October 23rd, 2013
Open Heart: Will It Open the Way for Data Sharing?
Pascal Meier, MD
CardioExchange editors Harlan Krumholz and John Ryan interviewed Pascal Meier about his new endeavor as Editor-in-Chief of Open Heart, an online-only, open-access journal set to launch in early 2014. It will be published by BMJ and the British Cardiovascular Society.
Krumholz and Ryan: Why did you want to start an open-access cardiology journal?
Meier: Although there are many established traditional cardiology journals, all are limited in the amount of research that they can publish in print. Consequently, they have to prioritize articles, usually based on how novel, topical, and citable they are. I am also working as Associate Editor for BMJ’s journal Heart and I know that there have been lots of high-quality, important articles which we had to turn down for this exact reason.
The global research activity continues to grow and we have to make sure the findings will also get published. Unpublished study results are a major concern leading to “publication bias” and distorting the view of what is effective and what is not. Open Heart will help to alleviate this problem. It will be fundamentally different from the current print-based journals. As an online-only, open-access journal, it doesn’t suffer from the space constraints of traditional print serials and doesn’t need to be so selective.
Many authors are now required to publish their research papers as open access in order to comply with their funder or institutional mandates. It therefore makes sense for new titles to reflect the changes happening in research and academia.
Krumholz and Ryan: When you talk about open data, will you require authors to share all their data when the paper is submitted? How will that work?
Meier: We need to move to “open data” and we strongly support the AllTrials initiative. For non-commercial drug or device trials, data sharing won’t be mandatory for non-commercial studies, but we will be encouraging authors to make their data available via a specialist data repository (such as Dryad) or an institutional repository, as supplementary files attached to the article, or upon request from readers.
Data sharing is important to improve transparency and reduce duplication of effort within the community, but we recognize that authors may be prevented from sharing some data for legal or competitive reasons. We’ll also encourage authors to publish research protocols with us which will be peer-reviewed and may provide valuable input, helping to improve the quality of the planned study.
Krumholz and Ryan: What is your goal from submission of a paper to publishing the paper online? Does the quick turnaround time raise concern about accuracy of review or reliability of data?
Meier: Beyond the standard submission process, we are implementing a fast-track model whereby authors will be able to submit just their abstract initially and we will make a quick decision about whether or not we’re interested in the full article. The aim is to avoid wasting authors’ and reviewers’ time with manuscripts that are out of scope or have fundamental flaws in their methodology.
Open Heart will benefit from BMJ‘s impressive turnaround times from acceptance to online publication — the average is just 22 days and continues to improve. However, scientific soundness has highest priority. The editorial committee includes statisticians and every paper will be statistically reviewed. Our editorial team also includes several people from the Cochrane Collaboration (Cochrane Heart Group).
Krumholz and Ryan: How much will it cost authors to publish?
Meier: The standard Article Processing Charge will be £1700, with a 50% discount for authors publishing protocols. Members of the British Cardiovascular Society will receive a 25% discount, as will anyone that has reviewed for Open Heart within the previous year and those who agree to data sharing. We hope this will encourage reviewers to work for us and publish with us. Open Heart will offer waivers or discounts to authors from Hinari Group A and B countries and to authors that are unable to pay the full amount.
Krumholz and Ryan: From whom will your journal accept articles?
Meier: Any researcher who aims to publish methodologically sound cardiovascular research and is aiming for high visibility. We will also use social media, the blogosphere, and BMJ’s contacts with medical journalists to further increase the impact of the published work. Even though we will be very thorough with the review process, we aim for a very constructive approach and to actively help researchers where need be. We will apply an open peer-review approach where peer reviewers have to declare their identity. We think this will improve transparency and will make the process more constructive.
