Robert A. Harrington, MD: Hi. This is Bob Harrington from Stanford University. I am joined here on Medscape Cardiology with my friend and colleague from Harvard Medical School and the Beth Israel Deaconess Hospital, Mike Gibson. Mike, thanks for joining me here today on Medscape Cardiology.
Charles Michael Gibson, MD: Always fun to do our end-of-the-year wrap up and look forward to next year.
Dr Harrington: Yes. Let us think about that, Mike. We are going to talk about 2015, the cardiology year in review.
Mike, I want to start with lipid therapy; move into antithrombotics; talk about heart failure and hypertension; get into valvular heart disease; discuss a whole series of what I will call sociocultural issues in medicine, which might include maintenance of certification, technology and mobile health, the recent announcement at the American Heart Association (AHA) sessions on the Google/AHA grant challenge; and then close up with some of the issues that you have been tweeting about a lot lately, dealing with drug pricing. How does that sound?
Dr Gibson: Sounds great.
FDA Doesn't Buy IMPROVE-IT/Ezetimibe
Dr Harrington: Mike, let us kick it off with lipid lowering. This week we had an interesting US Food and Drug Administration (FDA) advisory panel hearing on IMPROVE-IT,[1] which was the large trial that looked at the addition of ezetimibe to simvastatin vs simvastatin alone for low-density lipoprotein cholesterol (LDL-C) lowering. The sponsor put forward an application to expand the label of ezetimibe to include the clinical outcome data. You and I are not directly involved with the trial, but my former research group was and your former research group, the TIMI study group, was. We will be clear about that declaration. Talk to me about IMPROVE-IT and ezetimibe and how the FDA advisory committee viewed it or did not view it.
Dr Gibson: What was fascinating, Bob, was that everyone was holding their breath, waiting on the IMPROVE-IT results to inform the regulatory discussion surrounding the PCSK9 inhibitors. If IMPROVE-IT was positive, that would lend credence to the LDL-C hypothesis—namely, that achieving lower LDL-C levels yields better outcomes. Everyone was very excited to see that there was a part of that curve that kept going down. We could get LDL-C levels lower and see improved outcomes. IMPROVE-IT was right on the line where all of the other trials lie relating lower LDL-C to better outcomes. With that as a backdrop, the FDA did give a level of approval to the PCSK9 inhibitors at this point; obviously, not being widely used but being used in those patients with the most pronounced forms of hyperlipidemia.
On December 14, the FDA reviewed the IMPROVE-IT study. I watched the entire presentation, and basically the FDA said: We are not going to argue about the LDL hypothesis. We are not going to argue about the approval of other drugs, but throughout the meeting a lot of that happened. At the end of the day, the 15 members of the panel said that you reduced the endpoint from 34.7% in the simvastatin-alone group down to 32.7% in the combination group with ezetimibe. To them, that just was not a robust clinical finding over 7 years. They also raised a lot of questions about missing data. I would say that there was almost as much time talking about the missing data as there was talking about the data that were observed. This was a cautionary note for the future, for sponsors, that you must minimize missing data in your trials. Eleven percent, like that observed in IMPROVE-IT, is not going to go without notice at regulatory agencies.
We had 43 drugs approved in 2015, including female Viagra®, but here is a trial that met its primary endpoint, did in fact reduce cardiovascular events, and many of us were frustrated that the panel did not solely weigh in on the science, the trial, its integrity. They also decided how they thought the drug should be used in practice, which I think should be left to the purview of the practicing physician and perhaps the Centers for Medicare & Medicaid Services and payers. It seemed as though they thought they were charged with that mandate.
Dr Harrington: Yes. It was really an interesting discussion, and I agree with you. One of the panelists who actually voted in favor of approval said: Wait a minute. The [trialists] said what they were going to do. They set out and did it. They actually showed that they accomplished a modest reduction in clinical outcomes, which was almost exactly what they had predicted based on previous knowledge of LDL lowering. They demonstrated extensive, almost 10 years' worth of safety data, and yet they were really taken to task. It struck me, Mike, not for the first time, that there were a lot of agendas at play with some of our colleagues on the panel.
Dr Gibson: I agree. I thought it was a sad day for cardiology. We are not going to wake up one day and say, my gosh, coronary artery disease is gone. It is not going to disappear with one pharmacotherapy.
Dr Harrington: No. We are an incrementalism.
