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Podcast Transcript - December 18, 2007

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Hello, and welcome to this weeks Annals of Internal Medicine Audio Summary for our December 18, 2007 issue. I’m Michael Berkwits, Deputy Editor at Annals.

We’re closing out 2007 with another amazing issue for you this week, with two feature articles: the first on treadmill testing and risk stratification in patients with suspected coronary artery disease and the second on screening for carotid artery stenosis. I’ll review all the other articles in this week’s issue, and as a special bonus for this issue, you’ll hear from Dr. Anthony Fauci, Direction of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, who gave his impressions on topics ranging from emerging infectious diseases to bioterror in a wide-ranging interview conducted two weeks ago at the Institute of Medicine.

Bur first, here’s an in-depth summary of this week’s feature articles.

Exercise Treadmill Testing To Predict Survival in Patients With Suspected Coronary Artery Disease (Time: 00:52)

Our lead article this week describes a new risk score to predict survival in patients referred for exercise treadmill testing, or ETT. The standard tool used to predict risk in patients undergoing treadmill testing is the Duke Treadmill score. The Duke score, which is commonly reported with ETT results, uses treadmill exercise time, ST segment deviation during exercise, and exercise-induced angina pectoris to predict the probability of significant and severe coronary artery disease and 5-year mortality in patients without known coronary artery disease. But since the score was first reported in Annals in 1987 we’ve learned a lot more about how to predict risk, and researchers have identified additional cardiac variables, such as heart rate recovery after exercise, that significantly influence prognosis. So there have been many recent efforts to demonstrate changes in the prognostic accuracy of the Duke Treadmill Score, hopefully improvements in accuracy, with the addition of one or more of those variables to the standard model.

This week’s lead article reports what Annals editors thought was one of the best of those efforts. Lead author Michael Lauer from the Division of Prevention and Population Science at the National Heart, Lung, and Blood Institute at the NIH in Bethesda, and his colleagues from the Cleveland Clinic and Kaiser Permanente in Colorado analyzed data from over 33,000 patients who had undergone exercise treadmill testing at the Cleveland Clinic between 1990 and 2002. None had known cardiac disease or end-stage renal disease which could influence survival, and the authors excluded patients with abnormal baseline electrocardiograms, because they wanted to minimize the probability of patients have undiagnosed left ventricular dysfunction. They collected information easily accessible from talking to a patient or from treadmill testing—most notably standard coronary risk factors, abnormal heart rate recovery after exercise, and frequent ventricular ectopy during recovery – ; they followed the patients for a median 6.2 years to see who died and who survived; and then they analyzed the ability of that information to predict death and survival in the patient group.

In this week’s article, the authors report that the collection of variables they collected, combined into a risk prediction equation and transformed into a relatively easy-to-use score for use by clinicians, did better than the Duke Treadmill Score at predicting survival. This gets a bit technical, but you can compare risk prediction tools like these by comparing how well they distinguish people who develop an outcome from those who don’t; by seeing if their predictions accurately match what actually happened to individual patients; and by seeing if one tool more accurately reclassifies patients into lower- or higher-risk groups than the other. The risk prediction score reported in this week’s article clearly did better on the first two, that is, measures of discrimination and calibration; and the authors say it did better reclassifying patients, although it’s not altogether clear that’s true from the data they present in the article. Importantly, the authors verified their findings by applying the score to 10 separate subsamples, and to a group of patients from Colorado, and its accurate predictions held up.

So the authors conclude that they have a risk prediction score that’s based on easily obtainable pretest and exercise test variables, and that can accurately predict mortality in adults with suspected coronary artery disease and normal ECGs referred for exercise treadmill testing. They suggest that the practical role of the score may be greatest in its ability to help providers identify low-risk patients who don’t need further work-up, but they acknowledge that the utility of the score used for actual clinical decisions in this way should ideally be demonstrated before it can be recommended for routine clinical use. And while the new score does reclassify patients identified by the Duke Treadmill Score as high risk into lower risk categories, the authors don’t tell us if those were accurate reclassifications. So we would want to know that, in this and other populations, before using it universally.

