October 18th, 2012
FDA Panel Recommends Approval of Mipomersen for Homozygous Familial Hypercholesterolemia
Larry Husten, PHD
The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee gave a weak endorsement to mipomersen, an antisense oligonucleotide inhibitor manufactured by Genzyme, for use in homozygous familial hypercholesterolemia (FH). With its relatively close 9-6 vote, and with its comments, the committee expressed concerns about both the efficacy and safety of the drug, but ultimately the severity of homozygous FH led the panel to recommend approval.
“We need a toolkit, we need as many options as possible for these patients,” said one panel member.
On Wednesday the same committee voted 13-2 in favor of a similar indication for lomitapide capsules, manufactured by Aegerion. On both days, panel members strongly urged the FDA to restrict use of lomitapide and mipomersen to patients with homozygous FH and “avoid the slippery slope” of using the drugs in heterozygous FH or in patients with resistant hypercholesterolemia.
Some panel members voiced concern that the clinical trials with mipomersen excluded patients with apheresis. During the section for public comments, Sidney Wolfe said that the trials were unethical for this reason, since apheresis represents the gold standard of treatment for these patients. One panelist responded that though it was an unfortunate exclusion, it was not unethical. A Genzyme spokesperson reported that a trial is now underway looking at mipomersen on top of apheresis.
The panel agreed that mipomersen was effective in lowering cholesterol but felt the reduction was “modest” and that most patients would not reach LDL levels under 100. As with lopitamide, trials were not powered for clinical endpoints. Panelists wondered about the clinical effect of lowering LDL cholesterol from 400 to 300.
The committee did not appear to be greatly concerned about the possibility of a cancer signal brought up in the FDA review. Several panelists thought that the cancer signal may have reflected an ascertainment bias, and, further, that a young homozygous FH population would be less susceptible to an elevated cancer risk. Most of the cancers observed in the clinical trials occurred in elderly patients who did not have homozygous FH.
The biggest obstacle to mipomersen was the question over liver safety. Committee members wrestled with the issue without reaching a consensus, perhaps reflecting their faith (or hope) that the FDA’s proposed Risk Evaluation and Mitigation Strategy (REMS) will work as intended. The program, similar to the one proposed by the FDA for lomitapide, would “educate prescribers about the approved indication for use of mipomersen, the potential risk of hepatotoxicity associated with the use of mipomersen, and the need to monitor patients during treatment with mipomersen as per product labeling.” The REMS would require special certification for health care professionals and pharmacies that prescribe and dispense the drug.
October 18th, 2012
FDA Reviewers Recommend Approval of Lomitapide for Homozygous Familial Hypercholesterolemia
Larry Husten, PHD
The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13-2 on Wednesday to recommend approval of Aegerion Pharmaceuticals’ cholesterol-lowering drug lomitapide for use in patients with homozygous familial hypercholesterolemia (FH).
The lopsided vote does not completely reflect the views of many of the panel members, who expressed considerable concern that the drug might be used in lower-risk populations, in particular, patients with heterozygous FH. The committee also expressed concern about the use of lomitapide in children with homozygous FH, since they were not included in clinical trials, but might be considered candidates for therapy in clinical practice.
Panel members appeared to largely agree with one panel member, who explained that his yes vote was “specific for this condition” (homozygous FH) only. He said he could accept the “trade-off between a near-certain early demise versus the possibility of liver disease.”
Aegerion estimates that there are about 6000 homozygous FH patients in the U.S. and Europe.
The committee expressed support for the FDA’s proposed Risk Evaluation and Mitigation Strategy (REMS) that would limit access to the drug to medically appropriate patients and to provide education to prescribers about how to use lomitapide, how to prevent liver damage, and how to monitor patients during treatment. The REMS would require special certification for health care professionals and pharmacies that prescribe and dispense the drug.
On Thursday, the same committee will meet to discuss a similar indication for Genzyme’s mipomersen injection. Following the release of a highly critical FDA review, many observers believe the mipomersen panel will be much more contentious.
