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CardioExchange, an NEJM practice community for medical professionals dedicated to improving cardiac patient care, was active from 2009 to 2015. CardioExchange fostered discussion between clinicians from across the globe.

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November 17th, 2014

Selection from Richard Lehman’s Literature Review: November 17th

CardioExchange is pleased to reprint this selection from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.

The BMJ 15 November 2014 Vol 349

Anticoagulant Therapy During Primary PCI for Acute MI: A confession: these reviews are there to point you to the evidence, but do not constitute proof that I know much. For someone who never does percutaneous coronary interventions, there is simply no use in taking up brain space to try and remember which is the latest anticoagulant regimen to come up top in the meta-analysis stakes. Reporting the trials over the last 16+ years has been fun at times (this is a lie), but you can’t really expect me to remember my dabigatran from my enoxaparin. All it has done is give me a healthy scepticism about the possibility of a truly definitive and up to date meta-analysis. But here is the conclusion of the latest one: “In patients undergoing primary PCI, unfractionated heparin plus GpIIb/IIIa inhibitor and LMWH plus GpIIb/IIIa inhibitor were most efficacious, with the lowest rate of major adverse cardiovascular events, whereas bivalirudin was safest, with the lowest bleeding.” I’m a firm believer in shared decision making, but if I was about to undergo PCI, I think my eyes would just glaze over and I’d find myself saying “Just do whatever you think best, doctor.”

 

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November 17th, 2014

IMPROVE-IT Meets Endpoint and Demonstrates Real But Modest Clinical Benefit for Ezetimibe

After all the waiting and all the controversy it turned out to be pretty simple. The IMPROVE-IT trial did what it set out to do and reached its primary endpoint. The benefit wasn’t very big or impressive but it will be enough to put to rest concerns that ezetimibe might have been an expensive placebo or that LDL might not be a reliable surrogate endpoint. The IMPROVE-IT results will also provide comfort to companies developing the next generation of cholesterol drugs, since their approval may have depended on validation of LDL as a surrogate endpoint.

The  Improved Reduction of Outcomes: Vytorin Efficacy International Trial, presented Monday morning at the American Heart Association meeting in Chicago, randomized 18,144 high-risk patients within 10 days of an acute coronary event to either ezetimibe or placebo on top of a statin. These patients had LDL levels between 50-125 mg/dL, or between 50-100 mg/dL if on a prior cholesterol drug. Patients were followed for an average of six years. The trial ended after there were 5,250 primary endpoint events (CV death, MI, hospital admission for unstable angina, coronary revascularization more than a month after randomization, or stroke).

Primary endpoint events occurred in 34.7% of the control group versus 32.7% of the treatment group, representing a 6.4% reduction in risk (HR 0.936, CI 0.887-0.988, p=0.016). The investigators calculated that 50 patients would need to be treated for seven years to prevent one event. There was no difference between the groups in overall deaths, coronary deaths, or cardiovascular deaths, but there were significant reductions in MI (13%, p =0.002), stroke (14%, p=0.052), and ischemic stroke (21%, p=0.008). The effect was significant across subgroups, except for diabetics, who had a larger benefit than nondiabetics.

The results came about even though 42% of patients in each arm discontinued taking the study drug before the end of the trial. A secondary analysis, presenting the results of only the patients who stayed on the study drug, is scheduled for presentation on Tuesday.

As expected, LDL was significantly different throughout the trial; median levels were  69.9 mg/dL in the control group versus 53.2 mg/dL in the treatment group. No safety issues were found during the trial and there were no significant differences in cancer or muscle-related events.

In his presentation of the results, Chris Cannon said the trial provided a positive answer to three questions that have been hanging for more than a decade:

  • Whether lowering LDL with the non-statin ezetimibe can lower cardiac events?
  • Is it worthwhile to take an already low LDL cholesterol (65 mg/dL) even lower (50 mg/dL)?
  • Is ezetimibe safe?