Still, Annals editors agreed that this seemed like substantial work that might really improve risk stratification in a population of patients that general internists see every day. Interested listeners should consult the nomogram in Figure 3 of the article to get a sense for what this tool might offer, and they should consider adding to their Clinical Tools bookmark folder on their web browser the URL for the Department of Quantitative Health Sciences at the Cleveland Clinic, where the risk prediction score is available as a web-based tool. That’s at www.bio.ri.ccf.org/html/riskcal.html.

Subscribers to Annals can receive CME credits by answering 2 quiz questions about this article. Just go to cme.annals.org and click My CME to register, or sign in.

[For Annals of Internal Medicine, I’m Michael Berkwits]

Screening for Carotid Artery Stenosis (Time: 06:00)

Our other featured article this week is an update of the US Preventive Services Task Force Recommendations on Screening for Carotid Artery Stenosis. In 1996, the USPSTF concluded that there was insufficient evidence to recommend for or against screening asymptomatic people for carotid artery stenosis. But several large studies of carotid enarterectomy have been published since then.

The Task Force structured its evidence review around 4 key questions.

First, they asked if there was direct evidence that screening adults with duplex ultrasound for asymptomatic CAS reduced fatal or nonfatal stroke, and they found no evidence to asnwer the question.

Second, they asked how accurate and reliable duplex ultrasound is for detecting clinically important carotid artery stenosis. They found good evidence that the test has only moderate sensitivity and specificity for detecting stenoses of 60 to 90%, and leads to many false-positive results, and they found weak evidence that the test’s reliability is questionable, because measurement properties used among ultrasound labs widely varied to a clinically significant degree.

Third, they asked if there was evidence that endarterectomy reduced morbidity and mortality in people with asymptomatic stenoses of 60% to 90%, and they found good evidence, mainly from the ACAS and ACST trials, that the procedure reduces stroke and death by about 5%, but note that these findings are limited to selected patients and experienced surgeons, and that the benefits among asymptomatic people in the general population would be far less, and no greater than small.

Fourth, they asked if screening and treatment causes harm in people with asymptomatic stenoses of 60% to 90%, and they good-to-fair quality evidence that screening with angiography causes strokes; that endarterectomy leads to perioperative stroke and death of 3% in the very best medical centers, so that harms would very likely be greater elsewhere; and so any screening that leads to endarterectomy, especially in people with asymptomatic stenosis < 60%, would cause harm.

So altogether, this evidence review leads to a Grade D recommendation not to screen for carotid artery stenosis. As a reminder, Grade D means there is moderate or high certainty that screening has no benefits or harms that outweigh the benefits. However, in comments that appear incidentally throughout the evidence review and recommendation statement, the authors acknowledge that there are screening tests, such as magnetic resonance angiography, and treatments, such as carotid artery stenting, which have not been systematically studied. So the evidence base might yet shift in coming years to lead the Task Force to revisit their review and recommendation.

Subscribers to Annals can receive CME credits by answering 2 quiz questions about this article. Just go to cme.annals.org and click My CME to register, or sign in.

[For Annals of Internal Medicine, I’m Michael Berkwits]

Other Articles In This Week’s Issue (Time: 09:04)

Other articles in this week’s issue include a description of characteristics of patients with infective endocarditis caused by non-HACEK gram-negative bacilli, reporting that the infections were rare—<2% of all cases of endocarditis – but that when they did occur, they tended to be nosocomial, associated with implanted intravascular devices, and associated with high in-hospital mortality.