October 18th, 2012
Should Hypercholesterolemia Treatments Start Much Sooner in Life?
Keeping LDL cholesterol low throughout life is more effective at preventing atherosclerotic disease than starting statins in middle age, a series of analyses in the Journal of the American College of Cardiology shows.
Researchers first established the effects of several genetic variations on naturally lowering LDL. People with one or more of these variants had their risk for coronary heart disease reduced by over half for each 40 mg/dL reduction in long-term exposure to LDL, relative to those without the variants. Next, researchers found that trials of statin therapy, participation in which usually begins later in life, had a much lower risk reduction — about 25%.
Editorialists say that the analyses, in their view, justify “acting without waiting” for a randomized trial. They recommend focusing on lifetime risk — as opposed to the 10-year risk window of the Framingham risk score — and starting lifestyle changes or drug treatment much sooner.
Reprinted with permission from Physician’s First Watch
October 18th, 2012
Multivitamins May Confer a Small, but Significant, Cancer Risk Reduction in Men
Nicholas Downing, MD
Middle-aged and older men who take multivitamins have a modestly reduced risk for cancer, according to an industry-supported study in JAMA.
Nearly 15,000 male U.S. physicians aged 50 and older were randomized to a daily multivitamin or placebo and then followed for roughly 11 years. Multivitamin recipients had a small but significant reduction in total cancer diagnoses (17.0 vs. 18.3 cancers per 1000 person-years). There were, however, no reductions in site-specific cancers — including prostate cancer, the most frequently diagnosed.
The authors conclude: “Although the main reason to take multivitamins is to prevent nutritional deficiency, these data provide support for the potential use of multivitamin supplements in the prevention of cancer in middle-aged and older men.”
Reprinted with permission from Physician’s First Watch
October 16th, 2012
FDA Review Raises Safety Concerns About Mipomersen
Larry Husten, PHD
An FDA review raises a number of potentially significant safety concerns about the cholesterol-lowering drug mipomersen. The review appears ahead of a Thursday meeting of the Endocrinologic and Metabolic Drugs Advisory Committee to evaluate Genzyme’s new drug application (NDA) for use of the drug as an adjunct to maximally tolerated lipid-lowering medications and diet to reduce LDL, apolipoprotein B, total cholesterol, non-high density lipoprotein-cholesterol and lipoprotein (a) in patients with homozygous familial hypercholesterolemia (FH). Mipomersen is an antisense oligonucleotide inhibitor that targets apoB-100. (On Wednesday, the same committee will meet to discuss a similar indication for lomitapide capsules, manufactured by Aegerion.)
FDA reviewers said that mipomersen was generally effective in lowering LDL cholesterol. More than half of patients in clinical trials had more than a 20% decrease in LDL levels. In the pivotal trial with homozygous FH patients, mipomersen reduced LDL by 24.7%. As expected, mipomersen also resulted in significant reductions in apo B, total cholesterol, and non-HDL cholesterol.
Because of their small size, the mipomersen trials were not powered to assess cardiovascular outcomes, though cardiovascular benefit is of course the ultimate intended effect of the drug. However, the numbers in the phase 3 studies ran in the wrong direction. Serious adverse events of cardiac disorders occurred in 3.8% (10/261) of patients in the mipomersen group compared with 3.1% (4/129) in the placebo group. The reviewers concluded that “the possibility that mipomersen therapy increases the risk for cardiovascular events cannot be excluded.”
More troubling is the FDA safety review, mostly centering on liver-related problems. Mipomersen was associated with increases in serum transaminases and hepatic fat. In phase 3 trials, hepatic steatosis occurred in 7.3% (19/261) of mipomersen-treated patients compared with 1.6% (2/129)of placebo-treated patients. ALT increased in 9.6% of mipomersen-treated patients compared with 0.8% of placebo-treated patients. In a long-term extension trial, one quarter of mipomersen-treated patients had an average liver fat fraction greater than 20%. The FDA reviewers said they did not know whether long-term use of mipomersen could cause irreversible liver damage, but warned that patients could be at risk for cirrhosis and liver-related death if the observed liver changes progressed.
