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About mzoler

Mitchel Zoler is a reporter for International Medical News Group/Global Medical News Network based in the Philadelphia area.

New Anti-Inflammatory Drugs Will End Anti-TNF Dominance

Tumor necrosis factor inhibitor drugs began to dominate treatment of inflammatory diseases like rheumatoid arthritis, psoriasis, and the inflammatory bowel diseases ulcerative colitis and Crohn’s disease a little over a decade again. Now, the time when the importance of the anti-TNFs will wane and newer drugs will take their place is clearly visible on the horizon. It hasn’t happened yet, but the era of anti-TNF dominance for treating inflammatory diseases that persisted throughout the 2000s will end in the next 5 years.

The anti-TNF era began in 1998 with the approval of etanercept (Enbrel) for rheumatoid arthritis and infliximab (Remicade) to treat Crohn’s disease. In subsequent years, the list of approved anti-TNFs expanded to include adalimumab (Humira), golimumab (Simponi), and certolizumab (Cimzia), and the approved indications grew to include many inflammatory disease of joints, the GI tract, and skin. The anti-TNFs revolutionized inflammatory disease treatment and made treatment to remission possible for many patients.

tumor necrosis factor (green, purple, black) and TNF receptors (blue)/courtesy Bassil Dahiyat; Science

But reports from just the past month show that new agents are overtaking the anti-TNFs.

In May, I reported from Digestive Disease Week on phase III trial results with vedolizumab, which was compared against placebo for patients with ulcerative colitis. One of the study investigators noted that vedolizumab beat the placebo arm for steroid-free clinical remission by 30 percentage points. “Nothing else is that good,” Dr. William Sandborn, professor of medicine and chief of gastroenterology at the University of California, San Diego, told me, and the benchmark he had in mind was the performance of the anti-TNFs in similar patients.

More recently, at the European Congress of Rheumatology earlier this month I heard a report on a head-to-head comparison of the anti-IL-6 drug tocilizumab (Actemra) and the anti-TNF adalimumab in patients with rheumatoid arthritis. After 24 weeks of monotherapy, patients on tocilizumab had nearly a fourfold higher remission rate than patients on adalimumab. Though the monotherapy trial design did not mimic the way most rheumatoid arthritis patients get treated, the new drug tocilizumab absolutely blew adalimumab out of the water in a rare head-to-head comparison among different classes of anti-inflammatory drugs.

And at the same meeting several talks highlighted another new anti-inflammatory class of agents coming soon to the U.S. market, the Janus kinase (JAK) inhibitors, such as tofacitinib, which is expected to received FDA approval later this summer. Phase III results show that tofacitinib has safety and efficacy that seems at least comparable to anti-TNF drugs, with the advantage of oral dosing.

Vedolizumab, tocilizumab, and tofacitinib are just the tip of new waves of anti-inflammatory drugs that will soon substantially alter a landscape that the anti-TNFs have mostly had to themselves for the past 14 years. For the moment, the anti-TNFs have the advantage of a longer track record for safety, but changing that is only a matter of time.

—Mitchel Zoler (on Twitter “mitchelzoler)

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H5N1 Flu Papers Published, but Moratorium Continues

The highly controversial report from Dutch flu researcher Dr. Ron Fouchier on creating a form of H5N1 avian influenza that’s airborne transmissible between mammals finally appeared this afternoon in Science magazine, after months of dickering over whether this paper would get published and what information it would include.

But, with much of the content of both Dr. Fouchier’s paper, as well as a report on a similar study by Dr. Yoshihiro Kawaoka that appeared last month in Nature, already fairly well known and widely discussed, perhaps the biggest news in today’s reports came in some of the related papers published by Science and in an update about the H5N1 research moratorium made during a press conference yesterday.

courtesy Plaskov, Wikimedia Commons

At the height of the mammalian-transmissible H5N1 debate last winter, Dr. Fouchier and Dr. Kawaoka and several other flu researchers declared a voluntary, temporary stop to any further research on the transmissibility or pathogenesis of H5N1. Speaking at a press conference on June 20 organized by Science magazine to discuss today’s package of H5N1 reports and analysis, Dr. Anthony Fauci, director of the National Institutes of Allergy and Infectious Diseases (which funded the transmissible H5N1 work), said, “The reason why you have not heard any announcement about the moratorium is that we are still struggling with the criteria for the next phases of experiments. We are working hard right now to get processes in place where we could have broad general criteria for the kinds of experiments that could be done.” A meeting is scheduled in July in New York that will bring together a worldwide group of influenza researchers and surveillance experts who will try to produce those criteria, Dr. Fauci said. The meeting “will discuss in detail the kinds of approaches we can have to try to expedite as quickly as possible the lifting of the moratorium.”