Cannon added that the trial “reaffirms the LDL hypothesis, that reducing LDL prevents cardiovascular events” and that the results should be incorporated in future guidelines.

A Modest Proposal

Despite its history of divisive controversy, the discussion about IMPROVE-IT fell within a fairly narrow range of views. Most experts agreed that the trial results were trustworthy and genuine, but that the benefit seen in the trial was “modest.” Lipid experts in particular expressed relief that the trial did not invalidate the lipid hypothesis.

The result, said James Stein, “makes perfect sense and fits with the physiology just presented last week in the NEJM. Any drug that lowers LDL-C safely, given for a long enough time, will reduce cardiovascular disease risk. The key issues are extent of LDL-C lowering, duration, and baseline level of CVD risk. I am very glad to see these long overdue results as they give us another tool to help prevent heart attacks and strokes. They also help refocus us on the physiology — bad cholesterol — and away from the statin class of drugs as the only treatment for heart disease. It really is about the risk factors. And I can’t emphasize it enough. Anything that lowers LDL-C safely, when used for a long enough amount of time, will reduce CVD risk.”

Sekar Kathiresan, who was the senior author of the NEJM paper cited by Stein, was even more enthusiastic: “These results are a home-run for patients. In human genetics studies for heart-attack risk, LDL has always emerged as the key causal risk factor. And now, we have two medicine options for patients — statins and ezetimibe — proven in clinical trials to lower LDL as well as heart attacks. The question for LDL lowering and cardiovascular disease prevention now moves from ‘how low’ to ‘how long’.”

Kathiresan also argued that the NNT (number needed to treat) of 50 was “outstanding for a drug that basically has no side effects.” But Steven Nissen, a vocal critic of ezetimibe in the past, pointed out that the NNT occurred over seven years, so the yearly NNT was actually 350.

But Nissen also said that the trial result was trustworthy and that the trial was well conducted, but he emphasized the modest effect and asked “when have you ever seen a risk reduction as small as 6%?” He noted that the trial was powered to detect a 9% difference but got only a 6% reduction.

Nissen said he thought the results were strong enough to support the approval of the PCSK9 inhibitors for the limited indications of familial hypercholesterolemia and for those who are truly statin intolerant.

At the AHA press conference, Neil Stone, the chairman of the AHA/ACC cardiovascular guidelines committee, said that ezetimibe should now be viewed as a proven therapy. The results, he said, expand the options for additional proven lipid lowering therapies that have been shown to add incremental benefit.

Stone, Cannon, and others warned that the results of IMPROVE-IT should not be applied to lower-risk groups using ezetimibe for primary prevention. Cardiologist Melissa Walton-Shirley noted that most patients who now take ezetimibe are, in fact, low-risk patients taking it for primary prevention. Cardiologist Karol Watson pointed out that “the NNT goes up with low-risk patients but the NNH (number needed to harm) remains constant.”

Cannon said that the long length of the trial was at least partly a reflection of the excellent state-of-the-art treatment received by study patients. This was “good for the patients but bad” for those who wanted results sooner.

Cannon also pointed out that the 42% drop-out rate over the seven years of the trial worked out to 7% per year, which is actually better than other similar trials in the past.

For more of our AHA.14 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and member perspectives on the most interesting presentations at the meeting, check out our AHA.14 Headquarters.

 

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November 16th, 2014

Prolonged Dual Antiplatelet Therapy Affirmed in DAPT

The advent of drug-eluting stents dramatically reduced the restenosis rate associated with bare-metal stents but prompted new concerns about the rare but potentially lethal complication of stent thrombosis (ST). Cardiologists have relied upon dual antiplatelet therapy to prevent ST but there has been considerable uncertainty and controversy about the ideal duration of therapy.

The Dual Antiplatelet Therapy (DAPT) trial was coordinated by the Harvard Clinical Research Institute as part of a large-scale collaboration with the FDA, stent manufacturers, and pharmaceutical companies. The main results of the trial were presented on Sunday at the American Heart Association meeting in Chicago and published simultaneously in the New England Journal of Medicine.