Other safety issues in the trials included injection site reactions and flu-like symptoms. The committee will also likely spend time discussing the cancer findings. According to the review, during clinical testing, neoplasms – both benign and malignant – were detected in 3.1% (23/749) of patients who received mipomersen compared with 0.9% (2/221) of patients who received placebo. However, the FDA clinical reviewer noted that there was a diversity of malignant neoplasms and that two out of nine mipomersen patients who developed a malignancy had been on mipomersen for less than a month, “making it highly unlikely that mipomersen played a role.” The review concluded that “there are several confounding factors that make it difficult to conclude that mipomersen is playing a dominant role in this cancer imbalance.”
The FDA will also ask the panel to evaluate a proposed Risk Evaluation and Mitigation Strategy (REMS) if the drug gains approval. The program, similar to the one proposed by the FDA for lomitapide, would “educate prescribers about the approved indication for use of mipomersen, the potential risk of hepatotoxicity associated with the use of mipomersen, and the need to monitor patients during treatment with mipomersen as per product labeling.” The REMS would require special certification for health care professionals and pharmacies that prescribe and dispense the drug.
Given the severity and rarity of homozygous FH, it is difficult to predict how the committee will vote, but the safety concerns raised by the FDA make it extremely unlikely the drug could receive an expanded indication for heterozygous FH anytime in the near future.
The FDA will provide a free webcast of the committee meeting. Click here for information about accessing the webcast.
Click here to access the committee meeting materials.
Click here for a Scrip article handicapping the voting results of the panel.
October 16th, 2012
FDA Warns About Fungal Meningitis in Transplant Patient Who Received NECC Cardioplegia Solution
Larry Husten, PHD
The FDA said on Monday that it had identified a transplant patient with Aspergillus fumigatus infection who received cardioplegia solution during surgery. The solution was manufactured by the New England Compounding Center (NECC), which has been at the center of a broad investigation after the deaths of at least 15 patients from fungal meningitis due to contaminated vials of methylprednisolone acetate injection.
The FDA said it had also identified a patient who may have developed meningitis from an epidural injection of another injectable steroid made by NECC, triamcinolone acetonide. The agency noted that “there may be other explanations” for the infection in the transplant patient and that it has not confirmed that the two new cases were caused by NECC products.
Out of “an abundance of caution,” the FDA recommends that patients who received any injectable drugs manufactured by NECC “should be alerted to the potential risk of infection.” The FDA said this recommendation extends to patients who received injectable ophthalmic drugs made by NECC, although no infections have been reported with these drugs. The FDA also said patients should be told about the symptoms of meningitis and instructed to immediately report if they have any of these symptoms.
October 15th, 2012
FDA Reviewers Raise No New Red Flags Over Lomitapide
Larry Husten, PHD
FDA reviewers have raised no new concerns about lomitapide ahead of a Wednesday meeting of the Endocrinologic and Metabolic Drugs Advisory Committee. The FDA today released briefing documents that evaluate the new drug application (NDA) for lomitapide capsules, the microsomal triglyceride transfer protein (MTP) inhibitor from Aegerion Pharmaceuticals. It’s intended for use as an adjunct to a low-fat diet and other lipid-lowering drugs with or without LDL apheresis to reduce LDL cholesterol, total cholesterol, apolipoprotein B, and triglycerides in patients with homozygous familial hypercholesterolemia. (On Thursday, the same committee will meet to discuss a similar indication for Genzyme’s mipomersen injection. Briefing documents for that meeting will be released on Tuesday.)
The reviewers concluded that lomitapide was effective in lowering LDL cholesterol by about 40%. The drug also effectively reduced total cholesterol, apoB, triglyceride, non-HDL, VLDL, and Lp(a) levels. However, it also lowered potentially beneficial HDL and Apo A1 levels. The reviewers said that “the clinical consequences, if any, of these changes are unknown.”
