[india-drug] RFI: Coronary-Stent eluting drugs (2)

["Dr. Pramil Tiwari" <ptiwari@niper.ac.in>]

Nov 5, 2004
Dear group,

Further to the query of Prof Hardyal Singh on stents, I am pasting the
contents of the article provided by our Medicine Information Centre at
NIPER.

Hope it is useful to him, and the group in general.

Best wishes,
Dr. Pramil Tiwari, NIPER
--------------------------

A New Stent Revolution: Drug-Eluting Stents

New data on drug-eluting stents provide clear evidence that the second phase
of the stent revolution has arrived. Local drug delivery through the use of
drug-eluting stents allows the controlled delivery of a high concentration
of medications without excess systemic effects.

Sirolimus-eluting Stent Studies
RAVEL (Randomized Study with the Sirolimus-eluting Velocity
Balloon-Expandable Stent)
The RAVEL investigators utilized a sirolimus-eluting stent in de novo
lesions < 18 mm long, in vessels with a diameter of 2.5-3.5 mm. At 2 years,
the use of the sirolimus-eluting stent was associated with a persistent
reduction of in-stent restenosis, with a target lesion revascularization
(TLR) rate of 2.5%, and a major adverse cardiac event (MACE) rate of 10%,
both significantly lower than the rates for the bare metal stent arm. No
subacute or late thromboses or cardiac deaths occurred. RAVEL was the first
multicenter trial with 2-year follow-up to report zero late loss with very
low TLR rates. These findings may help allay concerns about the possibility
of late "catch-up" restenosis or adverse events with this new technology.

SIRIUS (SIRolImUS-Eluting Stent in De Novo Native Coronary Lesions)
In the United States, SIRIUS investigators evaluated the use of the
sirolimus-eluting stent in de novo lesions (15-30 mm) with vessel reference
diameter of 2.5-3.5 mm. At 12 months, the TLR rate remained low at 4.9%,
with an overall event-free survival of almost 92%. This patient population
represented a high-risk group, as 25% of patients had diabetes and almost
29% of patients required overlapping stents. The subacute and late
thrombosis rates remained low and were not different from those seen in the
bare metal stent group.

Late incomplete stent apposition was detected more frequently in the
sirolimus-treated group; however its occurrence has not translated into
clinical adverse events. There was no difference in aneurysmal formation
(about 1% for both bare metal and sirolimus groups). Angiographic analysis
in SIRIUS showed near complete elimination of late lumen loss within the
stent, with 49% lumen loss reduction in the proximal stent region. Residual
proximal stent restenosis may be due to balloon injury. These data suggest
that direct stenting, with the use of a single longer stent to cover the
entire lesion segment, and lower pressure deployment may reduce both
longitudinal and axial geographical miss that may be related to restenosis
outside the stented area.

Economic Analysis of SIRIUS
An economic analysis of SIRIUS showed that the use of sirolimus-eluting
stents was associated with an initial greater cost compared with the use of
a bare metal stent. However, at 1 year, this disparity was significantly
lowered and there was only a $300 difference in the total cost noted between
the 2 groups in favor of the bare metal stent group. This finding was due to
the fact that fewer resources were utilized during the ensuing year for
patients treated with a drug-eluting stent (25% reduction from bare metal
stent patients). The question of how to tackle the initial higher cost of
this new technology, however, remains unanswered. One possible
cost-effective approach may be to reduce the total number of stents used,
such as with single longer stents in individual patients.

E-SIRIUS and C-SIRIUS
E-SIRIUS in Europe and C-SIRIUS  in Canada randomized small groups of
patients to a Cypher or to a bare metal stent. Each of these studies
included patients with small-diameter vessels and longer lesions; a large
number of patients had diabetes. Both groups had a maximum stent length of
32 mm (vessel diameter range, 2.5-3.5 mm). At 9 months, the target vessel
revascularization (TVR) rate for the drug-eluting stent groups in both
studies was 4%, and the overall MACE rate ranged from 4% to 8%. These
studies demonstrated that in a more complex group of patients, the
sirolimus-eluting stent was just as effective as the earlier trials at
reducing neointimal hyperplasia as well as subsequent repeat coronary
procedures.