October 22nd, 2013
No Support for Broad Screening of Chronic Kidney Disease
Larry Husten, PHD
Although taught in medical school and widely used in clinical practice, broad screening of otherwise healthy people for chronic kidney disease (CKD) is unwarranted, according to new recommendations from the American College of Physicians published in the Annals of Internal Medicine. People with early kidney disease, who are classified as having stages 1 to 3 CKD, usually do not have symptoms and are generally diagnosed with laboratory tests or imaging.
The authors of “Screening, Monitoring, and Treatment of Stage 1-3 Chronic Kidney Disease” discuss the paucity of evidence in the field and highlight the absence of randomized, controlled trials evaluating the risks and benefits of screening for CKD or evaluating the sensitivity and specificity of screening tests.
“There is no evidence that evaluated the benefits of screening for stage 1-3 chronic kidney disease,” said Molly Cooke, ACP President, in a press release. “The potential harms of all the screening tests — false positives, disease labeling, and unnecessary treatment and associated adverse effects — outweigh the benefits.”
Although people with diabetes, hypertension, and cardiovascular disease are at higher risk for CKD, there is no evidence that shows that the benefits of screening outweighs the risks in people with these conditions, according to the document. The recommendations also state that people taking ACE inhibitors or ARBs do not need to be tested for proteinuria.
People who have hypertension and early stage CKD should take either an ACE inhibitor or an ARB. People with CKD who have elevated LDL cholesterol should take a statin. The benefits of these drugs have been demonstrated in clinical trials, though there are no proven differences between ACE inhibitors and ARBs, and the combination of an ACE inhibitor and an ARB increases the risk of adverse events.
The authors also recommended against periodic laboratory monitoring tests of people with early-stage CKD. “Ordering lab tests is not going to have any impact on clinical outcomes of asymptomatic patients with CKD without risk factors but will add unnecessary costs to the health care system due to increased medical visits and unnecessary tests,” said Cooke.
October 22nd, 2013
Are Sulfonylureas Dangerous?
Kasia Lipska, MD, MHS
CardioExchange’s editors asked endocrinologist Dr. Kasia Lipska to share her thoughts about a presentation by Craig Currie at this year’s annual meeting of the European Association for the Study of Diabetes in Barcelona.
THE STUDY
Dr. Currie, of Cardiff University, and his fellow researchers retrospectively analyzed data from the Clinical Practice Research Datalink (CPRD), which comprises about 10% of all primary care patients in the UK. Of roughly 92,500 patients with type 2 diabetes in the CPRD who started their diabetes treatment from 2000 to 2012, about 83% received metformin and about 17% received sulfonylureas as monotherapy. An analysis of two matched cohorts (metformin vs. sulfonylurea monotherapy), involving about 4000 patients who were directly matched and about 18,000 who were propensity-matched, showed that sulfonylurea recipients were 58% more likely to die from any cause than were metformin recipients (mean follow-up, 3 years).
In a press release, Currie made these two statements:
Mortality was significantly increased in patients prescribed sulfonylureas as first-line, glucose lowering monotherapy, compared with metformin monotherapy. Whilst residual confounding and confounding by indication may remain, this study indicates that treatment with first-line monotherapy with sulfonylureas should be reconsidered.
Not all general practitioners or other doctors are fully informed about the risks and benefits of commonly used drugs. Failure to identify the higher mortality associated with certain drugs could also be regarded as a failure of the regulatory system.
DR. LIPSKA’S RESPONSE
Metformin is widely regarded as a first-line treatment for patients with type 2 diabetes, given its favorable effects on glucose levels, weight, and cardiovascular events, as well as safety and cost. About 65% of U.S. patients who first start an oral agent for diabetes use metformin. But if metformin is contraindicated or not tolerated, sulfonylureas are considered a reasonable next choice. Given the findings by Dr. Currie and his colleagues, should this approach be abandoned?
Sulfonylureas are the oldest oral agents available for treatment of type 2 diabetes — the first-generation sulfonylureas became available in 1955. But despite 58 years of clinical use, I still find myself uncertain about the safety of this class of drugs. Head-to-head comparisons of diabetes therapies are simply lacking, leaving clinicians and patients without good evidence to inform treatment decisions.