We have a Brief Communication reporting observations from a phase 2 trial of rituximab for HIV-associated multicentric Castleman’s disease, suggesting that the drug led to symptomatic remission and radiological responses in most of the 21 studied patients

We have a meta-analysis of the use of vitamin D therapy for patients with chronic kidney disease, suggesting that while vitamin D compounds may improve some biochemical indices, demonstration of its effects on clinical endpoints is inconsistent across a large number of very small and heterogeneous trials; the paper ends with a call from the authors to the nephrology community to address these gaps in the evidence given how commonly vitamin D is used, a call echoed by Marcello Tonelli of the University of Alberta in Endmonton, Alberta, Canada in an accompanying editorial;

And we have an interesting perspective from Michael DeVita and Art Caplan entitled “Caring for Organs or Caring For Patients?”, reviewing the unintended consequences of the Uniform Anatomical Gift Act, a law enacted by 18 states and under consideration in another 12, which mandates that end-of-life care must be managed in a way that promotes organ donation. The unintended consequences, the authors say, is that the law prioritizes organ donation over palliative care or other end-of-life wishes; it doesn’t recognize the people might want both, and it legislates the countermanding of physician orders by organ procurement coordinators. In this week’s piece, the authors review how this contradiction has affected patients; and they highlight the way forward.

Excerpts From An Institute of Medicine Interview with Dr. Anthony Fauci (Time: 11:09)

And finally, we have excerpts from a recent interview conducted with Dr. Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. Two weeks ago he came to the Institute of Medicine in Washington D.C. to speak about drug development and infectious diseases threats as part of the IOM’s Forum on Drug Discovery, Development, and Translation. This doesn’t have anything directly to do with our Annals issue this week, but he touches on themes we publish about frequently, and he’s a smart guy with interesting things to say. So I listened to the wide-ranging 90-minute interview and am giving you here some of what I thought were the most interesting segments. In the following segments he talks about pandemic influenza, government-industry partnerships for drug development, emerging infectious diseases, bioterror, and more.

Pandemic and Seasonal Influenza

Vaccines are really the wave of the future, particularly when you’re trying to prepare against something like pandemic flu. Remember when we did the study in pandemic flu with the H5N1, we were able to induce what would be predictive of protective immunity, but it took 90 micrograms times two, which is an absolutely preposterous amount of material that you’d never be able to make enough of that in, particularly in the plans that we have.

Well, the studies now using an adjuvant have gotten it down to something like 1.75 micrograms with the adjuvant, compared to 90 micrograms with the adjuvant. Novartis has an influenza vaccine with their MF59 adjuvant that has been give to elderly people over 65 years old who don’t make a good immune response against influenza, which has dramatically increased their immune response. They’ve given it to ten-million people in Europe. So, this whole issue of, “You’ll never be able to make enough pandemic flu vaccine” now is no longer as ominous a challenge as it was before, because, if we do use adjuvants it’s likely we could have enough vaccine for everybody in the country pretty quickly.

But, whenever you put an adjuvant that’s something more powerful than alum into a vaccine, there will be more reactogenicity. And, then someone’s going to wake up and wind up with lupus and they’re going to say it was the adjuvant. So, the companies themselves don’t want to put the adjuvants in.

But we do not treat seasonal flu as seriously as we should. For all of our capabilities, technologically and otherwise, we should have a vaccine that protects everybody – even 65, 70 year olds. We should have drugs that you could give to somebody with the flu and immediately turn off the flu. We should have a variety of preventive and other measures that we don’t have because we’ve been complacent about seasonal flu.

So then when the threat of a pandemic occurs, we’re not prepared because we don’t have a good vaccine development capability. We were still stuck on egg-based manufacture which has not only limitations for a lack of ability to surge up, but it is very, very tenuous in complications that can arise vis-à-vis contaminations or what have you. So, we’re bringing vaccinology of influenza into the 21st century. We’re shifting to cell-based. We’re doing recombinant problems. We’re addressing, finally, the possibility of a universal vaccine where you can actually give a flu vaccine that would be good, not only against a drift of an H3N2 from one year to another, but would be good against a shift to a brand-new virus. There hasn’t been the investment because of the perception, as astounding as it is to people like me and my colleagues who are infectious disease people, that this isn’t a big deal. Influenza is a big deal. It kills a half-a-million people a year globally, 36 million in the United States, 200,000 excess hospitalization and yet we don’t say we need to get a much better vaccine or we need to get better drugs.