Dr Gibson: Right. We are working the edges. We are going to see modest improvements in outcomes. If people turn their noses up at modest improvements in outcomes, we are not going to see a path forward.
PCSK9 Inhibitors and Beyond
Dr Harrington: Let us talk about the PCSK9 inhibitors because they got approved on the basis of LDL-C lowering, leading to the assumption that somebody thinks that LDL-C lowering is worthwhile for patients. Certainly no one can argue against the fact that the group of patients with familial hypolipidemia, for whom the drugs are now approved, stand to benefit from LDL-C lowering. We are going to see, what, Mike, 70,000 to 80,000 worth of patients in clinical trials presented over the next couple of years?
Dr Gibson: That is correct. There was the spectre of high rates of intracranial hemorrhage (ICH) in the combination therapy group from IMPROVE-IT raised during the hearing yesterday, but that P value was .11. It was a handfuls of events. It was not statistically significant. Many people made mention of it in their assessment of the drug, but I think it was an undue concern about safety. I also want to caution people about extrapolating those non-statistically significant data forward to the PCSK9 class. As you mentioned, these are big trials. They have data and safety monitoring boards looking over the ongoing evidence all the time. Obviously, none of them have stopped the trials due to a risk for ICH. I think there was undue concern expressed about a nonsignificant finding that did not have any biologically plausible basis. We will see a lot of different ways to get PCSK9 levels down. One way is to give antibodies. That is where we are at right now with many of the drugs.
There is another drug coming along that you and I both know about very well from The Medicines Company that works through RNA inhibition. Rather than mopping up the PCSK9 that is floating around in the bloodstream due to an antibody mechanism, this drug turns down the production of PCSK9. As was presented at AHA,[2] there was a 40%-50% reduction in LDL-C at 6 months. It's behaving a little bit more like a vaccine. I think that could be very important.
Dr Harrington: It may be that an injection a couple of times a year is sufficient to keep your LDL-C down. The question will be whether that is associated with improvement in clinical outcomes and, maybe equally important, whether or not it is sustainable from a safety perspective.
Dr Gibson: Absolutely. Obviously, everyone is looking at neurocognitive deficits with formal testing. That will be a big part of the development plan. Oral drugs are also in development, but if you have an injectable drug that you give once or twice a year, that is one way to ensure compliance more effectively than giving a pill.
Dr Harrington: One of the more interesting things about the approach of the RNAi drug is that you may be able to not just give something that works but get something that works by increasing the level of adherence in that you come in quarterly or biannually for your cholesterol shot, so to speak.
NOAC Reversal Agents and Omitting Aspirin
Dr Harrington: Mike, let us now think about the antithrombotic agents, an area where you and I work a lot; there were some interesting developments in 2015. First off, the reversal agents for the oral factor Xa inhibitors and the direct thrombin inhibitors: Is this a big step forward? How do you interpret this?
Dr Gibson: Every time you turn on the TV, you see a 1-800-BAD-DRUG commercial. The reversal agents offer a seatbelt or an airbag when using these drugs. The first one out of the gate is Praxbind®, which works with dabigatran. It was studied in 90 patients and reported on in the New England Journal of Medicine[3] showing good pharmacokinetic (PK)/pharmacodynamics (PD) reversal of the drug for bleeding or surgery, great start. For the factor Xa inhibitors, of course, there is andexanet, which had its phase 3 data published in the New England Journal of Medicine[4] and presented at AHA showing reversal of PK and PD with both rivaroxaban and apixaban. Right now Stuart Connolly and I are leading a trial looking at the clinical outcomes with these drugs when people are bleeding. Even a few nonspecific strategies like prothrombin complex concentrates and recombinant factor VIIa are being used as almost a last ditch effort. There are not a lot of good data, though, for their use with factor Xa inhibitors. There are good data for their use with warfarin but not for factor Xa inhibitors. I do think this will be a step forward for the class.
Dr Harrington: We just had a discussion about the insufficient nature of a trial that is quite large with more than 5000 clinical events observed. Now we are talking about approval of agents on the basis of literally a handful of patients and an even smaller handful of clinical events, but there is such high emotion around the reversal agents that, in fact, there is some pressure to get these things on the market, is there not?
Dr Gibson: Absolutely. I think you are seeing the accelerated pathway as a result of that pressure.