The committee will likely focus on side effects and safety issues related to lomitapide. Gastrointestinal side effects are common with the drug. More troubling are concerns about possible liver damage. In the pivotal trial of the drug, 38% of the patients had ALT elevations greater than three times the upper limit of normal, and 24% had elevations five times the ULN. Most patients in the trials also had significant elevations in hepatic fat. The reviewers also noted that lomitapide might induce deficiencies in fat-soluble nutrients.
To address the safety issues related to lomitapide, the FDA will ask the committee to evaluate a Risk Evaluation and Mitigation Strategy (REMS) that would limit access to the drug to medically appropriate patients, and to provide education to prescribers about how to use lomitapide, how to prevent liver damage, and how to monitor patients during treatment. The REMS would require special certification for health care professionals and pharmacies that prescribe and dispense the drug.
The FDA will provide a free webcast of the committee meeting. Click here for information about accessing the webcast.
October 15th, 2012
Selections from Richard Lehman’s Literature Review: October 15th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint selections 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 10 Oct 2012 Vol 308
PCI Use in States with Public Reporting of Outcomes (pg. 1460): The first appeal for hospitals to disclose their outcome figures was made, believe it or not, in 1732, by Dr Francis Clifton of London. His canny eighteenth century colleagues shook their wigs, took a good pinch of snuff, and retorted that (a) individuals and institutions would try to cook their figures, and (b) this would act as a disincentive to accept the sickest patients or do risky procedures, even if they were potentially life-saving. Little has changed in nearly 300 years. This study examines percutaneous intervention rates and outcomes in US hospitals. “Among Medicare beneficiaries with acute MI, the use of PCI was lower for patients treated in 3 states with public reporting of PCI outcomes compared with patients treated in 7 regional control states without public reporting. However, there was no difference in overall acute MI mortality between states with and without public reporting.” This actually raises some pretty deep issues. But since most of my readers are not interested in cardiovascular outcomes research with special reference to the USA, I will move on. Those who are need to pore over this paper and also read the editorial.
Proneurotensin Related to CVD, Diabetes, Breast Cancer, and Mortality (pg. 1469): Another week, another prognostic marker for everything and nothing. “Exclusively in women, proneurotensin was related to incident diabetes (74 events; HR, 1.41; 95% CI, 1.12-1.77; P = .003), cardiovascular disease (224 events; HR, 1.33; 95% CI, 1.17-1.51; P < .001), breast cancer (123 events; HR, 1.44; 95% CI, 1.21-1.71; P < .001), total mortality (285 events; HR, 1.13; 95% CI, 1.01-1.27; P = .03), and cardiovascular mortality (75 events; HR, 1.50; 95% CI, 1.20-1.87; P < .001).” Measure enough weird chemicals in your cohort study, crunch the numbers, and hey presto! You have a paper in JAMA.
Lancet 13 Oct 2012 Vol 380
Vorapaxar for Secondary Prevention of Thrombotic Events for Patients with Previous MI (pg. 1317): Another Lancet issue with thin pickings for the jobbing clinician. Had you ever heard of vorapaxar? Maybe. Or of the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50 trial? Probably, if you are a cardiologist; otherwise, probably not. It was a vast 1,000-centre trial run by Merck to see it their new platelet inhibitor could win a place in the market of secondary prevention in patients with atherothrombosis. To this end, they chose a composite end-point of cardiovascular death, myocardial infarction, or stroke, and recruited nearly 27,000 subjects. They also pre-specified at least 7 subgroups, the largest being those with a myocardial infarction in the previous year—17,779 of the participants. In this group, vorapaxar does prove to have a protective benefit that outweighs the additional risk of bleeding. But the overall trial was stopped for harm, and cash-strapped health systems are unlikely to find the effect size sufficient to rush in and pay for the stuff to be given to every post-MI patient, especially when the field is already so crowded and hard to make sense of. For a valiant mapping attempt, see the editorial.