One of the new studies that accompany the Fouchier paper today is an analysis led by researchers at Cambridge University who used the findings on H5N1 mutations that contribute to mammalian transmissibility to develop a mathematical model to calculate the risk that such viruses could appear in nature. Their conclusion: Current best estimates indicate that the needed panel of mutations could evolve within a single mammalian host, making the possibility of a respiratory-drop transmissible strain of H5N1 virus occurring in nature “a potentially serious threat.” But a more quantifiable estimate of the risk—a specific number—is not yet possible, they said.

“We now know that we are living on a fault line, an active fault line,” when it comes to the potential for H5N1 to become mammalian transmissible in the real world, said Dr. Derek J. Smith, head of the Cambridge group, during yesterday’s press conference. “Now what we need to know is how likely it is.”

Another part of today’s H5N1 package dealt with steps that could be taken right now to speed up influenza vaccine production in response to a newly emerged pandemic strain, something that warrants its own blog post.

—Mitchel Zoler (on Twitter @mitchelzoler)

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Quickening Pandemic Flu Vaccine Production

If a strain of avian H5N1 influenza that readily spread from person to person were to appear in the real world, the great fear is that it would produce a deadly pandemic to dwarf what happened in 1918.

The best defense against flu pandemics are vaccines, and the most recent experience with a global flu pandemic, in 2009, highlighted the gaps that existed in getting vaccine quickly made in large amounts. Three years ago, despite the U.S. government marshaling all its infectious disease-fighting muscle, the effort wound up delivering most of the vaccine too late to matter. The pandemic peaked in October 2009, while the vaccine supply didn’t hit its stride until sometime in December.

Novartis influenza-vaccine plant in Holly Springs, N.C./courtesy Novartis

In a report published today in Science as part of its H5N1 flu package, Dr. Rino Rappuoli, head of vaccines research for Novartis, spelled out seven steps that could hasten vaccine production for a newly appearing pandemic flu. The two most novel moves involve having vaccine manufacturers prepare in advance synthetic “vaccine seed” viruses and also adopting new ways to quantify viral antigens, a process that alone took about 2 months in 2009, he said. Adopting these two technological innovations could transform the vaccine-producing process “from a mid-20th century system … into a 21st century system of instantaneous electronic information exchange followed by immediate production.”

The modernized system would mean sequencing a newly isolated pandemic virus in the field and then — instead of shipping the virus — just sending gene sequences, followed by replicating the hemagglutinin gene at a remote site, putting the new gene into a waiting scaffold vaccine virus, and launching vaccine production.

If these two changes had been in place in 2009, “the vaccine would have been available in large quantities before the peak of viral infection,” Dr. Rappuoli said in his paper.

More importantly, speaking at a June 20 press conference Dr. Anthony Fauci said that the National Institutes of Health, as well as the Centers for Disease Control and Prevention and the Food and Drug Administration, had already begun to move on this, adopting “the fundamental principles of bringing influenza vaccinology into the 21st century.” Steps already taken along the lines of what Dr. Rappuoli suggested carry the potential for “a significant change right now” in the time needed to get out a pandemic vaccine, Dr. Fauci said.

He particularly cited NIH studies underway using an immunoadjuvant to expand the coverage potential of stockpiled H5N1 vaccine, a step that would “markedly accelerate availability.

“We are right now in a much better position [to distribute pandemic vaccine quickly] than we were in 2009 when we had vaccine available only after the peak of the H1N1 pandemic,” Dr. Fauci said.

—Mitchel Zoler (on Twitter @mitchelzoler)

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The U.S. Obesity Epidemic and Surging Liver Cancer

If there is one truism that trumps everything else these days about U.S. health, it’s that America is a chubby country that keeps getting fatter.