In 1976, the University Group Diabetes Program (UGDP) trial reported an increased risk for cardiovascular death associated with the use of tolbutamide compared with placebo or insulin. Subsequently, the FDA mandated a black-box warning for all sulfonylureas. But the risk for cardiovascular death noted by the UGDP was not supported by the 1998 UK Prospective Diabetes Study, which showed no difference in cardiovascular risk between the use of sulfonylureas or insulin therapy but a benefit with the use of metformin. In fact, the 2008 ADVANCE study of intensive glucose lowering primarily used gliclazide in its intensive-glucose-control arm and found no cardiovascular risk associated with this strategy.
Craig Currie’s analysis undoubtedly bolsters the growing recognition that the exact strategy used for glucose lowering may actually matter. His data, supported by other analyses, do favor metformin over sulfonylureas with respect to safety and cardiovascular outcomes. I suspect that among the roughly 35% of patients who start treatment other than metformin as their first medication for diabetes, some could safely use metformin. But for those who can’t tolerate that drug or for whom it’s clearly contraindicated, what would you do?
Do sulfonylureas actually increase the risk for death, or is metformin protective? To what relative extents do the therapy used, the attributes of the patient, and the quality of the physician play a role? Unfortunately, until we have more trial data that directly compare glucose-lowering medications with respect to clinical outcomes, we will continue to ask these fundamental questions and go on operating in the dark.
JOIN THE DISCUSSION
Share your thoughts about the use of sulfonylureas in clinical practice, in light of Dr. Currie’s new research and Dr. Lipska’s analysis of it.
October 21st, 2013
Selections from Richard Lehman’s Literature Review: October 21st
Richard Lehman, BM, BCh, MRCGP
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.
JAMA Intern Med 14 Oct 2013 Vol 173
Cholecalciferol Treatment to Reduce BP in Older Patients With Isolated Systolic Hypertension (pg. 1672): Vitamin D is a most annoying vitamin. Observational studies link it to all sorts of things, like cognitive function, cardiovascular health, muscular strength, and pretty well everything else you want to hang on to. There are vitamin D receptors all over the body, with lots in the brain and arteries. But if you give extra vitamin D to people, it generally doesn’t do anything measurable. I suspect that this is because you need to have had enough early in life, perhaps even prenatally. By the time you are old and have systolic hypertension, meaning your arteries are stiff, it is a tall order to expect vitamin D to bring back their bounce. And indeed this trial of cholecalciferol to improve isolated systolic hypertension in the over-70s achieved nothing.
JAMA 16 Oct 2013 Vol 310
Quality of Life After PCI vs. CABG Among Patients With Diabetes and Multivessel CAD (pg. 1581): The FREEDOM trial showed that in patients with type 2 diabetes and multi-vessel coronary disease, coronary artery bypass graft (CABG) surgery resulted in lower rates of death and myocardial infarction, but a higher risk of stroke when compared with percutaneous coronary intervention (PCI) using drug-eluting stents. There is complete equipoise between the options, so the patient should be the one to decide. And thanks to the use of the Seattle Angina Questionnaire throughout the follow-up period, we have a very good idea of how the two procedures affected the way patients felt and functioned after the two procedures. For the first two years, there was a slight advantage in the CABG group, but after that it was no longer discernible. There’s a crying need for a decision aid to be used by all patients and doctors facing these alternatives.
BMJ 19 Oct 2013 Vol 347
BP Lowering and Major CV Events in People With and Without CKD: What is the best blood pressure treatment for lowering cardiovascular risk in people with mildly lowered renal function and raised BP? An ACE inhibitor? An angiotensin blocking agent? Not according to this meta-analysis of individual patient data from 23 randomized trials, with summary data from another three. “The results were similar irrespective of whether blood pressure was reduced by regimens based on angiotensin converting enzyme inhibitors, calcium antagonists, or diuretics/β blockers. There was no evidence that the effects of different drug classes on major cardiovascular events varied between patients with different eGFR.”