Dr Harrington: Anything else you like in the antiplatelet, anticoagulant world? I continue to be impressed with something that you and I would have found almost unthinkable a decade ago. People are willing to subtract aspirin from their antithrombotic regimen. In fact, we are starting to study regularly antithrombotic regimens without aspirin as backbone therapy. You want to comment on that? You are involved in some of those trials.
Dr Gibson: Absolutely. We went through a period in the '90s and early 2000s of adding. Now we are in a period of subtracting. I am running a trial called PIONEER AF-PCI[5] where we are taking away aspirin in those people who have both atrial fibrillation (AF) and acute coronary syndrome (ACS). Keep in mind that aspirin is a pretty weak antiplatelet agent and, obviously, contributes to gastrointestinal bleeding by inhibiting the protective prostaglandins. Keep in mind the results of WOEST,[6] a trial that showed that you can cut bleeding almost in half by getting rid of aspirin and replacing it with what I call a dual-pathway approach of a thienopyridine plus a factor Xa inhibitor. There are three trials ongoing: PIONEER, REDUAL-PCI,[7] and AUGUSTUS.[8] I will be reporting the results of PIONEER next year looking at a WOEST-like strategy with rivaroxaban, an ATLAS[9]-like strategy with rivaroxaban, and traditional triple therapy in those patients with the overlapping syndromes (AF and ACS).
Even in regular, old ACS patients without AF, we are trying out this strategy in a trial called GEMINI ACS 1[10] where you pick your antiplatelet therapy and then you add either aspirin or rivaroxaban to see what is going to be most safe and effective. Dropping aspirin from dual antiplatelet therapy is being tested out in two trials, GLOBAL LEADERS[11] and TWILIGHT.[12] Those studies are comparing ticagrelor alone vs aspirin plus ticagrelor. The interventional world seems to want to take things away and stop dual antiplatelet earlier. Of course, counter to that we have trials this year like the DAPT trial[13] and PEGASUS[14] saying to continue these drugs longer. I do not think we have seen a groundswell of support for those studies. Maybe with Bobby Yeh's risk score we can figure out those people who would benefit the most from prolonged therapy.
Dr Harrington: To me, the real issue here is your last comment, which is getting towards what I will call the personalization of antithrombotic therapy. I really have believed for a long time, Mike, that certain conditions, certain patients, certain situations, make one more apt to benefit from an antiplatelet agent vs an anticoagulant and vice versa. There are other situations where an anticoagulant might offer preferential benefit. Now what we have got to do is figure out in which group of patients, in which group of conditions, and at what time. Is it in the first couple of days? The first couple of months? Can we transition people to different regimens, different doses, different strategies over time? I think the work done by Bobby Yeh and the DAPT group at trying to understand both risk for ischemia balanced against risk for bleeding are the data that we are going to need to make personalized decisions along the way.
Dr Gibson: I agree completely. Sadly, though, Bob, if someone is at a greater risk for efficacy events, they are usually at a greater risk for bleeding events. It becomes very hard to tease out those patients who have efficacy without bleeding.
Dr Harrington: That has been one of the great challenges in the field of antithrombotic therapy for the few decades I have been involved with it. We are getting more sophisticated. We are going to have better biomarkers. We are going to have better understanding of the genetic influences. We are going to be able to measure more proteins, more metabolites. My prediction is that in a couple of years, you and I will have a conversation with data to support the notion of personalization of antithrombotic therapy.
Dr Gibson: Let us not forget about ST-segment elevation myocardial infarction (STEMI) and bivalirudin, cangrelor, and all that is going on there. Obviously, you represented cangrelor at the FDA. You and I were involved in the trials. You chaired them. It's an effective drug at reducing stent thrombosis. I think it is important for everyone to remember that about 15% of patients with ACS will vomit up their thienopyridines. We do need parenteral drugs. You can reduce stent thrombosis and MI and not have a big penalty in terms of bleeding with cangrelor. It is going to be given as foundation therapy in the HORIZONS-AMI II trial, the biggest primary percutaneous coronary intervention (PCI) trial ever. That is going to be 6840 patients. Gregg Stone is chairing this. Three pharma strategies will be examined. Obviously, there is some stent thrombosis with bivalirudin, and there will be a bivalirudin 4-hour infusion arm to see if that reduces stent thrombosis. There will be a bivalirudin arm with no infusion (the way most of us are using it now). We will see if cangrelor reduces the risk for stent thrombosis in that arm. There will be a heparin arm, again given with cangrelor, and we will see if that is the best strategy for net adverse clinical events.