After receiving a drug-eluting stent and one year of treatment with a thienopyridine and aspirin, 9,961 patients were randomized to 18 additional months of treatment with a thienopyridine or placebo. Both groups continued to take aspirin. The trial is the largest randomized controlled trial to examine the key issue of dual antiplatelet therapy duration.

The results provided compelling evidence that long-term dual antiplatelet therapy can reduce the risk of stent thrombosis and major adverse cardiovascular and cerebrovascular events, though at the cost of increased bleeding.

  • Stent thrombosis: 19 (0.4%) in the 30-month group versus 65 (1.4%) in the 12-month group (HR 0.29, p<0.001)
  • Death, MI, and stroke: 211 (4.3%) versus 285 (5.9%) (HR 0.71, p<0.001)
  • MI: 99 (2.1%) versus 198 (4.1%) (HR 0.47, p<0.001)
  • Severe or moderate bleeding: 119 (2.5%) versus 73 (1.6%) (p=0.001)

In an accompanying editorial, Antonio Colombo and Alaide Chieffo take note of “a recent drive within the interventional cardiology community to shorten the duration of dual antiplatelet therapy… from 12 months of therapy to 6 or even 3 months.” They write that dual antiplatelet therapy is still clearly mandatory in the early period, when the risk for stent thrombosis is still unacceptably high. But it is less clear whether the benefits outweigh the risks in the period of extended therapy studied in the DAPT trial. Prolonged therapy is most likely to be indicated in stent patients who are at high risk for stent thrombosis or MI but at low risk for bleeding. “It is possible that the patients who were excluded from randomization because of a previous major adverse cardiovascular or cerebrovascular event are the very patients who would have benefited the most from prolonged treatment,” they write.

Mortality in DAPT

One concern that emerged was that mortality went in the opposite direction of the other components of the major adverse cardiac and cardiovascular events endpoint and favored the control arm. Overall mortality marginally favored the control arm and there was a large difference in noncardiovascular deaths, though there was no difference in cardiac or vascular deaths.

Death: 2% versus 1.5%, p =0.05

  •    Cardiac death: 0.9% versus 1%, p=0.98
  •    Vascular death: 0.1% versus 0.1%, p=0.98
  •    Noncardiovascular: 1% versus 0.5%, p=0.002

The investigators speculated that this unexpected finding was likely explained by the play of chance and perhaps reflected a baseline imbalance in the number of patients with known cancer before enrollment.

To address the “potential public health importance” of the mortality finding, the DAPT investigators performed a separate systemic review and meta-analysis of the mortality findings in trials testing extended duration dual antiplatelet therapy. The results were published in the Lancet. They analyzed 14 trials that randomized nearly 70,000 patients to different durations of dual antiplatelet therapy and  found no significant differences in all-cause, cardiovascular, or noncardiovascular mortality.

At an AHA press conference most experts did not express concern about the mortality finding. Kirk Garratt said it was likely a “red herring.”

Prasugrel Problem?

The DAPT trial was composed of four individual studies sponsored by different stent manufacturers. The TAXUS Liberte Post-Approval Study (TL-PAS) used prasugrel as the thienopyridine and contributed the largest number of  patients who received a paclitaxel-eluting stent. In this arm of the study, withdrawal of prasugrel, either at 12 or 30 months, was associated with an increase in ischemic events, mostly MI, for the first 90 days. The investigators said they were unable to say whether the same effect would occur with other antiplatelet regiments and/or other drug-eluting stents.

 DAPT in the Real World: It’s Complicated.

In an editorial in the Lancet, Gilles Lemesle writes that “one size may not fit all” when it comes to the length of dual antiplatelet therapy. “Physicians should precisely assess each individual (in terms of risk–benefit ratio) when it comes to making a decision about whether to pursue or shorten dual antiplatelet therapy. If extended dual antiplatelet therapy definitely benefits some patients, it might also be deleterious for others.” He further states that the duration of therapy need not be decided immediately after the initial procedure: “Patients should be prescribed dual antiplatelet therapy for 6–12 months and then be re-assessed at each timepoint if they are event-free.” Future ischemic and bleeding events should have a strong influence on the decision, he writes.