The consequences seep into every corner of the nation’s medical state, including the surprising fact that obesity and the type 2 diabetes it causes are likely pushing up the incidence of liver cancer—hepatocellular carcinoma—to unprecedented heights.

courtesy Wikimedia Commons

When I covered Digestive Disease Week in San Diego recently, one of the biggest stories I heard was that U.S. liver-cancer rates tripled from 1975-2007, and that the numbers continued to rise from the mid to the late 2000s. (My full report on this is here).

Granted, factors other than just obesity play into the liver cancer surge, notably the sizable number of Americans infected with either hepatitis B or C virus, and the fact that as they age their risk for developing hepatocellular carcinoma rises.

But new U.S. infections by hepatitis B and C are largely under control these days (although people infected elsewhere continue to emigrate to the United States). The part of the booming liver-cancer story that is by no means under control is the obesity part.

Every time I see a new CDC map for U.S. obesity prevalence, the colors on it keep getting redder and darker (the CDC’s code for higher prevalence rates).

courtesy CDC

courtesy CDC

Earlier this year, the CDC reported a 36% obesity prevalence rate for the entire U.S. population–and still on the rise–and just a few weeks ago we heard that obesity among children and adolescents had hit a new high of 17%. With obesity seemingly on an unchanging upward trajectory, one can only wonder what rates of liver cancer it might produce in the future. Obesity carries a special relationship with the liver, and it’s not pretty. Just consider any goose headed to a foie-gras future.

Until now, the evidence linking obesity and liver cancer, and type 2 diabetes and liver cancer has been epidemiologic. Compelling, but just an association. At DDW, a new study provided more observational data on the diabetes-liver cancer link, and while still circumstantial it further supports the notion and also carries an intriguing punchline.

The study, done in Taiwan, examined 97,000 hepatocellular carcinoma patients and 195,000 matched controls. The analysis showed that people with diabetes had a two-fold increased risk for liver cancer compared with those without diabetes. Even more striking, the analysis also showed that people with diabetes treated with the oral hypoglycemic drug metformin had their risk for liver cancer cut in half compared with those not on metformin, and those with diabetes treated with a glitazone drug (such as pioglitazone–Actos) had their risk cut nearly in half.

The best solution would be if people avoided obesity and type 2 diabetes all together. Both conditions cause a lot of medical problems, and this new evidence indicates more strongly than ever before that liver cancer is one of them.

—Mitchel Zoler (on Twitter @mitchelzoler)

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Influenza Toys with the Human Race

The current U.S. influenza seasonal epidemic, the mildest in years, is in its death throes, based on infection trends over the past several weeks, including the most recent data released on May 11 by the Centers for Disease Control and Prevention.

During the week that ended on May 5, 13.7% of U.S. respiratory surveillance specimens tested positive for influenza, continuing the clear downhill slope of U.S, flu cases since this season’s U.S. epidemic peaked at 30% positive during the week of March 11-17. The CDC hasn’t yet declared the current, 2011-2012 flu-season’s epidemic, which started in late February, officially over—it can’t until the influenza-positive rate falls back below 10%–but the epidemic curve’s steep downward track (see graphic) is as well defined as the far side of L’Alpe d’Huez.

graphic courtesy of the CDC

With the current influenza epidemic nearly ended, the season’s numbers paint a decidedly benign picture. So far, 22 children have died from influenza; if that figure continues to grow as it has so far it will top out as the lowest since the CDC began collecting these data in 2004.

Other markers of how mild the 2011-2012 season has been include the number of U.S. patients hospitalized for influenza, which sits below past seasons, and the proportion of deaths attributable to pneumonia or influenza has hovered below the epidemic threshold for that measure all season.

During a winter and spring where the influenza world focused on mammalian-transmissible H5N1 flu, strains dubbed by some the “doomsday” virus, having such a mild seasonal flu season tossed at us can’t help but be seen as some ironic, natural-world prank. On a purely rationale basis, year-to-year variations in seasonal flu have nothing whatsoever to do with the looming danger from H5N1 flu, but with this infectious-disease juxtaposition I can’t help but imagine that somewhere, off in the distance, I hear a quiet, cosmic chortle.

—Mitchel Zoler (on Twitter @mitchelzoler)

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Controversy Over H5N1 Flu Continues

Just when it seemed like consensus existed on how to handle the hot potato of mammalian-transmissible H5N1 influenza, the public release on Friday afternoon of a letter sent April 12 from the respected influenza and public health researcher Dr. Michael Osterholm to a National Institutes of Health official collapsed the apparent consensus like a house of cards.