October 21st, 2013
Refining the Optimal Duration of Dual Antiplatelet Therapy After DES Implantation
Cheol-Whan Lee, MD and Seung-Jung Park, MD.,Ph.D
CardioExchange’s Harlan Krumholz interviews Cheol Whan Lee and Seung-Jung Park about their study group’s randomized trial comparing dual antiplatelet therapy with aspirin alone beyond 12 months after drug-eluting stent implantation. The findings are published in Circulation.
THE STUDY
At 24 centers in South Korea, 5045 patients who received a drug-eluting stent (DES) and were free of major adverse cardiovascular events and major bleeding for at least 12 months after the procedure were randomly assigned, in open-label fashion, to receive aspirin alone or to continue clopidogrel plus aspirin. Incidence of the primary endpoint — a composite of death from cardiac causes, myocardial infarction, or stroke at 24 months after randomization — was similar in the two groups (aspirin alone, 2.4%; dual therapy, 2.6% (hazard ratio, 0.94; 95% CI, 0.66–1.35; P=0.75), as were the individual risks for all-cause mortality, MI, stent thrombosis, and stroke. The incidence of major bleeding was 1.1% in the aspirin-alone group and 1.4% in the dual-therapy group, (HR, 0.71; 95% CI, 0.42–1.20; P=0.20).
THE INTERVIEW
Krumholz: In your study, the benefit of extending dual antiplatelet therapy beyond 12 months was similar to that of aspirin alone. What is the usual practice in South Korea?
Lee and Park: Dual antiplatelet therapy (DAPT) for 6 to 12 months after DES implantation is usual practice in Korea. Beyond 6 to 12 months after DES implantation, most doctors discontinue DAPT and use either aspirin or clopidogrel alone.
Krumholz: In a previous study of yours, you found a similar result. Why was it necessary to do this study?
Lee and Park: As we describe in our introduction, the long-term dual-therapy arm in the first study was associated with a trend toward increased risk for cardiac death and myocardial infarction. We did the second study to confirm this observation.
Krumholz: Your confidence intervals are quite wide. You cannot exclude a benefit of as much as a 34% lower risk. Given that lower limit, do you feel confident that you can really exclude a benefit of longer DAPT?
Lee and Park: We agree. To narrow the confidence interval, we would need a much larger study. However, this is now difficult because 6 to 12 months of DAPT is usual practice in the era of new DES.
Krumholz: You powered the study for a 50% reduction. On what basis did you identify that as the right effect size to detect? Wouldn’t people care about a smaller effect than that?
Lee and Park: We agree. The sample size was based on the first study’s findings. As you know, this kind of study is difficult to conduct because of low patient participation and poor compliance.
Krumholz: What is the next study that should be done in this area?
Lee and Park: DES technology has improved greatly during the past decade. New DES seems to be safer than bare-metal stents, and stent thrombosis mostly occurs within 3 months after new DES implantation. Therefore, we think that the duration of DAPT can be further shortened in the era of new DES, a topic for the next study.
JOIN THE DISCUSSION
What effect will the trial conducted by Dr. Lee and Dr. Park have on your practice and on the direction of research on dual antiplatelet therapy after drug-eluting stent implantation?
October 19th, 2013
Was Dick Cheney’s ICD Vulnerable to Hacking?
Larry Husten, PHD
It happened in Homeland. Could it happen in real life?
In a 60 Minutes segment, Dick Cheney says that his doctors turned off the wireless function of his implanted cardioverter-defibrillator (ICD) “in case a terrorist tried to send his heart a fatal shock,” according to the Associated Press.
Years later, Cheney watched an episode of the Showtime series Homeland, in which such a scenario was part of the plot.
“I found it credible,” Cheney tells 60 Minutes in a segment to be aired Sunday. “I know from the experience we had, and the necessity for adjusting my own device, that it was an accurate portrayal of what was possible.”