Countries were judged by how well-prepared they were by how much Tamiflu they had in their stockpile. As if Tamiflu was a miracle drug. Tamiflu is approved because if you give it within 24 to 48 hours of symptoms, it shaves off 1.3 days of illness. Wow! So, we really need to do much better than that. And, now we are. There’s a lot of investment both in our vaccine production capacity as well as in the development of new drugs.

So at the end of the day, if we don’t get a pandemic in the next few years, and we continue on the road of vaccinating more and more people in keeping the influenza vaccine industry alive and well, when the next pandemic occurs you won’t have to start from such a low baseline. You’ll be able to, essentially, transition over into pandemic mode relatively easily.

The Status of Attempts to Develop An HIV Vaccine

We don’t have any guarantee that we’re going to get a vaccine for HIV because the body does not seem to make an immune response that can eliminate the virus because, once the virus takes hold and integrates itself into your genome, it not only has the capability of mutating and changing, but it is very elusive to the immune system. The immune system cannot seem to recognize or make a neutralizing antibody very readily. So, we are still struggling to try and figure out how we can induce an immune response that might be protective. Attempts have been made and studies that we and others have sponsored to get what’s called a therapeutic vaccine. But the fundamental mechanism, what you’re asking the body to do, is if the virus itself is not stimulating an immune response that is adequate, why do you think a vaccine is going to do better than that? People who are infected have also eliminated a substantial proponent [sic] of their profile of HIV-specific CD4 positive T cells. So, it’s going to be very difficult. It’s not an impossible task. It has been tried. It has not yet been successful. But, that is what the concept is: To try and go in and vaccinate someone with a form of the virus that might be better at eliciting an immune response than the natural infection is.

One of the “tricks” in vaccinology is take a vector like a relatively harmless cold virus, like an adenovirus, and insert the genes of HIV into it so it can express proteins and then that’s a very powerful way to immunize people. It may be that the activation associated with the prior immunity to that cold virus, which is an adenovirus, activated the immune system enough to make the paradoxical effect that people who were vaccinated and who had an underlying immune response to the adeno actually had more of a chance of getting infected if they were exposed to HIV in the natural condition. You’ve got to tell people in vaccine trials that there is a possibility that the vaccine, if you expose yourself to HIV, the vaccine could have activated the immune system to make it more vulnerable so that, when a person does put themself at risk, and gets exposed to HIV that there may be a greater chance of their getting infected. That has to be in the consent forms now.

But, I can tell you even if we do get a successful vaccine that’s safe, it is unlikely that vaccine will be a free-standing preventive measure. Unlike Polio, during the Polio years, what you did is you stayed away from swimming pools or they closed swimming pools. You didn’t go to crowded places in arenas or movie theaters. That was putting yourself at risk. When the Polio vaccine came it was so good that you didn’t have to worry about any risk after that. You could swim wherever you wanted to swim; you could go to whatever movie theater you wanted to go. It’s not going to be that way even if we get an HIV vaccine. It would likely have to be part of a comprehensive school kit of preventive measures.

One other comment about prevention is that we’re faced with an interesting situation. Globally, and even nationally, where there are clear-cut proven preventive measures, but if you look around, particularly at lower-middle income countries, there’s anywhere from five to (no more than) twenty percent of the people who could benefit from those preventive measures - have access to those prevention. So, not only do we have to determine and make a preventive measure, but we’ve got to get it accessible to the people who need it, like condom distribution, and needles, and drugs, and pre-exposure and post-exposure prophylaxis.