To recap: On March 29 and 30, the U.S. government’s National Science Advisory Board for Biosafety (NSABB), organized by the NIH’s Office of Science Policy, met to reconsider the NSABB’s original decision last December that said the paper written by Dr. Yoshihiro Kawaoka and another paper by Dr. Ron Fouchier on their respective efforts to produce and study H5N1 mutants transmissible by air from ferret to ferret should only be published without the methods sections, a way to prevent release of the details on how they developed these potentially dangerous mutant strains. The initial NSABB recommendation to allow publication of only the redacted papers failed to win support from a panel convened by the World Health Organization in February, creating a conflict between the NSABB (and hence the NIH) and the WHO. Claiming that new data first revealed to the WHO group led to the different outcome, Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases — the U.S. agency that sponsored the work of both Dr. Kawaoka and Dr. Fouchier — called on the NSABB to rethink its initial decision, which resulted in the NSABB reversing itself on March 30 and supporting full publication, in a unanimous vote for Dr. Kawaoka’s work, and in a 12-6 vote for Dr. Fouchier’s. So, by early April, the NSABB (and hence, pending official U.S. policy) and the WHO agreed that full H5N1 publication could proceed. Peace reigned across the land.

Dr. Michael Osterholm

Until 2 weeks later, when Dr. Osterholm an NSABB member, upset the tranquility by writing his bombshell letter to Dr. Amy Patterson, NIH’s associate director for Science Policy. In it, Dr. Osterholm took vigorous swipes at how the NIH set up the NSABB’s reconsideration session and detailed his grave concerns about public release of how the H5N1 work was done. Both “Science” and “Nature” received the letter on April 13, and according to a report in “Nature,” Dr. Osterholm said he was not the source for the leak.

“I believe the agenda and speakers for the March 29 and 30 NSABB meeting as determined by the Office of Biotechnology Activities [part of the NIH’s Office of Science Policy] staff and other U.S. government officials was designed to produce the outcome that occurred,” Dr. Osterholm charged in his letter. “It represented a very ‘one-sided’ picture of the risk-benefit of the dissemination of the information in these manuscripts. The agenda was not designed to promote a balanced reconsideration of the manuscripts.”

A major problem, he said, was that the “experts that addressed [the March NSABB session] have a real conflict of interest in that their laboratories are involved in this same type of work and the results of our deliberations directly affect them too.” The same problem occurred at the WHO meeting in February, he added.

Dr. Osterholm tempered his charge by saying he did not “suggest that there was a sinister motive by the U.S. government,” but still leveled a hefty blast, saying “I believe there was a bias toward finding a solution that was a lot less about robust science- and policy-based risk-benefit and more about how to get us out of this difficult situation.”

The upshot was that in the revised decision NSABB, U.S. policy makers, and researchers failed to “come to grips with the very difficult task of managing dual-use research of concern and the dissemination of potentially harmful information to those who might intentionally or unintentionally use that information in a harmful way.” His worry is — if not in this case — “will the Board ever find a bright line for redacting publication” of any future research that could potentially threaten public health?

Dr. Osterholm cited a major danger if details of this research became fully public: “A ferret-to-ferret experiment is expensive and technically demanding, and could only be done by a handful of labs in the world. Once the mutations are public, individuals … in many other labs could generate the mutants in a few weeks given several thousand dollars for gene synthesis,” using reverse genetics.

Finally, Dr. Osterholm questioned the public-health benefit from full release of the methods sections of the two H5N1 papers. “The most important aspect of the results in these two studies on surveillance and control has already been accomplished namely alerting the world to the possibility that H5N1 influenza virus surely can become a mammalian-transmitted virus and poses real pandemic potential.” Publication of more details from the research will not add to that alert, nor would it immediately help in the development or production of countermeasures against a potential H5N1 pandemic, he said.

Despite his concerns over full disclosure of the methods, Dr. Osterholm affirmed his overall support for this H5N1 research in a comment to “Nature” on Friday.  “I have been and continue to be a supporter of this kind of research,” he told the journal.