Dr Harrington: You are getting into personalization with that description. It is not just as you said, one drug on top of another. We are really getting into strategies of care, are we not?
Dr Gibson: It is good to see people from the other side of the Atlantic working with us on designing the trial and helping come up with the appropriate way to test out the strategy.
SPRINT Hypertension
Dr Harrington: Let us take a sprint through a few more topics.
Dr Gibson: Absolutely.
Dr Harrington: Let us start with hypertension and the SPRINT trial.[15] I consider this one of the big pieces of news of the year. What about you?
Dr Gibson: Big news. I think there was some angst about the trial results being released in the press release before all of us saw the absolute risk reductions at AHA, but it lived up to the promise of a reduction in mortality. That was real both in relative risk terms and absolute risk terms, and biggest in heart failure patients. It is not consistent with what had been seen in the past [in ACCORD],[16] but what had been studied in the past was this question in diabetic patients. These were not diabetic patients, and the answer in a much larger study was quite different. I think it changed practice.
Dr Harrington: I think it will change practice as well. Certainly, I already have begun having conversations with my patients about pushing their blood pressure control a little harder and recognizing that it's going to take multiple drugs to do it.
Dr Gibson: Multiple cheap drugs too, Bob. These are cheap drugs.
Dr Harrington: Yes. Generic drugs. You made the comment that you did not like the way that the trial was released. I agree with that, Mike. Why did they have to have a press conference telling us how good the results were and then not provide us any data for a few more months? I just do not understand that. They should have either provided us the data when they released, or they should have not said anything until they released it.
Dr Gibson: You had CNN and every other channel having physicians on saying get your blood pressure down to 120 mm Hg. Turns out that is the answer, but we did not have enough data at that time to make that recommendation.
Dr Harrington: Yes. I will venture to say if that were a pharmaceutical company who had had that press release as opposed to the federal government, the press would not have been so kind to the press release.
Dr Gibson: There would have been a lawsuit over it. Absolutely.
Bioprosthetic Valve Thrombosis and Physician Learning
Dr Harrington: We had talked a little bit about thrombosis. Let us talk about this interesting observation that has come up in the world of aortic valve replacement and the notion that on imaging studies, some of these valves might have thrombosis[17] or at least some decreased excursion of the valve associated with implantation. What do you think about that? Do you think that is something we should worry about?
Dr Gibson: It is an imaging finding. Many people in the transcatheter aortic valve replacement (TAVR) community are not that concerned about it. What I found compelling were the observational data (not randomized data) showing that anticoagulation reduced this risk. That speaks more towards causality and that this may be real. Just so the audience knows, there is a 3000-patient trial[18] planned now to look at the impact of rivaroxaban in reducing this problem in TAVR patients, if it exists.
Dr Harrington: Yes. That is the question. Is it a real clinical finding, or is it the result of sophisticated imaging?
Dr Gibson: This is a pretty big trial to go and answer a question, when we are not even sure if there is a there, there yet.
Dr Harrington: I am with you, but it has gotten people's attention. I think that we are going to have to look at this carefully. I predict a lot more information to come in 2016. Couple more topics, Mike. Maintenance of certification—certainly, you and I have been critical of the American Board of Internal Medicine (ABIM) and the whole maintenance of certification process. Our friend and colleague, Paul Teirstein, has done an incredible job of leading the charge to get physicians mobilized to speak up for ourselves on behalf of the profession and the notion of lifelong learning but not necessarily through the ABIM. Do you want to comment?
Dr Gibson: Yes. We now have 3000 MDs that are board certified through the National Board of Physicians and Surgeons. We have a growing number of hospitals that accept that board certification as the sole method of certification. ABIM did change and concede on some points. We have told them we are not going away. We are going to continue because we really do think it is time, not just for negotiation, not time for working the edges, but for a real overhaul of the way we educate and certify physicians. I think the anesthesiologists are doing a good job with this. They are doing away with the secure, high-stakes, 10-year exam and replacing it with what they call the MOCA Minute. You answer 120 questions per year by email or on a mobile app or a portal.