At a press conference on DAPT there emerged  a broad consensus among leaders in the field about general principles, but there was little agreement about specific details or recommendations. The general principles, in accord with the Lancet editorial, were that DAPT should be discontinued early in patients at high risk for bleeding complications and should be prolonged in people at high risk for ischemic events. The problem, said Laura Mauri, the principal investigator of DAPT, is that people at high risk for ischemic events also have an elevated bleeding risk. “So it’s complicated,” she said.

Two smaller studies — ISAR-SAFE and ITALIC — that tested shorter durations of dual antiplatelet therapy were also presented at the AHA and discussed at the press conference. These studies both generally supported treatment shorter than one year, but it is impossible to draw firm conclusions from the trials because they were discontinued early for futility due to lower than expected event rates. In general, said experts at the press conference, the tendency is toward shorter duration in Europe and longer duration in the United States.

Commenting on all the trials, Gilles Montalescot said that the accumulated evidence from all the available trials supports both a shorter and a longer dual antiplatelet therapy strategy. He concluded that dual antiplatelet therapy can be safety stopped after six months in patients at high risk for bleeding. If there is no safety concern he said that treatment could be extended out to one year or longer. But he said it is difficult to identify the patients who may benefit from continued therapy and there is “no common rule” for  duration of therapy.

One intriguing finding repeatedly mentioned was the continued long term risk for MI in DAPT that was clearly not related to the stent and that was reduced by prolonged antiplatelet therapy. It is unclear, though, whether the same regimen that prevents stent thrombosis is the best regimen for the long-term prevention of ischemic events, said Richard Chazal, Vice President of the ACC, in an interview.

For more of our AHA.14 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and member perspectives on the most interesting presentations at the meeting, check out our AHA.14 Headquarters.

 

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November 16th, 2014

Ryan’s Rules for #AHA14

John Ryan provides some helpful hints for managing your experience at the AHA 2014 cardiology conference. For more cardiology-related tips and tricks, you can follow him @drjohnjryan. For more of our AHA.14 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and member perspectives on the most interesting presentations at the meeting, check out our AHA.14 Headquarters.

  1. Always have your talk on a jump drive.
  2. Always have a phone charger—if you leave it in the hotel room, you’ll regret it!
  3. Dress casually—no, scratch that! Wear a suit! Definitely wear a suit, unless you’re prepared to stand out!
  4. Early career folks should go to the early career sessions & reception.
  5. Go to the Opening Session and Presidential Address—it is always pretty inspiring.
  6. Go to your friends’ talks—they appreciate the support.
  7. Go to the poster sessions—that is where the magic is.
  8. Don’t go to your Chief’s talk- you hear them speak enough at home #no_disrepect #new_frontiers.
  9. Go into a random room that you know nothing about—you will learn the most there.
  10. Say hello to people you used to work with. It’s always worthwhile.
  11. If you see your cardiovascular hero standing by themselves, introduce yourself.
  12. Review your slides in the Speaker Ready Room before you talk.
  13. Tell those back at work & at home what you learned and saw at AHA.
  14. There’s more to Chicago than #AHA14. Go check it out.
  15. Exercise for 30 minutes every day while at AHA—it is an AHA recommendation after all.
  16. Go to your councils dinner—if you don’t have a ticket, just ask the council chair to pay #networking_is_why
  17. Find the room where you are giving your talk an hour before you are to give the talk—you don’t want to be struggling to find S401bcd 5 minutes before your talk.
  18. Take off your lanyard/nametag when you go out in the evening.
  19. Don’t lose your lanyard/nametag when you go out in the evening.
  20. “Have fun, enjoy yourself—it’s a great time”. I stole that from Tom Ryan, AHA prez 84-86. #no_relation #greatest_AHA_president

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November 16th, 2014

AHA 2014: There’s an App for That

CardioExchange fellow Tariq Ahmad is blogging from AHA.14 in Chicago this week.  For more of our AHA.14 coverage of late-breaking clinical trials, interviews with the authors of the most important research, and member perspectives on the most interesting presentations at the meeting, check out our AHA.14 Headquarters.