—Mitchel Zoler (on Twitter @mitchelzoler)

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Making the Case for H5N1 Influenza Research

The biologic properties that allowed mutated strains of avian H5N1 virus to pass between ferrets in a model of mammalian transmission all share certain, apparently critical biologic traits, Dr. Ron Fouchier said at an open meeting on H5N1 research held today and on April 4 in London.

“There is clearly a pattern of what biologic traits a virus needs to get” to allow mammalian transmission, an important clue to what to look for in naturally-occurring H5N1 mutations, said Dr. Fouchier, a researcher at Erasmus Medical Center in Rotterdam and head of one of the two groups that generated the controversial research papers that may now soon be published.

Along with the American Society for Microbiology, the UK’s Royal Society sponsored the two-day session that provided the most thorough information yet available on the H5N1 research done by Dr. Fouchier, and separately by Dr. Yoshihiro Kawaoka at the University of Wisconsin in Madison, as well as comments on the appropriateness of the research and its publication by several other speakers.

Dr. Kawaoka/image by Mitchel Zoler

Dr. Kawaoka described how he focused on the impact of mutations in the H5 hemagglutinin protein in viruses that combined the mutated gene with other genes from the 2009 pandemic H1N1 strain. He concluded from his work so far that “we need to enhance surveillance and the capacity to analyze H5N1 viruses and continue to identify mutations that would convert H5N1 viruses to those transmissible in mammals.” He also noted the “striking similarity” in findings between his work and that of Dr. Fouchier, even though they used different approaches for generating mammalian-transmissible forms of H5N1 (but both used ferret-model systems). Dr. Kawaoka also downplayed drawing a distinction between the mutations he generated and studied in his experiments and what might occur in the real world. “The risk is out there in nature” for the potential formation of H5N1 that is transmissible between mammals through the air. The four mutations he found that made airborne transmission possible between ferrets “is nothing” for a highly mutable virus like influenza.

Dr. Fouchier agreed. So far, spread of H5N1 virus from birds to mammals has been studied for 15 years. Air-borne spread of H5N1 between mammals will “eventually” happen he said; all it will take will be the passage of time, chance, and selection.

Dr. Fouchier/image by Mitchel Zoler

Dr. Fouchier noted that his experiments differed from Dr. Kawaoaka’s by not involving a reassortment step and dealing exclusively with the avian H5N1 virus. He said he was satisfied that the transmissible model strain he now has, which is not very efficiently passed between animals nor very pathogenic, was sufficient to move on to the next studies he wants to do: Look at the biologic traits of the transmissible virus and identify a set of key biologic properties that can be used for surveillance of naturally-occurring mutant strains; determine whether all H5N1 viral lineages have the potential to become transmissible between mammals; and determine whether any vaccine types seem best for pandemic preparedness.

Also speaking at today’s session was Dr. Thomas Inglesby, director of the Center for Biosecurity of the University of Pittsburgh, who reiterated his prior opinion that creating and studying engineered H5N1 mutants posed too big a health risk to proceed. He said that similar, valuable information could be obtained by studying naturally-occurring H5N1 mutations.

In his presentation, Dr. Paul Keim, acting chairman of the U.S. National Science Advisory Board for Biosecurity (NSABB), cited four reasons why the NSABB voted last week to recommend full publication of both Dr. Kawaoka’s and Dr. Fouchier’s papers on their research, reversing the position the Board first took last October. The revised versions of both articles that the NSABB examined last week had better clarity on the balance of risk and benefit from the research, and the Board also received additional, non-public information on benefits and risks, he said. The NSABB also drew on a new policy announced last week that set an official U.S. position on dual-use research, and the NSABB was also swayed by the lack of a mechanism for distributing restricted parts of the reports to approved recipients.

—Mitchel Zoler (on Twitter @mitchelzoler)

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U.S. Biosecurity Board Synchs with WHO on H5N1 Flu Papers

Late this afternoon, the U.S. National Science Advisory Board for Biosecurity announcedthat it reversed its initial ruling, and will support open publication of two research articles that describe the creation of mutant strains of H5N1 avian influenza that are capable of air-borne transmission between mammals.

The new NSABB decision, which came at the end of two days of consideration of revised versions of both papers, brought the U.S. panel into agreement with a review panel convened by the World Health Organization in February that also supported full publication of the papers.

