay.
Address reprint requests to: Thomas J. Linnemeier, MD, FACC, which the Palmaz-Schatz stent was deployed in the Northside Cardiology, 8333 Naab Road, Suite 200, Indianapolis, IN OSTI (Optimal Stent Implantation) trial.1 0 This labor intensive study, which included both core lab QCA cluded that the geometry of the corrugated ring stent (quantitative coronary angiography) and core lab alone compared to the slotted tube stent design was ICUS, provided several interesting conclusions. First, responsible for the reduction in injury, thrombosis, and the adequacy of stent deployment was more accurately neointimal hyperplasia in this animal study.
assessed by ICUS than by QCA. Secondly, incremen- Goy et al. reported in 1995 that the slotted tube tal increases in pressure resulted in progressive stent had a lower restenosis rate than a coil design increases in stent dimension. Finally, even for opera- stent.13 In a porcine model in 1997 Carter reported that tors with extensive stenting experience, the angio- stent design does indeed matter.14 A multicellular geo- graphic difference between optimal and sub-optimal metric matrix stent design reported less neointimal stent deployment were so subtle that angiography hyperplasia and less restenosis at a mean follow-up of alone could not replace ICUS in guiding Palmaz- 56 days compared to a slotted tube stent design.
The ASCENT randomized human clinical trial Further insight into stent technique was gained by reported in 1997 by Baim et al. showed that the Multi- Baim et al. with the Multi-Link® stent (Guidant, Santa Link (corrugated ring design) stent had a lower 30-day Clara, California).1 1 The IVUS Multi-Link trial studied major adverse clinical event (MACE) rate, a lower rate 49 patients with a protocol similar to OSTI, where seri- of device delivery failure, a lower 30 day mortality, al ICUS was performed at 8, 12 and 16 atm of pressure and a better final percent diameter stenosis, than the post-stent deployment. The anticoagulation protocol Palmaz-Schatz (slotted tube design) coronary stent.15 was ASA + coumadin. Successful deployment wasaccomplished in all 49 patients with no instances of Stent pharmacology. Equally important to coronary
subacute stent thrombosis or other major complications.
stent technique and coronary stent design are the phar- Stent expansion to 16 atm led to significant increases in macological agents and pharmacological regimens used intrastent dimension by both QCA and ICUS.
in conjunction with coronary stenting. The studies quot-ing high incidences of subacute stent thrombosis and Stent design. Stent technique should not be a surro-
bleeding complications of the Medinvent®, Palmaz- gate for good stent design. Four basic coronary stent Schatz, Gianturco-Roubin, and Wiktor (Medtronic, designs are in clinical use today. The coil stent is com- Inc., Minneapolis, Minnesota) stents were in the era of posed of a single strand of wire, which though flexible intense anti-coagulation regimens.4 – 7 Most early studies has a tendency to recoil. The slotted tube stent is cut with coronary stenting required anticoagulation with from a continuous metal tube and provides radial ASA, dipyridamole, low molecular weight dextran, strength though is less flexible. The mesh stent is self heparin and coumadin. The focus of attention was the expanding and is available in large sizes, but by design inherent thrombogenicity of the stent and on anticoagu- shortens significantly. The ring design stent consists of lant regimens rather than antiplatelet regimens. These repeating modules of short coils and provides excellent anticoagulant concerns likewise overshadowed the inher- flexibility with modest radial strength.
ent flow characteristics,i . e . the rheology of the vessel.
An elegant animal study of stent design was pub- Subsequent authors have noted that the majority of lished by Rogers and Edelman in 1995.12 The vascular the patients in Colombo’s series were on ASA + ticlopi- response to denuded rabbit iliac arteries was examined dine, and that the antiplatelet activities of ticlopidine at 14 days in slotted tube versus corrugated right stent might be an additional or even alternative explanation as designs. Virtually all factors were held constant in this to the low, 0.8% incidence of subacute stent thrombosis.