RESEARCH (Rapamycin Eluting Stent Evaluation at Rotterdam Cardiology
Hospital)
The "real world" experience with sirolimus-eluting stents was first
presented by the Rotterdam group. The RESEARCH study included all patients
who had been treated with sirolimus-eluting stents at the Thoraxcenter
(Rotterdam, The Netherlands) since April 2002.  Overall, 563 consecutive
patients received at least 1 sirolimus-eluting Bx VELOCITY stent. Many of
these patients had diabetes (19%), multivessel disease (55%), and
bifurcation lesions (17%). Interestingly, the mean stent length per patient
was 39 mm, considerably longer than in the original trials. The 6-month TLR
rate was very low at 1.2%, with a MACE rate of 5.7%. Subacute thrombosis
occurred in 2 patients (0.4%). A subgroup of RESEARCH included acute MI
patients (n = 66).  The procedural success rate in this group was high at
92%, and no cases of stent thrombosis were reported.  After 2.2 months of
follow-up, the sirolimus-stented group showed a trend toward reduced repeat
revascularizations.

Sirolimus-eluting Stents for the Treatment of Bifurcation Lesions
The use of sirolimus-eluting stents for bifurcation stenting has shown
impressive initial results in the RESEARCH study.  T-stenting, Y-stenting,
and kissing stents were all techniques utilized in this group of patients.
The restenosis rates were slightly higher than the rates for single lesions
(7.4% for main lesion, 14.8% for side branch), with an overall low TLR rate
of 9.8% and an adverse cardiac event rate of 12%. Another group of
investigators utilized sirolimus-eluting stents in bifurcation lesions,
which were treated with a modified T-stenting technique. This group had low
restenosis rates (8%) with very low TVR rates (4%).  These results are
encouraging and suggest that sirolimus-eluting stents will improve the
long-term outcome of these more complex lesions. Aside from the implantation
technique used in treating bifurcation lesions, drug-eluting stents will
also play an important role in minimizing restenosis in these difficult
lesions.  However, randomized studies may be necessary to define the most
optimal technique utilizing drug-eluting stents for bifurcation lesions.

Sirolimus-eluting Stents for Saphenous Vein Graft Lesions
The SECURE (Compassionate Use of Sirolimus-Eluting Stent) study represented
the first US experience using the sirolimus-eluting stent for the treatment
of saphenous vein graft lesions.  The study enrolled 19 patients, many of
whom had presented following brachytherapy failures. All lesions were
treated successfully, with no deaths and no subacute stent thromboses. Of
the 5 patients with complete angiographic 8-month follow-up, 4 had TLR. It
remains unknown whether these results may be due to the late effects of
radiation therapy. The long-term follow-up results of this group will be
presented later this year.

Sirolimus Summaries
These initial studies with the sirolimus-eluting stent suggest favorable
long-term outcomes with very low restenosis rates, even in patients with
longer lesions and diabetes. The subacute stent thrombosis rate is
comparable to that of bare metal stents when antiplatelet agents are used
for 2-3 months, with an equally low MACE rate. The total duration of
antiplatelet therapy, the adjunctive role of glycoprotein IIb/IIIa
inhibitors, and the use of these stents in more complex lesions such as
in-stent restenosis and left main lesions are ongoing questions that are
currently being addressed.

Paclitaxel
Paclitaxel has also emerged as a candidate drug to inhibit restenosis, as it
halts cell division by shifting microtubule equilibrium toward microtubule
assembly. The persistence of medial necrosis and fibrin deposition after
local delivery of paclitaxel demonstrates a possible cytotoxic effect as one
of its mechanisms of action.