Scientific Sessions have started today in Chicago, and many of us have already mapped out our schedule for the next few days. (Almost) gone are the days of the program book and the yellow highlighter.

Now there is an app for it.

It took me some time to find the app for my iPhone: it can be downloaded here from the Apple Store or Google Play under AHA events.

Once it’s on your phone or tablet, you can browse the sessions for each day and add them to your schedule. You can create an online profile for yourself that other users can see, and then add them as friends. This can allow you to communicate with them in cyberspace. You can even see what sessions your friends have added to their schedule.

The app can also connect you to social media websites like Twitter and Facebook.

It includes a nice maps of the conference center and surrounding area.

I’d love to know: what do others think about this app?

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November 15th, 2014

AHA.14 Headquarters

News:

Perspectives:

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November 12th, 2014

Newly Identified Mutations Act Like a Lifetime of Treatment with Ezetimibe

A very large genetic study published in the New England Journal of Medicine offers compelling evidence in support of a central role for LDL cholesterol in coronary heart disease.

In a series of studies analyzing blood samples from nearly 100,000 people, Sekar Kathiresan and colleagues identified 15 rare mutations that block the activity of a single gene — called Niemann-Pick C1-Like 1 (NPC1L1). The mean LDL level was 12 mg/dL lower in mutation carriers than noncarriers. There were just 11 carriers of the mutations among 29,954 people with CHD versus 71 carriers among 83,140 people without known CHD (carrier frequency: 0.04% vs. 0.09%).  This worked out to a 53% reduction in CHD risk for mutation carriers.

NPC1L1 is the same gene that is blocked by the cholesterol-lowering drug ezetimibe, and the researchers believe that the newly identified mutations may produce an effect that would be similar to a lifetime of ezetimibe treatment. Ezetimibe is the controversial drug being tested in the soon-to-be-revealed IMPROVE-IT trial. But the new genetic study is unable to answer whether the relatively short-term impact of drug treatment is able to deliver benefits that are comparable to the lifelong effects of the genetic mutations observed in the study.

James Stein, the Director of Preventive Cardiology at the University of Wisconsin Hospital and Clinics, offered the following comment about the paper:

I think this is expected and gets to the often forgotten or at least confused point, that lower LDL-C is better. If you can lower LDL-C safely for a long enough amount of time, you will have less CHD events. This mutation is associated with lower LDL-C and even a modest reduction in LDL-C like seen here– when considered over a lifetime– will reduce risk of coronary heart disease. Though the pleiotropic effects of statins are an interesting and a sexy topic, I always have thought that their main effect is lowering atherogenic lipoproteins (mainly LDL). Indeed, many of the so-called “pleiotropic” effects may be a direct effect of lowering LDL.

What does this say for ezetimbe? If it is safe, its long term use likely will reduce CHD risk. It is unclear if any of our current studies will be adequate to test that. I am looking forward to seeing the results of IMPROVE-IT, but its results won’t really have any effect on the findings of this study or the fundamental truth that lower LDL means less CHD risk.

Echoing Stein’s perspective, Kathiresan offered the following comment:

One of the key concepts here is that it may not be “how you lower LDL” or “how low you take LDL” but rather “how long the LDL is lowered.” We should think about LDL like we do smoking. Smoking is typically quantified as “pack-years”, a product of the number of years smoked times the number of packs per day. The concept to stress may be “LDL-years”.