study except 1) stent geometry and 2) a proprietary Schomig randomized 517 patients after Palmaz- polymer coating. The study concluded that the corru- Schatz stent implantation to an anticoagulation regi- gated ring design, though having exactly the same men of ASA, heparin and phenprocumon (260) or amount of metal, surface area and implantation tech- ASA and ticlopidine (257) in the ISAR (Intracoronary nique, consisted of 29% fewer strut-to-strut intersec- Stenting and Antithrombotic Regimen) trial.16 The pri- tions which translated into 1) a 42% lower vessel mary cardiac endpoint of death, MI, CABG or repeat injury score; (p < 0.0001); 2) a 38% reduction in PTCA occurred in only 1.6% in the antiplatelet therapy neointimal hyperplasia at 14 days (p < 0.0001); 3) a group vs. 6.2% in the anticoagulant group (p = 0.01). In marked reduction in monocyte adherence at 14 days (p addition, the primary non-cardiac endpoint of death < 0.001); and 4) a marked reduction of thrombosis at from non-cardiac causes, CVA, severe hemorrhage and 14 days (p < 0.01). The polymeric coating virtually peripheral vascular events occurred in 1.2% in the eliminated thrombosis in the corrugated ring stent antiplatelet therapy group vs. 12.3% in the anticoagulant design (15% vs. 0% in the non-coated vs. coated; p < group (p < 0.001). With antiplatelet therapy there was 0.04) and reduced thrombosis from 42% to 8% in the an 82% lower risk of myocardial infarction and a 78% slotted tube stent design (p < 0.01). The authors con- lower chance of repeated interventions. This study Coronary Stenting Challenges: Technique, Design and Pharmacology clearly favored altering the pharmacologic regimen over the past several years, and will serve as a plat- after Palmaz-Schatz coronary stenting from ASA + form from which to launch new studies and protocols The STARS1 7 (Stent Anticoagulation Regimen Study) trial randomized 1,650 patients after Palmaz- REFERENCES
Schatz coronary stenting to one of three groups: 1)ASA + ticlopidine; 2) ASA + coumadin; and 3) ASA 1. Fischman DL, Leon MB, Baim DS, et al. A randomized com- alone, with the primary endpoint being MACE at 30 parison of coronary-stent placement and balloon angioplasty inthe treatment of coronary artery diseas e. N Engl J Med days. These data showed the incidence of MACE to be 0.55% in the ASA + ticlopidine group, 2.6% in the ASA 2. Serruys PW, De Jaegere P, Kiemeneij F, et al. A comparison of + coumadin group and 3.5% in the ASA alone group, balloon-expandable-stent implantation with balloon angioplasty again clearly favoring the antiplatelet regimen of ASA + in patients with corona ry artery dis ease. N Engl J Med1994;331:489–495.
ticlopidine as the treatment of choice after Palmaz- 3. Kuntz RE, Safian RD, Carrozza JP, et al. The importance of acute luminal diameter in determining restenosis after coronary B a r r a g a n1 8 suggested that a post-stent antiplatelet atherectomy or stenting. Circulation 1992;86:1827–1835.
regimen of ticlopidine alone, without ASA, was ade- 4. Sigwart U, Puel J, Mirkovitch V, et al. Intravascular stents to prevent occlusion and restenosis after transluminal angioplasty.
quate to prevent subacute stent thrombosis. However, N Engl J Med 1987;316:701–706.
with data clearly supporting ASA in acute myocardial 5. Schatz R. A vie w of v asc ular s te nts. C i r c u l a t i o n infarction and other unstable anginal syndromes the 6. Roubin GS, Cannon AD, Agrawal SK, et al. Intracoronary stent- ing for acute and threatened closure complicating percutaneous The EPIC,2 0 E P I L O G ,2 1 and CAPTURE2 2 trials all support the use of abciximab (ReoPro®, Eli Lilly, Indi- anapolis, Indiana) for conventional PTCA and those 7. de Jaeger PP, Serruys PW, Bertrand M, et al. Wiktor stent subsets of patients that received stents as “bailouts.” implantation in patients with restenosis following balloon angio-plasty of a native coronary arte ry. Am J Car diol The EPILOG Stent is in the study phase at present.
Clopidogrel, a new antiplatelet agent with actions 8. Serruys PW, Beatt KJ, van der Giessen WJ. (editorial) Stenting similar to ticlopidine, allegedly without the neutrope- of coronary arteries: Are we the sorcerer’s apprentice? E u r nia side effects of ticlopidine, has just been released in 9. Colombo A, Hall P, Nakamura S, et al. Intracoronary stenting the USA, and seems worthy of further investigation in without anticoagulation accomplished with intracoronary ultra- sound guidance. Circulation 1995;91:1676–1688.
These three avenues of coronary stent investiga- 1 0 . Stone GW, Goar F, Fitzgerald P, et al. The Cardiovascular Insti- tion, technique, design and pharmacology have lead to tute, El Camino Hospital, Mountain View, CA, USA. The Opti-mal Stent Implantation Trial — Final Core Lab Angiographic and improved outcomes for patients over the past several Ultrasound Analysis. J Am Coll Cardiol 1 9 9 7 ; 2 9 : 7 8 2 – 7 8 6 .