I asked three experienced electrophysiologists — the cardiologists who implant ICDs — whether this was a realistic concern. The short answer is that this has never happened in the real world but that it’s impossible to rule out the possibility. So perhaps Cheney and his doctors weren’t paranoid, just excessively careful.
John Mandrola is a cardiac electrophysiologist practicing in Louisville, Kentucky:
The Homeland conclusion last year was fictional because right now at least, you cannot change programming of an ICD ‘remotely.’ In that episode, terrorists deactivated the ICD, then induced VT/VF. They did an EP study but didn’t bring the patient back. [Editor’s note: During an EP study a patient’s heart is intentionally stopped and then restarted. This is a typical example of electrophysiology humor.]
‘Remotely’ is different than ‘wirelessly.’ In the office, you can make wireless contact with an ICD once a wand is waved over it, and you stay in close contact — a few feet, I think.
It’s probably not long before remote programming is possible. Then, such security may be an issue.
Edward J Schloss is the Medical Director of Cardiac Electrophysiology at The Christ Hospital in Cincinnati, Ohio:
In order to reprogram a modern ICD, we need to place a telemetry wand directly over the device to establish communication. After that we can continue to to communicate with the device (including reprogramming) as long as we are in close proximity (~30 feet, I think). We can’t reprogram an ICD from a longer distance than that….
I am not intimately familiar with the mechanisms of ICD telemetry when it comes to hackery. I would not exclude the possibility that someone with a lot of resources and technical knowhow could develop a technique for remote reprogramming. I just know that with currently available hardware, I could not do it unless I was able to get in close proximity to the device.
If I were the vice president, I would probably want to work with industry to minimize my risk.
Westby Fisher practices at NorthShore University HealthSystem in Evanston, IL and is a Clinical Associate Professor of Medicine at the University of Chicago’s Pritzker School of Medicine:
Daniel Halperin with William Maisel, MD, and colleagues set out to hack a Medtronic ICD and did in a paper published in 2008 in IEEE.
They were within 4 inches of the device and reverse-engineered the telemetry protocol. Their point: data are not encoded. This since has been changed, but devices that once used electromagnetic coupling have been “upgraded” to radio waves in the medical frequency (400-405 MHz). Though no device has ever been hacked with the new technology to my knowledge, the new technology offers potential opportunities IF an electromagnetic handshake first weren’t required, like it is now.
Cheney’s paranoia was a bit excessive, but then again, who knows in the world of espionage…
Here’s a highly detailed blog post about the Homeland episode from the perspective of computer security experts.
October 18th, 2013
FDA Approves New Pulmonary Hypertension Drug from Actelion
Larry Husten, PHD
The FDA today approved macitentan (Opsumit, Actelion), a new oral endothelin-receptor antagonist that is an enhanced version of the company’s bosentan (Tracleer). The drug is indicated to delay disease progression in patients who have pulmonary arterial hypertension (WHO Group I).
Last August the results of the pivotal phase 3 trial, SERAPHIN (Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome), were published in the New England Journal of Medicine. After 2 years of treatment with macitentan or placebo, significant reductions in the primary endpoint (a composite endpoint of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension) occurred in the patients who took macitentan. The best results were seen in the group which took 10 mg of macitentan, the dose approved by the FDA.
The Opsumit label will contain a boxed warning that the drug should not be used in pregnant women since it can harm the fetus. Women will be only able to receive the drug through a Risk Evaluation and Mitigation Strategy (REMS) Program. The program will require prescribers and pharmacies to be certified. Female patients will need to be enrolled in the program and comply with applicable pregnancy testing and contraception requirements, the FDA
Actelion said the drug would be available to U.S. patients in November.