By design, it takes you a minute or 2 for each question. If you get it wrong, you are asked the question again later in the year to see if you have learned. I think that is going to be the future—true continuous medical education, not every 10 years cramming medical education approaches. I think the anesthesiologists are showing us the way.
Dr Harrington: None of us would disagree with the notion of lifelong learning. The question is: How do we do it? Let us get lifelong learning in tune with the tools that we have. Let us do it at the point of care. Let us do it continuously. Let us do it in a way that is consistent with how we get our education throughout the year. The way that it is being done now is really out of date and needs to change.
Techies in Biomedical Research
Dr Harrington: Social media, Google, Apple, and technology companies are getting involved with biomedical research. What is going on, Mike? We are now looking at Google, Apple, and other tech companies being major funders of biomedical research or major collaborators in biomedical research. Is this the future?
Dr Gibson: I think so. You and I have been early to embrace social media. I look at the news every morning, and I share it with my audience. We now have about 200,000 followers. I think it is a very, very fun and powerful way to learn. They are getting more and more into healthcare. Google Health did not succeed on its first go-round, but now they are trying to do something that is much more dramatic, truly delving into the biology of people at the genomics level. We will see what happens with the implantable, wearable world. I do not think we know how to digest the terabytes of information being collected daily. I have led trials for 15 years looking at implantable devices monitoring ST-segments. We will be presenting the results at the FDA meeting here coming up in the spring. We will see how the world reacts to what we are learning.
Bob, you have been very involved with Google and the Baseline study that you are working or partnering with Google on and the grant between Google and AHA. Tell us a little bit about that.
Dr Harrington: First off, colleagues here at Stanford, Euan Ashley, Mike McConnell, and Alan Yeung, launched the MyHeart Counts study with Apple to enroll people in a clinical study using the smartphone. Almost 100,000 people downloaded the app. More than half gave us consent to capture their data. In a very rapid fashion, you collect data on things like physical activity, and it is mindboggling, the potential here to really rethink how we do clinical investigation. Likewise with Google, we have a project with Stanford and Duke and our friends at Google Life Sciences to try to reclassify and rethink about the state of normal being, physiologically, and how one thinks about the progression to disease—in this case, atherosclerotic disease and cancer. There is still a lot to come.
Finally, there is this grant challenge between Google Life Sciences and the AHA each putting forward $25 million to compose a team to take on the problem of coronary heart disease. It was an exciting piece of news in 2015. It will be a bigger piece of news in 2016.
"Extortion" Drug Pricing
Dr Harrington: Let us close, Mike, with something that I have been following on your Twitter account for the last few weeks; it affects all of us as providers, as patients, and that's the drug pricing issues. We are seeing gouging of the public through some of these small startup companies that exist for no other purpose than to buy a cheap generic drug and then to increase the price 100- if not 1000-fold, for an immediate quick profit, and then they get out of the business. It is pretty distasteful.
Dr Gibson: It is. This is not pharmaceutical development. This is extortion. It is essentially saying to patients, "your wallet or your life," when you have lifesaving therapies, and they are charging people their entire life savings for the drug. That is not a way to improve public health or even ensure your company's viability. A parasite cannot kill the host. That is what is happening with some of these smaller biotech companies.
Dr Harrington: We understand the notion of certain prices that need to support innovation. That is not what we are talking about here. We are talking about greed, pure and simple. People are jacking up the price of a generic drug that has been available in some cases literally for decades. They are trying to extort a quick profit.
Dr Gibson: Yes. There was no development cost. This was simply a monopolistic practice that is extorting money from not just patients but the payers as well. People act like this is a victimless crime. I am just sticking it to the insurance companies and charging them. We all pay for it when we have to pay our insurance premiums. Of course, we want people to be incented to innovate, but that is not what we are talking about here.
Dr Harrington: We are both in favor of creativity and innovation and the investment thereof. That is not what we are talking about.
Mike, let us say to our listeners here, it has been a great year for cardiology news in 2015. A lot is coming ahead in 2016. Can I get you to do this next year as well, Mike?
Dr Gibson: Yes. 2015 was an exciting year. I think 2016 will be just as exciting.
Dr Harrington: Thanks to you, Mike, and thanks to our listeners for tuning into Medscape Cardiology and the Year in Review of 2015.
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Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
Cite this: Robert A. Harrington, Charles Michael Gibson. Cardiology 2015: The Year in Review - Medscape - Dec 21, 2015.
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