years. As with any technology that is advancing, 11. Carrozza JP, Hermiller JB, Linnemeier TJ, et al. Quantitative inevitably new questions arise. It is clear that low coronary angiographic and intravascular ultrasound assessment pressure (i . e . < 12 atm) stent implantation may of a new non-articulated stent: Report from the advanced cardio-vascular systems Multi-Link pilot study. J Am Coll Cardiol enhance subacute stent thrombosis, but is 18 or 20 atm pressure necessary in all patients and with all stent 12. Rogers C, Edelman E. Endovascular stent design dictates exper- designs? Does high pressure enhance edge dissec- tions? Is ticlopidine with ASA more important than 13. Goy JJ, Beckhout B, Stauffer JC, Vogt P. Stenting of the right pressure? Can stent outcomes be further improved coronary artery for de novo stenosis. A comparison of Wiktor with IIb/IIIa platelet inhibitors? Will oral IIb/IIIa and the Palmaz-Schatz stents. Circulation 1995;92:2258A.
platelet inhibitors be more effective in preventing sub- 14. Carter AJ, Scott D, Bailey LR, et al. Stent design: In the “ends” acute stent thrombosis than the established regimen of it matters. J Am Coll Cardiol 1997;29:2259A.
1 5 . Baim DS, Cutlip DE, Midel M, et al. Acute 30-day and late ASA + ticlopidine? Will clopidogrel be as useful as clinical events in the randomized and the Palmaz-Schatz stent.
ticlopidine in coronary stenting and does it reduce the Circulation 1 9 9 7 ; 9 6 : 3 3 0 9 A .
incidence of neutropenia? Finally, will further refine- 16. Schomig A, Neumann FJ, Kastrati A, et al. A randomized com- ment in stent design and polymeric coatings make stent parison of antiplatelet and anticoagulant therapy after the place-ment technique and adjunctive pharmacologic agents less important? As gamma and beta irradiation studies 17. Leon MB, Baim DS, Gordon P, et al. Clinical and angiographic progress, will intro- and post-procedural pharmacolog- results from the stent anticoagulation regimen study (STARS).
ical regimens and technique need to be altered? This Circulation 1996;I-685,4002A.
1 8 . Barragan P, Sainsous J, Silvestri M, et al. Coronary artery stenting triad of improving coronary stent technique, refining without anticoagulation, aspirin, ultrasound guidance or high stent design and improving pharmacologic agents pressure. Study of 1051 consecutive patients. Cathet Cardiovasc and regimens has improved coronary stent outcomes 1 9 . Linnemeier TJ. Stenting without ASA (editorial)? C a t h e t is lesion characteristics. If the lesion is hard you need Cardiovasc Diagn 1 9 9 7 ; 4 2 : 3 7 4 – 3 7 5 .
high pressure. If the lesion is soft a medium pressure is 20. Topol EJ, Califf RM, Weisman HF, et al. Randomized trial of sufficient most of the time. We must recognize that an coronary intervention with antibody against platelet IIb/IIIa inte-grin for reduction of clinical restenosis: Results at six months.
optimal result reduces restenosis, but is far from being the most important determinant of restenosis. Again, 21. Simoons ML, et al. The CAPTURE Investigators. Randomized lesion selection and some patients’ characteristics are placebo-controlled trial of abciximab before and during coro- frequently more important. The best approach is to nary intervention in refractory unstable angina: The CAPTUREstudy. Lancet 1997;349:1429–1435.
select the right patient and take the right lesion. We allknow this approach is not possible. A lot of improve-ments have occurred in stent design in the last years.
These improvements translated more to facilitate stent PANEL DISCUSSION
deliverability rather than reducing restenosis. Animportant new addition to our stent gallery is the cov- ANTONIO COLOMBO: Many factors that control ered stent. This is certainly an important device with a restenosis are related to lesion selection and they can field of application in saphenous vein grafts and in the only be modified by picking a different lesion. Throm- treatment of some emergencies like vessel rupture.
bosis is more easily controlled, and this problem can Concerning IVUS, I believe that there are no doubts be controlled most of the time with a good result and a that IVUS-implanted stenting gives a better immediate proper antiplatelet therapy (ticlid and aspirin). I agree result compared to angiographic-guided stenting. The that clopidogrel has a better tolerance profile compared true impact of this approach on restenosis and, more important, on clinical restenosis still needs to be deter- Concerning the appropriate pressure for balloon mined. We should not, however, forget that the MUSIC inflation, I think we have to look at this parameter in Trial reported an 8% angiographic restenosis rate which the context of balloon size and balloon to artery ratio.
is the only single digit restenosis rate so far reported.
The other element which has to come into the equation This trial had stent implantation guided by IVUS.
PALASH KUMAR SARKER Profile: Now I have been working as a Lecturer in Environmental Chemistry in Independent University, Bangladesh (IUB) from 23 January 2007 to date. Objective: My career objective is to serve as a Chemist in my beloved country after getting a higher degree from abroad and engage myself in advanced innovative research. Academic Career: Name of Univer