H5N1 virus/courtesy CDC; Cynthia Goldsmith, Jackie Katz

When the NSABB first reviewed the original versions of the papers last December, it decided that publication of the methods sections of the article written by Dr. Yoshihiro Kawaoka of the University of Wisconsin in Madison, and a second article written by Dr. Ron Fouchier of Erasmus Medical Center in Rotterdam, posed too much of a public health risk because of the “dual use” risk of their work. The NSABB said it feared that full disclosure of details of how these researchers produced the mutated H5N1 strains that allowed the highly pathogenic virus to spread through the air from mammal-to-mammal (in a ferret model) posed too great a danger that the information could be used in a way that endangered public health.

In its statement today, the NSABB said that “While the communication of the information in these revised manuscripts still presents dual use concerns, the additional information changed the Board’s risk/benefit calculation.”

The NSABB said that it voted unanimously to recommend full publication of Dr. Kawaoka’s revised manuscript, and that it voted 12-6 in favor of full publication of Dr. Fouchier’s revised manuscript.

“The data described in the revised manuscripts do not appear to provide information that would immediately enable misuse of the research in ways that would endanger public health or national security,” the NSABB said.

Although the NSABB statement did not elaborate on the nature of the revisions, Dr. Fouchier said at an open meeting in February that the mutant influenza he had produced was not as easily transmitted nor as pathogenic as initial press reports had suggested. Speaking at that meeting, Dr. Anthony Fauci , director of the National Institute of Allergy and Infectious Diseases, said that this revised information from Dr. Fouchier had led to the WHO’s decision, and prompted him to ask the NSABB to reconsider both manuscripts.

—Mitchel Zoler (on Twitter @mitchelzoler)

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Prevent Atherothrombotic Events? It’s Complicated

When researchers reported earlier this week at the American College of Cardiology’s annual meeting results from the TRA 2P-TIMI 50 trial, which tested a novel anticoagulant drug, vorapaxar, for preventing cardiovascular death, myocardial infarction (MI), and stroke in stable patients with cardiovascular disease, the results showed a questionable balance between benefit and bleeding risk that only looked good if you squinted and confined the analysis to patients with just a history of MI, no history of stroke, a body weight of at least 60 kg, and, ideally, those who were younger than 75 years old. Even within this pared-down universe, experts differed on whether vorapaxar had an unequivocal net benefit after taking into account the bleeding risk it caused.

But if vorapaxar someday gets FDA approval and appears on the U.S. market, physicians will face the tricky calculus of how to use it compared with the other new, potent antithrombotic drugs.

blood clot/courtesy Janice Carr; Public Health Image Library

Looking at vorapaxar’s performance in patients with stable cardiovascular disease, it was hard not to recall last November’s report on the ATLAS ACS 2-TIMI 51 trial, which tested adding a 2.5 mg b.i.d. dosage of another new anticoagulant drug, rivaroxaban, in acute coronary syndrome (ACS) patients also treated with aspirin and clopidogrel. In ATLAS, adding this small dose of rivaroxaban led to benefit and a bleeding risk that was strikingly similar to the pattern seen with vorapaxar in TRA 2P.  Rivaroxaban on top of aspirin and clopidogrel produced an absolute, 1.6% cut in the combined rate of cardiovascular death, MI, or stroke while boosting the rate of major bleeds by an absolute 1.2%, and the rate of intracranial bleeds by 0.2%. The new vorapaxar results showed that in the best-case subgroup, adding the drug to aspirin and clopidogrel cut cardiovascular death, MI, or stroke by an absolute 1.9%, while boosting major bleeds by 1.0% and intracranial hemorrhage by 0.2%.

A big difference in the two analyses was that the benefits and risk seen with 2.5 mg rivaroxaban was in the entire study population of 5,100 patients, with no need to resort to subgroup analyses. The vorapaxar result was in about 9,500 patients, roughly 70% of all patients enrolled in the trial. Another big difference was the major impact of rivaroxaban was on cutting cardiovascular deaths. Vorapaxar’s main effect was to lower nonfatal MIs. It cut cardiovascular deaths too, but not as well as low-dose rivaroxaban.

Many experts whom I spoke with at the meeting seemed confident that low-dose rivaroxaban is on track for FDA approval later this year for treating ACS patients. Whether Merck, the company developing vorapaxar, will seek FDA approval for its drug in stable patients based on the TRA 2P data remains to be seen.