 

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November 12th, 2014

Popular Diets Achieve Only Modest Long-Term Weight Loss

Four of the most popular current weight loss diets produce at best only modest long-term benefits, a new study published in Circulation: Cardiovascular Quality and Outcomes shows. The study also found few significant differences across the four diets, offering little hope that any one diet can produce a serious dent in the obesity epidemic.

Mark Eisenberg and colleagues systematically searched the literature for studies evaluating the effects of the Atkins, South Beach, Zone, and Weight Watchers diets. They identified 12 randomized, controlled studies with follow-up of at least 1 year. Ten studies compared one of the diets with usual care. In these trials, Weight Watchers was the only diet to consistently outperform usual care in achieving weight loss, but this difference was modest at best, yielding a 1-year weight loss range of 3.5 to 6 kg with Weight Watchers compared with 0.8 to 5.4 kg with usual care. In the two head-to-head trials, Atkins and Zone resulted in a similar but modest weight loss. Longer-term data out to 2 years — available only for two diets Weight Watchers and Atkins — showed that some of the original weight loss was regained over time. Only one small trial studied the South Beach diet.

Some of the studies also looked at the effect of the diets on cardiovascular risk factors like cholesterol and blood pressure. Consistent with the weight loss findings, there were no large differences across the diets, and the impact of the diets on these risk factors was modest at best.

The authors note that the effects of these diets in real life may be even worse than in the “ideal conditions” of randomized, controlled trials. Observational studies suggest that the effect may be even smaller in real life and that the weight loss seen in the trials “overestimates that achieved by patients seen as part of everyday clinical practice.”

The findings also appear to be consistent with a previous study that looked at earlier popular diets, including Jenny Craig, LA Weight Loss, and again, Weight Watchers. The authors of the earlier study concluded that “with the exception of 1 trial of Weight Watchers, the evidence to support the use of major commercial and self-help weight loss programs is suboptimal.”

“Despite their popularity and important contributions to the multi-million dollar weight loss industry, we still do not know if these diets are effective to help people lose weight and decrease their risk factors for heart disease,” said Eisenberg, in a press release. “With such a small number of trials looking at each diet and their somewhat conflicting results, there is only modest evidence that using these diets is beneficial in the long-term.”

In an accompanying editorial, David Katz writes that one limitation of the study is the narrow range of diets examined by the authors, since three of them represent variations on the low-carbohydrate theme. Missing from the analysis is “the full expanse of competing dietary claims,” including “low fat as well as low carbohydrate diets; vegan and vegetarian diets; low glycemic diets; Paleo diets; Mediterranean diets and diets incubated at the National Institutes of Health.”

But Katz argues passionately that the focus on individual diets or specific macronutrients is misguided and unhelpful. He proposes a simple formula — “wholesome foods in sensible combinations”– and states that traditional diets, despite superficial differences, “are more alike than different.” Blue Zone populations — a term for the world’s healthiest and longest-lived people — “range from vegans in California, to the quintessentially Mediterranean dieters of Crete, to the traditional Asian dieters of Okinawa,” writes Katz. “The diets all emphasize foods direct from nature, a variety of plants, and none of the hyper-­processed, willfully unsatiating  junk that makes up so much of the typical American diet. They are all nutrient rich, high in fiber, and low glycemic. But they are not uniformly low or high in any given macronutrient. The emphasis is consistently on wholesome foods in sensible, time-­honored combinations — and the macronutrients fall within broad ranges.”

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November 7th, 2014

What You Need to Know About IMPROVE-IT

The IMPROVE-IT trial will be big news when its results are finally presented on November 17 during the annual meeting of the American Heart Association. The results of the trial — underway for nearly a decade — have been long and eagerly awaited by everyone interested in cardiovascular medicine.  The trial could impact the future sales of a key Merck drug, ezetimibe; because it is nearing the end of its patent life the commercial significance is somewhat limited. However, IMPROVE-IT will also have very important implications beyond its specific effect on one drug franchise and could influence the fate of several new drugs now being investigated and may even alter the entire drug development and evaluation process.