The approval of macitentan comes a little more than a week after the FDA approved Bayer HealthCare’s riociguat (Adempas). The drug, a soluble guanylate cyclase stimulator thought to have vasodilating, antiproliferative, and antifibrotic effects, received a broader indication that included not only pulmonary arterial hypertension but also persistent or recurrent chronic thromboembolic pulmonary hypertension (CTEPH) after surgical treatment or inoperable CTEPH to improve exercise capacity and WHO functional class. Riociguat also contained a boxed warning and women will likewise be able to receive the drug only through a REMS program.
October 17th, 2013
New Insights Into Surgery vs. Stents for Diabetics with Multivessel Disease
Larry Husten, PHD
Last year the large NHLBI FREEDOM trial demonstrated that coronary-artery bypass graft (CABG) surgery was superior to PCI when treating diabetic patients who have multivessel coronary disease. CABG resulted in significant reductions in death and MI, but this was offset slightly by a higher rate of stroke in the CABG group. Now, a new report from FREEDOM published in JAMA suggests that the reduction in important clinical endpoints may not translate into large differences in health status and quality of life.
The quality of life substudy shows that the CABG patients had “slightly better intermediate-term health status and quality of life” than did PCI patients, though the differences between the two groups were not large. As might be expected, in the first month after the procedure PCI patients had a greater improvement in health status and quality of life. By six months, this trend reversed and CABG patients did better with less angina, greater physical activity, and a higher overall quality of life.
However, the investigators characterized these differences as small and perhaps not clinically meaningful. More than 70% of patients were free of angina in both groups at each follow-up point, while the absolute difference in complete angina relief ranged from 0.5% to 5.6%. They noted that the differences between the two revascularization procedures in FREEDOM was smaller than the difference between PCI plus optimal medical therapy versus optimal medical therapy alone in the COURAGE trial.
At 2 years there were no longer any consistent differences between the 2 groups, which the investigators attributed in part to the higher rate of repeat procedures in the PCI group.
The authors stated that their findings “suggest that CABG should be strongly preferred as the initial revascularization strategy for such patients.” But, they continue:
“Given the increased rate of stroke, as well as the well-recognized longer recovery period with CABG surgery, however, some patients who do not wish to face these acute risks may still choose the less invasive PCI strategy. For such patients, our study provides reassurance that there are not major differences in long-term health status and quality of life between the 2 treatment strategies. Nonetheless, it is important for patients to recognize that the similar late quality-of-life outcomes with PCI and CABG in the FREEDOM trial were achieved with higher rates of antianginal medication use and the need for more frequent repeat revascularization procedures among the PCI group.”
October 17th, 2013
Questioning Digoxin Use for Patients with Systolic HF
James Freeman, MD, MPH, MS
CardioExchange editor John Ryan interviewed James Freeman about his research group’s evaluation of the contemporary effectiveness and safety of digoxin therapy among a large, diverse, community-based cohort of adults with newly diagnosed systolic heart failure (HF). The study found that digoxin use in patients with incident systolic HF was independently associated with a higher risk of death, but revealed no difference in HF hospitalization. The paper appears in Circulation: Cardiovascular Quality and Outcomes.
Ryan: AHA HF guidelines for 2013 state as a Class IIa indication that “Digoxin can be beneficial in patients with HFrEF, unless contraindicated, to decrease hospitalizations for HF (484-491). (Level of Evidence: B).” Do you agree with this and are your data sufficient to change this recommendation?
Freeman: The current guideline recommendations for the use of digoxin in patients with HFrEF are largely based on the findings of the DIG randomized trial, which showed that digoxin had no effect on the risk of death but a lower risk of hospitalization for HF. However, the DIG trial enrolled patients between 1991 and 1993 before several significant advances in HF therapy and a significant shift in the epidemiology of systolic HF towards more ischemic cardiomyopathy, which may significantly influence the effects of digoxin.
Our cohort differed in a number of very important ways from that older, very sub-selected trial population and more likely represents the current patient characteristics and concurrent HF treatment of contemporary patients treated with digoxin for HFrEF. Our findings that incident digoxin use was associated with a higher risk of death were consistent with a secondary analysis of the Valsartan Heart Failure Trial (Val-HeFT) and other recent observational studies. Taken together, we believe these recent studies suggest that the use of digoxin should be re-evaluated for the treatment of systolic HF in the modern era and that this should be reflected in the guidelines.