But while rivaroxaban won’t receive labeling for treating non-ACS patients, all that separates an ACS patient and a patient who is stable but with a history of prior MI is time; in fact, just a few weeks or months. The point at which an acute ACS patient becomes a stable, post-MI patient is pretty murky. Would anyone consider treating a stable, post-ACS patient with low-dose rivaroxaban? The labeling probably won’t cover it, but will the temptation be there? And the what-ifs don’t stop there.

Both the low-dose rivaroxaban study and the vorapaxar study used aspirin and clopidogrel as standard, background treatment. But U.S. physicians are increasingly switching from clopidogrel to the newer, more potent antiplatelet drugs already on the market, prasugrel and ticagrelor, several experts told me at ACC. Putting a patient on prasugrel or ticagrelor plus aspirin will likely preclude any thought of also adding rivaroxaban, not to mention vorapaxar. These combinations have not been tested, and given the bleeding risks that these drugs pose individually, the idea of using them in combination is downright scary.

After several years when clopidogrel plus aspirin reigned alone as the top treatment for preventing atherothrombotic events, the last few years brought a flurry of new agents. How these drugs compare and relate to each other, and how they are optimally used alone or in combination, will take several more years to sort out.

—Mitchel Zoler (on Twitter @mitchelzoler)

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Everlolimus-Eluting Coronary Stents Notch a Major Thrombosis Victory

What a difference a few years, and a new generation, has meant for the fortunes of drug-eluting coronary stents.

In the late summer of 2006, at that year’s meeting of the European Society of Cardiology, the specter of stent thrombosis first rose around the drug eluting coronary stents of that era, the sirolimus- and paclitaxel-eluting devices. The concern led to an abrupt plunge in the use of drug-eluting stents, routine use of more prolonged dual antiplatelet therapy with aspirin and clopidogrel, and eventually the development and marketing of second-generation stents, which used new drugs—everolimus and zotarolimus—and new polymers to bind the drugs to the stent.

Over the past couple of years, the second generation has given drug-eluting stents a renewed, more robust profile. And now, a new meta-analysis published online in The Lancet brings the best news so far for the new generation: the cobalt-chromium everloimus-eluting stent–marketed as both Xience V and Promus—fared significantly better than bare metal stents in their rates of stent thrombosis both 1 and 2 years after placement, and the cobalt-chromium everolimus-eluting stent also significantly surpassed all of its competition, both first- and other second-generation coronary stents.

image courtesy Abbott Vascular

image courtesy Abbott Vascular

The Lancet article that described the meta-analysis, which included 49 trials with more than 50,000 patients, called the finding “a paradigm shift,” something that, if confirmed in a prospective trial, “would have profound clinical implications.” A drug-eluting coronary stent that’s actually substantially safer than a bare-metal stent for the important safety endpoint of stent thrombosis. Who would have thought it possible just a few years ago?

The editorial accompanying the new analysis, by New Zealand cardiologists John Ormiston and Mark Webster, cautions that as a meta-analysis the finding can strictly be regarded as only hypothesis generating, but they also note that a head-to-head randomized comparison of the cobalt-chromium everolimus-eluting stent and a bare-metal stent for this endpoint is unlikely to ever happen. They also said that while the new finding was “unexpected,” the cobalt-chromium everolimus-eluting stent must now be “regarded as the standard against which future design improvements [in stent technology] are compared.” The “firestorm” about stent safety, first set ablaze 5.5 years ago at the ESC  “is now barely smoldering,” they concluded.

The authors of the meta-analysis said that the suggestion that this everolimus-eluting stent could actually best bare-metal stents for stent thrombosis first became plausible at last August’s ESC, in results from the EXAMINATION study, which compared the two stent types in about 1,500 acute myocardial infarction patients. The meta-analysis pooled results from two head-to-head comparisons of the cobalt-chromium everolimus-eluting stent against a bare-metal stent in a total of about 3,800 patients (including the EXAMINATION population), and found that the everolimus-eluting device cut the 1-year thrombosis rate by 86% and the 2-year rate by 65% compared with bare-metal stents. The cobalt-chromium everolimus-eluting model also significantly surpassed every other first- and second-generation drug-eluting stent for their 1-year rate of definite stent thrombosis.

Hypothesis generating or not, it’s a result that cardiologists will find hard to ignore.

—Mitchel Zoler (on Twitter @mitchelzoler)

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