The Politics of Black Boxes

It's been several months since the black box warning on clopidogrel (Plavix) appeared and most cardiologists I know have not changed their practice as a result. I asked them to write about this on this blog, but because of the potential future legal ramifications of admitting as much, they politely declined.

For those unfamiliar, this black box warning, added to the drug's package insert by the FDA in March of this year, tells doctors who use this drug:

• Effectiveness of Plavix depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19.


• Poor metabolizers treated with Plavix at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function.


• Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy (and to)


• Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.

When you ask interventionalists what they think about this genetic testing to assess who might be a "poor metabolizer" you get a blank stare and many reasons why no one does it, like:

• That black box was warning based on a single non-published crossover trial on 40 subjects:

  A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metabolizer groups, evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg per day and 600 mg followed by 150 mg per day, each for a total of 5 days. Decreased active metabolite exposure and diminished inhibition of platelet aggregation were observed in the poor metabolizers as compared to the other groups. When poor metabolizers received the 600 mg/150 mg regimen, active metabolite exposure and antiplatelet response were greater than with the 300 mg/75 mg regimen. An appropriate dose regimen for this patient population has not been established in clinical outcome trials.

• Presence of a gene does not mean it is expressed clinically.


• There are no data to demonstrate that outcomes have been effected by the use of genetic testing in a large cohort of patients, only a retrospective analysis of outcomes reported in the New England Journal of Medicine.

Forty prospective patients. Non-peer-reviewed data. Retrospective studies. And a black box warning, the FDA's most severe.

We know that there is a political push by President Obama and his NIH director, Francis Collins, MD, PhD (a geneticist) to use "personalized medicine" (read: genetic tests) as a way to come up with recommendations for medical care:

"As we learn more about individual's risk – from family history to DNA testing to understanding of environmental exposures – we ought to be able to come up with recommendations that are more personalized. I think people are ready for that. I think they're hungry for that. I think they are more likely to be responsive to that, but we have a long ways to go in terms of preparing people for that kind of individualized approach to medicine."

Ironically, Dr. Collins admitted:

Today, "you can get fancy DNA tests for hundreds of dollars," Collins told The Endocrine Society meeting - but your better bet for now may be a simple family tree of health, checking what ailments Mom, Dad and Grandpa had to predict your own future. "That's a free genetic test of great power."

So we should ask ourselves why a 40-patient crossover trial and retrospective analysis of outcomes qualifies as top-notch research on which to base a black box drug warning that also supplies no dosing recommendations to doctors if such a test is positive.

It wouldn't be the money generated by genetic testing for companies (see here and here) and hospitals who stand to make a pretty penny on them, would it?

-Wes

Addendum 18 Jun 2010: They just won't quit, and admit:

"The challenge is to deliver the benefits of this work to patients. As the leaders of the National Institutes of Health (NIH) and the Food and Drug Administration (FDA), we have a shared vision of personalized medicine and the scientific and regulatory structure needed to support its growth. Together, we have been focusing on the best ways to develop new therapies and optimize prescribing by steering patients to the right drug at the right dose at the right time."

Look for more black boxes applied to more drugs with no understanding of the legal ramifications of their use. Is this the caliber of scientific rigor we are to expect from our government's reform agendas?

Addendum 29 Jun 2010 @ 14:38PM: TheHeart.org reports on the ACC and AHA's recommendations regarding the black box warning.

Plavix, Proton Pump Inhibitors, and Data Mining

This morning I was privy to a study that will be released in tandum with this blog post (I was sworn to secrecy by the PR firm that gave me a heads up about the results of the trial until 1:30 CST today). It's about another Medco pharmacy study that demonstrated inhibition of the platelet inhibitor clopidogrel (Plavix) with most of the currently-available proton pump inhibitors on the market: pantoprazole (Protonix), esomeprazole (Nexium), omeprazole (Prilosec), and lansoprazole (Prevacid). It seems they data-mined their pharmacy databases and looked for a combined endpoint (subtext: beware of data mining for "combined" endpoints - individual endpoints might not be as bad as the study suggests) compared the incidence of MI in people taking clopidogrel and proton pump inhibitors to people taking clopidogrel alone, and a higher incidence of myocardial infarction was found.

As background, here's how the study was performed (from MedCo's press release (pdf)):

The Clopidogrel Outcomes Study investigated medical and pharmacy claims data of 16,690 patients who
were taking clopidogrel following a stent procedure and tracked the study subjects (editors note: using pharmacy and medical claims data) for a 12-month period from 2005 to 2006. The study compared a group of 6,828 patients who were concurrently taking a PPI and clopidogrel to a group of 9,862 patients who were only taking clopidogrel. When PPIs were examined individually, all of the associations were highly statistically significant.

No prospective data, mind you, but the results were "highly statistically significant."

