Para 1 - rapamycin inhibits cell proliferation. Paclitaxel inhibits proliferaton and migration. Both are key elements of restenosis, and both are key elements of inflammation. Rapamycin is used clinically to supress the immune response - by inhibiting proliferation of T lymphocytes.
Para 2 - is all about pharmacokinetics. My point exactly: that's where the action is. Cypher has good kinetics early, but the polymer's never gone. Drug has to be there more than 90 days because the disease it's treating is done? Ya lost me.
Para 3 - BMS have been used for about 10 years. DES for about 3. They are mechanincally durable. I did not recommend rethinking the whole procedure. Others did. In fact, that's what we're in the process of right now.
Cypher work two ways: in the G1 phase, cytostatically turning off the cell as it is receiving cellular mediators to begin restonic proliferation. Turns the cell in a hibernated state. Unlike Taxol that works in the S phase of the cell cycle, terminating the cell. Cypher also works in the inflammatory response.
The drug is completely eluded after 90 days on a Cypher stent (IFU), while 90% of Taxol on Taxus stays within the polymer indefinitely (DFU). This can be a hypothesis as to way their is an increase in non-Q wave MI in overlapping Taxus stents (DFU) and not Cypher. May also provide insite as to the potential of higher late events with Taxus. Half of Cypher's drug is gone in 8 days, yet you grouped all DES in the category of long drug release mechanisms. Drug does need to be there more than 90 days, because most of the inflammation and resulting health (restonsis) stage are complete by then.
You did not comment on my statement about the length of time stents have been used and their durability, yet you recommend rethinking the hole procedure completely.
I absolutely don't agree that taxol is a terrible choice for CAD. In fact it's excellent and - at least theoretically - a better choice than sirolimus or zotarolimus
Taxol, a microtubule stabilizer, inhibits two key steps in the restenosis process. First, it inhibits smooth muscle proliferation, because microtubules have to disassemble and reassemble for a cell to divide. Both sirolimus and zotarolimus also inhibit cell proliferation, by a different mechanism.
Taxol's advantage is that it inhibits a second key step in restenosis - smooth muscle migration. In restenosis, the smooth muscle cell migrates from the middle of the artery to the inner lining - the site of injury. Migration also requires dynamic microtubules. By stabilizing microtubules, taxol limits migration.
Neither sirolimus nor zotarolimus have this property.
IMO, the problem with DES is not because of the drugs. It's because of the pharmacokinetics of the stent. They deliver drug far too long. Restenosis is an early process. If it hasn't occurred by 6 mo post-procedure, it never will. Therefore, the drug should be gone by 6 mo (and preferably much sooner). Right now it isn't, and that IMO is the problem.
Yesterday, I said the following:
I said in every instance stent placement is one alternative and it is NEVER the standard of care. That means that there is no instance where PCI with stent represents the legal standard of care, from which there is no reasonable alternative and the failure to do PCI/stent represents actionable malpractice. If anyone believes that's wrong, please come forward and explain precisely why it's wrong.
I also said that I believe that stents will eventually rule the day.
The two statements are entirely consistent.
What I did not say is that "longs will eventually rule the day." I decided not to go short, but that is not the same thing as joining your side.
Now you think the longs will rule the day? That DES is the treatment of choice. Well, welcome to our side.
This is what you said yesterday though:
Interventional cardiologists may not make money on it, but in every single instance where a stent is placed - bare metal or DES - there is an alternative, often multiple alternatives:
For symptomatic single vessel disease, there is the alternative of drug therapy
For proximal LAD disease, or for two-vessel disease, there is the alternative of drug therapy or CABG
For left main disease, the patients should go to CABG, and placing a stent is malpractice unless the patient is unable to tolerate surgery
And so it goes. In every instance, stent placement is but one alternative. It is NEVER the standard of care.
let me make clear where I'm coming from and what I'm saying.
I'm an MD and I trained in internal med at Penn. Realized I loved the science of medicine but couldn't stand patient care, so left the profession. Got an MBA because hey, going to school sucks but it beats working.
Now I make my living by providing investment advice in the pharma and med device sectors to private clients. I make mistakes all the time. My clients are well aware of it. But they are professionals too and they know everyone does. They keep coming back because they think I add value.
I've been evaluating BSX as a possible short. Pretty much reached the conclusion that that's inadvisable at this time. In other words, I think there's a good chance you longs might be right.
I have absolutely no doubt that DES will eventually rule the day and they will make substantial contributions in both cardiovascular disease and stroke. In many patients with coronary disease - but by no means all - they already have.
My concern is that this first iteration of DES is full of problems. I have no dog in the fight, just a keen interest in this very important medical field. IMO, it's time to take a very substantial step backward, assess where we're at, and decide what needs to be addressed next. I could be entirely wrong. Wouldn't be the first time. Wouldn't be the first time this week, as a matter of fact. But many outstanding cardiovascular thought leaders agree with me on this assessment.
Nope. Not a chest cracker.
But since you bring up CV surgery, you do agree that there are situations where bypass surgery is superior to percutaneous intervention with stent?
You'd agree, for example, that CABG is superior to PCI for unprotected left main disease (though I admit there's one abstract at this year's TCT meeting suggesting that PCI could yield equivalent results).
You'd also agree, I assume, that CABG is superior to PCI for proximal 3 vessel disease, especially with impaired LV function?
And what about the other direction? What about relatively mild CAD? In such situations, shouldn't the doctor recommend a trial of medical therapy before proceeding to PCI? Isn't that even more true since we don't know the long term thrombogenicity of stents, bare metal or DES?
Roberto is just another chest cracker, complaining because he went into CV surgery instead of Inventional cardiology. You can spot them a mile away. Doom and gloom. The only thing that is in peril is the number of By-pass cases because of successful Stent cases (Bare-metal or Drug-Eluding). Stent and go home tommorrow, or have my chest cracker and months of rehab!!!! Which one would you choose?
To which cardiovascular thought leaders answer:
"Drug-eluting stents are being widely used outside the confines of the rigid inclusion criteria that applied in clinical trials . . . Reports of isolated cases of subacute stent thrombosis late in patients is worrisome" Terry Ferguson, Texas Heart Institute
"The demonstration of an ongoing and pretty constant risk is the sobering component of this. . . with drug-eluting stents, we need to worry about the long term, not just the first six months after placement . . ." Chris Cannon, Harvard
You can't make this problem go away by ignoring it.
Old news? Tuesday's ARC announcement was old news? No, it wasn't.
That committee argued for a new definition of late in-stent thrombosis that completely changed the equation. Furthermore, I think the proposed new definition makes sense. If the FDA accepts it, it markedly narrows the gap in late thrombosis between DES and BMS. BMX didn't submit data to the ARC, but said the committee will be doing a separate analysis of their data in the next few weeks.
What's old news is what was discussed in Barcelona. We've moved way beyond that now. The story is in a very rapid state of flux and if you have money in BSX, JNJ, MDT, etc, you'd do well to keep up.