Here’s some background information and links to useful resources:

Ezetimibe

Ezetimibe blocks the absorption of cholesterol in the intestine. This leads to an increase in LDL-cholesterol receptors in the liver. These receptors then remove LDL from the blood. When added to statin therapy, ezetimibe generally lowers cholesterol by an additional 20-25% over the statin alone. In the U.S. it is marketed by Merck as Zetia (ezetimibe alone) and Vytorin (ezetimibe in combination with simvastatin).

Ezetimibe was originally developed by Schering Plough and co-marketed by Merck, which ultimately acquired Schering Plough. The drug was first approved by the FDA in 2002. It quickly became a blockbuster, with sales reaching more than $5 billion a year within a few years. Critics of the drug noted that, despite its success, there were no trials showing that the drug conferred any actual clinical benefit besides lowering LDL. This stood in sharp contrast to the already established statins, as a long series of trials had already firmly established their clinical benefits.

ENHANCE

But there were no serious challenges to the drug’s commercial success until the ENHANCE trial controversy. ENHANCE was not a cardiovascular outcomes trial. It was a smaller trial that compared the effect in people with familial hypercholesterolemia of ezetimibe or placebo in combination with simvastatin on a surrogate endpoint, in this case the progression of atherosclerosis in the carotid and femoral arteries as measured by ultrasound. The trial found no advantage for ezetimibe. By itself this might have been only minor news and likely would only have had a small effect on the commercial market, but the importance of the trial was greatly magnified due to the enormous amount of prepublication publicity that came about because of revelations that the sponsor, Schering Plough, had interfered with the trial and delayed its presentation. When the results were finally presented they had a dramatic effect on the drug’s reputation but a more modest effect on sales. Although ezetimibe remains a successful drug to this day — worldwide sales still total more than $4 billion each year — the ENHANCE trial put an end to the drug’s explosive growth, and provoked an explosion of criticism and concern that has yet to entirely die down.

IMPROVE-IT

The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) is a true cardiovascular outcomes trial and was designed to test the effect of adding ezetimibe to simvastatin in patients with an acute coronary syndrome (ACS). Earlier this year the IMPROVE-IT investigators reported that the trial had randomized 18,144 patients with ACS. These patients had LDL levels below 125 mg/dL if they were not already taking a cholesterol drug or below 100 mg/dL is they were taking a cholesterol drug. By itself the simvastatin dose was chosen to achieve an LDL level below 70 mg/dL, the target cholesterol goal according to the cholesterol guidelines at the time the trial was started. Trial enrollment began in 2005 and was completed in 2010.

The primary endpoint of IMPROVE-IT is cardiovascular death, nonfatal MI, nonfatal stroke, rehospitalization for unstable angina (UA), and coronary revascularization.

Along the way the trial design has been modified several times. The most important change was the increase in the number of patients, from 10,000 to 18,000. This was because of a lower than expected number of primary endpoint events. The trial was designed to accumulate 5,250 primary endpoint events after a minimum 2.5 years of followup for all patients. These parameters were chosen in order to detect a 9.3% reduction in the primary endpoint with ezetimibe, based on an anticipated 15 mg/dL drop in LDL in the ezetimibe group.

In addition to closely monitoring the safety of the patients in the study (for a while during the trial there was a concern that ezetimibe might raise the risk of cancer — this concern has been since dispelled) the data and safety monitoring board has performed three efficacy analyses. The protocol included stopping guidelines for “overwhelming efficacy” so it is clear that the results, at best, will be somewhat modest. But the protocol did not contain stopping rules for futility, so it is possible, as some think, that the DSMB has known for some time that the trial will not show a significant benefit for ezetimibe.

A distinct possibility, raised by the study investigators and others, is that because LDL levels will be low in both groups and because the difference in LDL between the groups will be modest, the results at best will show only small and unimpressive clinical differences. A good example of the attempt to prematurely discount the eventual result of IMPROVE-IT is an opinion piece published earlier this year in the European Heart Journal  which concludes that the likely negative results of the trial will not help understand whether ezetimibe is beneficial in people with higher cholesterol levels at baseline.