Strategies to Encourage Antibiotic Development

We still have an issue of needing to incentivise pharmaceutical companies to get into the antibiotic development business. We have a very robust microbial-genomic project where we now are applying genomics, proteomics, and informatics to [a] variety of isolates of microbes, both resistant and sensitive, to identify not only vulnerable targets but the molecular basis of resistances, how you can circumvent resistance. We’re trying to partner more with the pharmaceutical companies to provide for them the fundamental science and the concept developments so that they will then “take the ball” and say, “Okay, I’m going to develop a drug based on your observation that this is the genetic profile of resistance to this class of microbes.” What we’re going to do is that we’re going to use this, now, as a target. No one was paying a heck of a lot of attention to MRSA, even though MRSA was creeping up and creeping up and then, all of a sudden, there comes a report out that there’s, you know, 90,000 deep infections in 2005 and 18,650 deaths, and then all of a sudden – BOOM! – MRSA’s on everybody’s radar screen. But, MRSA falls under the category where we can do the fundamental basic research but we need the pharmaceutical companies to get involved in making new drugs and a new pipeline of drugs. We can understand mechanisms of resistance and that’s what we do well, particularly at the genomic level now that we have the capability of rapidly sequencing microbes. So how much money do you put into drug resistance of microbes like, Staphylococcus aureus? Well, we’re putting more and more money in, we’re trying to cultivate the field to get people interested in it at the same time as we partner with the pharmaceutical companies.

Biodefense

The interesting thing about biodefense from a research standpoint, that I think we handled correctly, is that we made the decision, with the agreement of the administration and the Congress, to invest significant amount of resources into more generic fundamental research that would benefit our understanding of all microbes and our understanding of the immune response to microbes. So, money was put into understanding innate immunity, its relationship to adaptive immunity, a lot of money put into the sequencing project for microbes, understanding the pathogenic mechanism of microbes, the study of adjuvants, al the kinds of things that would be very appropriate for developing a biodefense counter-measure, like a better smallpox vaccine, or an anthrax vaccine, or botulism antitoxin, etc, but it would also have the secondary effect of really feeding the field of microbiology and immunology so that you cold benefit all areas including what is unquestionably a greater threat than a bioterror event is a naturally-occurring event. The chances of our having a serious epidemic or pandemic from something that naturally occurs, in my mind, is much, much greater than somebody dropping anthrax in a vent somewhere and a bunch of people getting sick. You could probably treat them, which you can, if you get them early enough compared to something like a SARS that would have gotten out of control or a pandemic influenza, or what have you. So, the investment in the biodefense we made has now positioned us to be much better prepared for a naturally emerging and re-emerging infection.

That was Dr. Anthony Fauci, Director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, in wide-ranging comments he made in an interview conducted for the Institute of Medicine’s Forum on Drug Discovery, Development, and Translation. Listeners interested in hearing more should go to the Forum’s website where the interview is posted in its entirety. It’s a long web address, so I won’t spell it out for you here, but I’ll include it in the transcript of our podcast, available on our podcast homepage at www.annals.org/podcast/.

[Dr. Anthony Fauci Interview URL: www.iom.edu/CMS/3740/24155/47596.aspx]

Well that’s it for today.

Technical support for this summary was provided by Andrew Langman, Neil Kohl, and Beth Jenkinson.

Special thanks to Kevin Stahl and all our friends at WHYY, public radio and television of Philadelphia, who helped produce these podcasts.

As the year closes out, consider making it a resolution to tell your colleagues about this podcast. We need more listeners, as well as your feedback, suggestions, comments, and criticisms about this summary and the journal. Send those as always to podcast{at}annals.org.

However you celebrate or spend your days this time of year, have a good end-of-year season.

And cancel your plans now for New Year’s Eve so you stay at home and be the first to hear the complete summary of our regularly scheduled January 1, 2008 issue, which will be released on New Year's Eve around 6 PM.

Have a great 2 weeks.

I’m Michael Berkwits, and thanks for listening.

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