Now, is this evidenced-based medicine or correlationally-based medicine? Not that these data might not be important. But when we use medical claims data to guide medical treatment recommendations, as Medco seems to be suggesting, we tread on a potentially very slippery slope. For instance, the presence of "myocardial infarction" on a medical insurance claim may be there to assure payment for services rendered, rather than to identify a new heart attack. As such, claims data are notoriously poor at conclusively identifying clinical endpoints. Should physicians change patient's medication regimens based solely on datamining studies like this? Or would prospective randomized trials be more appropriate to make treatment recommendations? Can the claim that this interaction "increased hosptial costs by 40%" (as their press release claims) be substantiated? Or is this a means of marketing Medco's services to their clients, the largest of which might become the federal government?

It is interesting to note the rush to datamining as the United States implements rationing policies in the name of "personalized medicine." But we only have to harken back to the days of PVC suppression in my field where we thought that reducing PVC's must inherently be helpful at reducing sudden death risk. These assumptions started on the basis of correlational analysis. Only though a carefully-designed prospective, randomized trial (the CAST Trial) did we find the opposite was true: that antiarrhythmic medications designed to suppress PVC's actually increased mortality.

While general correlations are helpful to identify areas for future study, we have to be cautious not to leap to full blown treatment recommendations based on retrospective correlational studies derived from database mining alone.

-Wes

Could Potent Antacids Affect The Effectiveness of Antiplatelet Agents?

Today's Journal of the American College of Cardiology reports that omeprazole (Prilosec®), a potent antacid that works by proton pump inhibition and is commonly presribed to prevent gastrointestinal bleeding in patients administered clopidogrel (Plavix®) following coronary interventions, interacts with clopidogrel to reduce its effectiveness as an antiplatelet agent.

The clinical implications of this remain uncertain but clinicians should be aware of this possible interaction following angioplasty or stenting procedures.

-Wes

The Missing Kaplan Meier Curve

With all the buzz this week about the potential approval of prasugrel (Eli Lilly), it was interesting to note that the study published in the New England Journal of Medicine failed to have one important Kaplan Meier Curve: that of overall mortality. Certainly the benefits of the drug were shown for death from cardiovascular causes, nonfatal myocardial infarction [MI], or nonfatal stroke, but this advantage was offset by an increased risk of fatal bleeding. But when one looks at the TOTAL mortality from death by ANY cause (non-fatal MI, non-fatal stroke, or non-CABG-related nonfatal TIMI major bleeding), there were 249 deaths in the prasugrel group and 239 deaths in the clopidogrel group (p=0.43).

The authors looked for the reason why the data were so lackluster in regards to mortality, so they did a multivariate analysis and discovered "high risk" groups: age >=75, body weight <60 kg (135 lbs) or those with higher stroke. Was this study powered to differentiate these end-points in regards to mortality benefit? Of course not. So to make this point retrospectively sounds like data manipulation in the interest of corporate economics, and in the era of an FDA with hypersensitive tentacles to patient safety, the early release of this drug to the market seems suspect.

But then again, certain well-connected people think otherwise.

-Wes

Addendum 2220 CST 19 Nov 2007: The full plenary session at the AHA 2007 meeting.

CMS Could Retrict Payment for Drug-Eluting Stents

The Center of Medicare and Medicaid Services (CMS) is considering limiting reimbursement strategy for drug-eluting stents that are placed "off-label," like diabetics and those who having heart attacks. According to the Wall Street Journal this AM:

..."the Centers for Medicare & Medicaid Services, or CMS, says it is considering reopening its decision about how broadly to cover the stents. An agency spokesman said such a process, known as a National Coverage Determination, could result in restricting coverage of the stents to FDA-approved uses, keeping coverage the same, or something in between.

This could spell more bad news for Johnson and Johnson and Boston Scientific if further cuts in reimbursement for drug-eluting stents are implemented.

Almost on cue, data from a single-center observational study were published earlier this week in the American Journal of Cardiology that suggested that drug-eluting stents might be superior to bare metal stents in such "off-label" patients:

Abstract: In clinical trials of highly selected patients, drug-eluting stents (DESs) decreased restenosis but not the rate of acute myocardial infarction (AMI) or death. Whether DES use has an affect on the rate of AMI or death in unselected patients is uncertain. Bare metal stents (BMSs) were placed in 1,164 consecutive patients in the year before the introduction of DESs. DESs were subsequently placed in 1,285 consecutive comparable patients at Wake Forest Baptist Medical Center. Early and late clinical outcomes were compared. Propensity score analysis was used to adjust outcomes for baseline differences. Patient and procedural characteristics of the 2 groups were similar, with an overall incidence of 72% for acute coronary syndromes (p = NS). At 9 months, target vessel revascularization (2.8% vs 8.6%, p <0.001), AMI (3.7% vs 4.7%, p = 0.257), and death (4.9% vs 7.1%, p = 0.030) were lower in the DES group than in the BMS group. Propensity score-adjusted Cox proportional hazard ratios for DES versus BMS at 9 months were 0.71 (95% confidence interval 0.42 to 1.19) for AMI, 0.56 (95% confidence interval 0.36 to 0.87) for death, and 0.60 (95% confidence interval 0.42 to 0.86) for the combined end point of AMI or death. In conclusion, in this single-center observational study, use of DESs in consecutive unselected patients, most of whom would not have been eligible for inclusion in the randomized trials of DES versus BMS, was associated with lower AMI and death rates than in a comparable group of patients treated with BMSs in mid-term (9-month) follow-up.

This study was sponsored by Johnson and Johnson. What the effect on long-term clopidogrel therapy, recently recommended to prevent the late in-stent thrombosis of drug-eluting stents has on these "off-label" patients, especially after nine months (when in-stent thrombosis is seen), remains untested. Look for significant positioning by these companies to continue the status quo.

-Wes

References: Robert J. Applegate, Matthew T. Sacrinty, Michael A. Kutcher, Talal T. Baki, Sanjay K. Gandhi, Renato M. Santos and William C. Little, Comparison of Drug-Eluting Versus Bare Metal Stents on Later Frequency of Acute Myocardial Infarction and Death, The American Journal of Cardiology, Volume 99, Issue 3, 1 February 2007, Pages 333-338.

Keith Winstein, "Agency Reviews Stent Coverage," Wall Street Journal (Subscription), 6 February 2007, Page D4.

FDA and Stents: Bet on Aspirin and Plavix

There seems to be a lot of gnashing of teeth about what to recommend for people who have received drug-eluting stents. Should patients continue the anti-platelet (and hence, anti-clotting) drugs, aspirin and clopidogrel (Plavix) indefinitely? Or should these drugs be stopped sometime after one year?

A big, manufacturer-friendly, FDA “advisory panel” will convene on Thursday and Friday in Gaithersburg, Maryland to discuss this topic and review meta-analyses, anecdotal-isms and retrospective registries. No one will have any prospective, randomized data over many years comparing the risk of clot-formation in stents compared to the risk of bleeding from Plavix and aspirin.

It is important to remember that restenosis of bare metal (non- drug-eluting) stents due to the growth of scar-like tissue (called "neointimal hyperplasia") inside the bare stent was a real problem in patients before drug-eluting stents hit the market. Smaller diameter stents were most likely to develop this complication compared to larger diameter stents. But after drug-eluting stents burst into the market, this problem became much less prevalent. Cardiologists stopped seeing the "frequent fliers" for repeat stenting and no longer performed the more complicated brachytherapy (radiation) to prevent restenosis. Cardiologists aren't stupid: they liked this feature of drug eluting stents.

Unfortunately, over the course of time, it was eventually discovered that drug-eluting stents occassionally clot shortly after the Plavix medication was discontinued. This didn't happen all the time, mind you. It happened about 5 percent of the time. But unlike restenosis of bare metal stents that occurs slowly, the clotting seen after stopping Plavix in a drug-eluting stent is often an abrupt, sudden event leading to much larger heart muscle damage.

It became clear that taken together, Plavix and aspirin are important deterrents to the formation of blood clots in stents. But the long-term risks of life-long Plavix, especially it’s risk for developing later bleeding complications, are unknown. And Plavix is expensive. Many cannot afford the drug and Medicare doesn’t cover the drug unless individuals carry a supplemental drug benefit.

The problem now, in my view, is that there are lots and lots of drug-eluting stents in patients already out there. Stents, once deployed, can’t be removed. And we cannot abandon our patients. So the clot-preventing drugs aspirin and Plavix must be continued for at least a year, or better yet, indefinitely unless the risks of bleeding are excessive.

Also, it would not be surprising if the FDA recommended that larger-diameter stents be bare metal, since restenosis risk is lower in these larger-diameter stents. And look for the advisory panel, in the interest of "safety" to require new stents (and new competitors to the panel's companies they represent) to have to submit "more data," delaying approval of the other companies' stents.

Finally, I would not be surprised if the FDA recommends that a registry be developed to track complications (the FDA loves registries: just look at the recent defibrillator recall fiasco). This might permit a later development of data-based guidelines based on probabilities. One such decision support tool that uses retrospective data has recently been deployed in Kansas.

For the non-cardiologist, issues on how to handle non-cardiovascular surgery in patients on Plavix and aspirin still need to be better defined, but I doubt the panel can cover all of this territory in the short two days ahead.

For now, though, a lot of this will be “flying without instruments.” And the weather is still partly cloudy…

-Wes