Ryan: It has been more than 10 years since digoxin therapy has been shown to be associated with an increased risk of death among women. With these data readily available, and lack of demonstrated benefit with digoxin, why do you think it is still prescribed so frequently?
Freeman: A post-hoc analysis of the DIG trial by Rathore and associates showed that digoxin was associated with a significantly higher risk of death among women (HR 1.23; CI, 1.02 to 1.47), but not men (HR 0.93; CI 0.85 to 1.02; P=0.014 for the interaction). The authors suggested that their results may be due to gender-associated differences in the pharmacokinetics of digoxin, which would suggest that lower dosing may be required for women to maintain an optimal SDC.
These data certainly raised concern regarding digoxin use over a decade ago, however, differential pharmacokinetics for digoxin by patient gender has not been well demonstrated in subsequent years, and because the data were from a secondary analysis of a trial population, the scientific and clinical communities may have been seeking multiple studies confirming this finding. Our results showed that the increased risk of mortality associated with digoxin use did not vary in men and women. We are hopeful that our work, combined with other recent studies, will serve as a sufficient body of evidence to change clinical practice.
Ryan: Who would you give digoxin to now?
Freeman: Our study suggests that digoxin use may not be safe for the treatment of patients with HF and that we critically need more data to determine whether digoxin use is safe in other clinical contexts, such as atrial fibrillation.
October 16th, 2013
FDA Advisory Panel: No Expanded Indication for Vascepa Without Outcomes Trial
Larry Husten, PHD
An FDA advisory panel today failed to recommend an expanded indication for Vascepa, the purified EPA fish-oil product from Amarin. Vascepa is currently indicated only for the relatively small number of people with severe hypertriglyceridemia (>500 mg/dL). The proposed new indication would have greatly expanded the patient population eligible to receive Vascepa to the 20% of the U.S. population who have elevated triglycerides (>200 mg/dL) and existing CV disease or who are at high risk for CV disease.
The supplemental new drug application (sNDA) for the indication was based on the ANCHOR trial, which showed that Vascepa lowered triglycerides in the target patient population. But the FDA review (available here) raised two troubling issues. The first problem concerned the performance of the mineral oil placebo used in the trial. An unusual 9% increase in LDL levels in the placebo group led the FDA and panel members to wonder whether the placebo was not really biologically inert. This made it difficult to assess the true effect on lipids of Vascepa. Panel members wrestled with this issue but ultimately concluded that the triglyceride-lowering effect of Vascepa was genuine, though difficult to measure precisely.
But the panel didn’t agree that the triglyceride-lowering effect of Vascepa would translate into a significant clinical benefit. In its review the FDA said that several trials in recent years with niacin and fibrates (ACCORD-Lipid, AIM- HIGH, and HPS2-THRIVE) had failed to demonstrate cardiovascular benefits in patients already taking statins. In a vote of 9-2, the advisory panel members said that they preferred to wait for the results of the large ongoing Vascepa outcomes trial, REDUCE-IT, which has enrolled more than 6000 of an eventual 8000 patients. Amarin said the trial is expected to be completed in 2016.
Panel chairman Robert Smith summarized the committee’s viewpoint as uncertain, both as to the magnitude of the effect on triglycerides and to whether these changes would result in improvements in cardiovascular outcomes.
Panel member Ellen Seely agreed that Vascepa effectively reduced triglycerides in the study population but that there was no evidence for any effect on outcomes. Seely stated her concern that the “bar may now be too high” for small companies and this may stifle competition. Her decision was somewhat eased because physicians still retain “some flexibility” because Vascepa will remain on the market and can be prescribed off-label.
Some panel members worried about the potential confusion that would ensue if the expanded indication was granted and REDUCE-IT turned out to be negative.
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