TAXUS II
In TAXUS II, patients were randomized to a paclitaxel-eluting stent (slow-
or moderate-release formulation based on polymer) or a bare metal stent for
short lesions (10-12 mm) in large vessels (3.0-3.5 mm). At 12 months, the
paclitaxel group had a low rate of TLR, ranging from 3.8% to 4.7% and an
overall MACE rate of 9.9% to 10.9%. Patients were treated for 6 months with
antiplatelet therapy, and the stent thrombosis rate in the paclitaxel group
remained low at 0.75%. Despite the cytotoxic effects of paclitaxel, the
stent thrombosis rate remained low even after the antiplatelet agents were
stopped. Longer-term (beyond 1 year) follow-up data are expected to
determine the lack of late "catch up" of restenosis and will establish the
ultimate clinical benefit of this technology.

DELIVER (RX ACHIEVE Drug-Eluting Coronary Stent System In the Treatment of
Patients with De NoVo NativE CoronaRy Lesions)
In the DELIVER study, more than 1000 patients were randomized to receive a
paclitaxel-eluting stent (without a polymer) or a bare metal stent. At
6-month follow-up, no difference was observed in angiographic restenosis,
TVR, or MACE between the paclitaxel and bare metal stent groups. This group
of patients had a complex set of lesions including total occlusions,
bifurcation, and long lesions. Up to 40% of the paclitaxel may have been
lost during stent expansion. These data highlight the importance of a
polymer to ensure consistent dosing, controlled-release kinetics, and
structural integrity of the agent prior to delivery.

Other Delivery Agents
Everolimus, an immunosuppressive agent with a similar mechanism of action to
that of sirolimus, has been demonstrated to be a promising anti-restenotic
agent, as it binds to cytosolic FKBP12 and inhibits the proliferation of
smooth muscle cells and T cells. In a porcine model, stents coated with
everolimus were compared with stents coated with sirolimus. Both stents were
equivalent in terms of inhibiting neointimal hyperplasia. Complete healing
without any cytotoxicity was seen in the everolimus stent group.

In FUTURE I,  42 patients were randomized to an everolimus-eluting stent
which contained a bioadsorbable polymer or a bare metal stent. In the
everolimus-eluting stent group, binary in-stent restenosis was completely
abolished, a result similar to what was initially observed with the
sirolimus FIM (First in Man) study, and a significant reduction in late loss
and intimal hyperplasia volume by intravascular ultrasound (IVUS) was
detected at 6 months. Overall, MACE rates were similarly low in both groups.
Everolimus appears to be a safe and effective anti-restenotic drug and will
be the subject of additional trials (eg, FUTURE II).

Tacrolimus is another immunosuppressive agent that inhibits cell division at
the G1 phase. PRESENT I (PREliminary Safety Evaluation of Nanoporous
Tacrolimus eluting stents) was a safety trial that utilized 60 mcg of
tacrolimus adhered to a ceramic-coated stent.  After repeat
revascularizations occurred in 3 patients, the study was halted. IVUS
demonstrated the presence of moderate intimal hyperplasia.

In PRESENT II, a higher dose of tacrolimus (230 mcg) was adhered to the
stent surface. However, the 6-month TVR rate remained high at 28%. The
PRESENT III study is currently testing a high dose of tacrolimus placed on
the stent without a polymer.

In the EVIDENT (Endo-Vascular Investigation Determining the Safety of a New
Tacrolimus Eluting Stent Graft) trial, a PTFE-covered stent containing a
moderate dose of tacrolimus was utilized in vein graft lesions. The 6-month
TVR rate remained high at 27%, with an identical angiographic binary
restenosis rate as that seen in the control group. These trials highlight
the differential impact of specific stent designs, as well as drug dosages
and drug carrier characteristics, on clinical outcomes.