BEYOND EZETIMIBE

The IMPROVE-IT authors also discussed the implications of the trial beyond what it will tell us about ezetimibe:

… the practical value of a positive trial will serve as a definitive proof of concept that LDL-C lowering with compounds other than statins can affect outcomes. The trial may provide support for driving LDL-C to levels below those previously recommended and will raise the issue of whether other molecules — such as PCSK9 antibodies — could have similar proportional benefit as an adjunct to statins.”

I have argued in the past that the fate of the new PCSK9 inhibitors (potent LDL-lowering antibodies under development by Amgen and Sanofi/Regeneron) may depend on the results of IMPROVE-IT. If the trial meets its primary endpoint then the FDA will be reassured and will likely accept LDL-lowering as a surrogate endpoint, leading to early approval of the PCSK9 inhibitors without evidence from cardiovascular outcomes trials (which are now taking place). However, if IMPROVE-IT does not meet its primary endpoint then it seems to me that the FDA and its advisors will need to take a much more critical look at LDL as a surrogate endpoint. Failure of IMPROVE-IT will almost certainly encourage critics who will condemn the FDA for approving a new class of cholesterol-lowering drugs without evidence of significant clinical benefits.

Others have argued that the far greater potency of the PCSK9 inhibitors means that any comparison with ezetimibe is inappropriate.

If the results of IMPROVE-IT are positive they will also be used to support the use of ezetimibe in people who can’t tolerate high-dose statins and in people with persistently high LDL levels who are already taking statins. If it does not meet the primary endpoint, the authors say, the results “could certainly affect beliefs about the ‘lower is better’ hypothesis.”

The Bottom Line

In the end there are a few likely scenarios.

Negative Effect — Ezetimibe treatment results in worse cardiovascular outcomes than placebo. This is probably the least likely of the likely scenarios, because there is little suggestion of harm in previous studies, but the possibility should not be entirely dismissed. A true negative effect would have a stunning impact not only on the ezetimibe franchise but on the future of LDL as a surrogate endpoint and the development and approval pathway of future cardiovascular and metabolic drugs.

Positive Effect — A strong positive effect is perhaps slightly more likely than a strong negative effect. This would give a big boost to the final years of the ezetimibe franchise and would be welcomed by developers of the PCSK9s and other LDL lowering drugs, providing ammunition for their argument that LDL is a reliable surrogate that can be used to gain FDA approval.

Small, Mixed, or Ambiguous Effect — This is what most observers probably expect. There may be a small, beneficial effect that either just reaches or just misses statistical significance. Or there might be a significant effect, negative or positive, in one or another of the primary endpoint components, but no overall significance or clear signal. The possible variations of confusing outcomes are nearly innumerable.

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Categories: General, Prevention
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November 6th, 2014

Agent Could Potentially Reverse Anticoagulation Associated with Edoxaban

PER977 — a cation that binds to all of the new oral anticoagulants and heparin — may help reverse the anticoagulant effects of edoxaban, according to results of an industry-conducted trial published in the New England Journal of Medicine. Edoxaban, an oral factor Xa inhibitor, was recently recommended for approval by an FDA advisory panel.

Researchers studied whole-blood clotting time in 80 healthy people who were given PER977 following a dose of edoxaban. After receiving edoxaban, participants’ mean whole-blood clotting time rose by 37%. But after administration of PER977, whole-blood clotting time fell to within 10% of the baseline value in 10 minutes or less, and the effect lasted for 24 hours. Participants receiving placebo took 12 to 15 hours to reach that level.

The researchers did not observe signs of procoagulant activity with PER977, and adverse events were minimal.

This compound may also be effective and will likely be tested in the other new oral anticoagulants, as well as unfractionated heparin and low-molecular-weight heparins.

Categories: Anticoagulation
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