In the EASTER (Estradiol Eluting Stents for the Prevention of Restenosis in
Native Coronary Arteries) study, patients with de novo lesions were
randomized to either a bare metal stent or a 17-beta estradiol-eluting
stent. IVUS analysis demonstrated that percent intimal hyperplasia was
almost 24% (or 33 mm3 by volume), which compares favorably with the results
for bare metal stents. In this group, 1 non-Q wave MI and 1 repeat TLR
occurred.  This study shows the overall safety of the placement of
estradiol-coated stents without the need for prolonged (> 1 month)
antiplatelet therapy. Binary restenosis occurred in 2 patients (7%). These
initial results suggest that further large-scale studies should be
undertaken. Improvement in the drug-loading process will result in better
control of drug dosing and elution, which may improve the anti-restenosis
effects of estrogen.

Several novel therapies were presented at the ACC meeting as well.
Irinotecan phosphorylcholine-eluting stents placed in the aortas of
hypercholesterolemic rabbits reduced restenosis and neointimal hyperplasia.

Angiopeptin, a somatostatin analogue, was coated on a stent and used in low
and intermediate doses in a small group of humans to treat larger vessels (>
3 mm) with short lesions (< 18 mm). The binary in-stent restenosis was
relatively high at 16%, with 19% intimal hyperplasia by IVUS volumetric
analysis. The intermediate dose appeared to be more effective. Future trials
with this agent will need to be performed.

Another study evaluated the effectiveness of using a BiodivYsio containing a
matrix HI polymer coating (MBIO) without a drug compared with a bare metal
stent of the same design. The study, which included approximately 300
patients, proved to be disappointing, as the MBIO coating had a high rate of
restenosis (37%) compared with the restenosis rate observed for the standard
stent during in the SOPHOS (Study Of PHosphorylcholine coating On Stents)
trial (17%).

A new rapamycin analogue agent, A24 (ABT-578), has been placed on stents
containing a polymer and utilized in a porcine overstretch coronary model.
The percent neointimal hyperplasia (NIA) and NIA area were both
significantly reduced compared with the bare metal stent or a stent with the
polymer alone. Clinical data are not yet available.

Stents with a new coating, titanium nitride oxide (NO), were placed in a
small group of human patients, which yielded a 6-month in-stent binary
restenosis rate of 23%, and a 1-year TVR rate of 25%. This new polymer may
be utilized as a drug reservoir in the future.

Another group utilized a stent covered with PTFE coated with silicone and
sodium nitroprusside (an NO donor) in a porcine carotid overstretch model.
The carotid arteries with the drug-containing stent showed a significant
reduction in intimal thickness and restenosis, as well as a reduction in the
level of inflammation. Further studies with such compounds in humans are
warranted, as nitric oxide has many favorable influences on endothelium and
platelet function and may be used as adjunctive therapy with other
antiproliferative medications.

Carvedilol has been shown to reduce myofibroblast migration into the media
and adventitia. Carvedilol-eluting BiodivYsio stents also reduced neointimal
formation and restenosis when placed in porcine coronaries.

And finally, initial results in an ongoing study using a rat carotid
stenting model demonstrated reduced neointimal formation in animals treated
with a flavopiridol (a cyclin-dependent kinase inhibitor)-coated stent.

Conclusion
Sirolimus-eluting stents have been shown to cause dramatic reductions in
restenosis and TVR in a number of ongoing multicenter studies. Such
long-term (3 years in FIM and 2 years in RAVEL) suppression of intimal
hyperplasia with few major adverse events demonstrates superior efficacy and
safety and will likely change the way cardiologists approach coronary
disease in the near future.

Other drug-eluting stent technologies such as paclitaxel and
everolimus-eluting stents hold promise with good initial results in humans.
The outcomes of other studies utilizing taxol-eluting stents will soon
become available.The stent design, polymer configuration, drug dosage, and
technical aspects of stent delivery all affect the level of inhibition of
restenosis and inflammation and need to be investigated carefully prior to
large human trials. All efforts should be made to minimize vessel injury
outside the stented covered segment, and to avoid gaps between drug-eluting
stents, which is a common phenomenon with T-stenting technique in
bifurcation lesions. The paradigm of stenting technique may shift from
"bigger is better" to "longer is better."

Reference: http://www.medscape.com/viewprogram/2336_pnt