Arch Int Med 8 Oct 2012 Vol 172
Atenolol vs. Metoprolol for Hypertension: We often used to begin treating our hypertensive patients with ß-adrenergic blocking drugs, until long-term studies showed that atenolol actually didn’t seem to do any good and might even cause an increase in cardiovascular events. But can we say the same of metoprolol? Probably, and the way we can do it is by a simple retrospective database study—like this one, which shows no difference in a head on comparison of atenolol or metoprolol for uncomplicated hypertension. Even better, you could examine the issue prospectively by a very simple instant randomised allocation trial in UK primary care: except that nobody would opt to use beta-blockers for hypertension any more.
October 15th, 2012
Stable Anticoagulation, Unstable Gait
Jeff Dickey, MD and James Fang, MD
A 91-year-old man with mild drug-controlled hypertension and atrial fibrillation has long-term, well-managed stability on warfarin anticoagulation. After developing problems with his balance and some gait instability, a physical exam reveals a carotid bruit. Carotid ultrasound and magnetic resonance angiography (MRA) confirm >95% stenosis of the right internal carotid artery. Brain CT is negative.
Questions:
1. What should this man’s anticoagulation regimen be?
2. What would you recommend for the ICA stenosis?
3. Would you perform brain MRA?
Response:
October 22, 2012
This 91-year-old man has developed balance and gait instability that may or may not be explained by the incidentally noted high-grade carotid stenosis. (Intermittent unilateral lower-extremity weakness or sensory loss could result in balance and gait issues but should be confirmed by a careful neurologic exam.) The patient otherwise appears to have few medical issues other than atrial fibrillation. If a detailed neurologic evaluation documents posterior-circulation findings, an MRA of the posterior circulation would be reasonable to establish another diagnosis (e.g., of vertebral-basilar insufficiency).
If no symptoms are clearly attributable to the carotid stenosis, continued management with warfarin anticoagulation and statins is reasonable. The patient’s bleeding risk is modest despite his age. Although he has a risk for falling, such risks are often overestimated. Bleeding risk can be estimated from various scoring systems such as HAS-BLED. Adding aspirin would be likely to increase his bleeding risk without appreciably decreasing the risk for stroke from his carotid stenosis and atrial fibrillation, although aspirin is frequently added in practice.
Some would advocate carotid endarterectomy (CEA), but it typically takes a few years for a stroke-prevention benefit of CEA to be evident in asymptomatic patients. I would advocate CEA if, as noted above, the patient experiences symptoms that can be attributed to his carotid stenosis. His operative risk is acceptable if local expertise in CEA has been associated with a <3% incidence of postoperative stroke or death.
Follow-Up:
October 29, 2012
The patient’s gait instability was diagnosed by the neurologist as polymyalgia rheumatica. During my exam I apparently didn’t appreciate morning hip stiffness as the basis for gait instability. His symptoms dramatically improved on prednisone.
The neurologist, in consultation with the cardiologist, decided on treatment with 81 mg/day of aspirin and continued warfarin (INR goal, 2-3). The patient is taking omeprazole for the GI risk from the combination of aspirin, prednisone, and warfarin.
A link between temporal arteritis (which may be associated with polymyalgia rheumatica) and carotid stenosis, as documented in case reports, may or may not be relevant to this patient.
October 12th, 2012
Free Cardiac And Spine Surgery For Walmart Employees At Six Hospitals
Larry Husten, PHD
Starting next year 1.1 million U.S. Walmart employees and their dependents will be eligible for free heart, spine, and transplant surgery at six highly regarded health care organizations. Walmart employees will have no out-of-pocket costs, including travel, lodging, and food for the patient and a caregiver.
On Thursday the company announced that its “Centers of Excellence” program, which had previously provided free transplants to Walmart employees, would expand to include heart and spine surgeries. Here are the six health care organizations involved in the program:
- Cleveland Clinic in Cleveland, Ohio
- Geisinger Medical Center in Danville, Pa
- Mayo Clinic sites in Rochester, Minn., Scottsdale/Phoenix, Ariz., and Jacksonville, Fla.
- Mercy Hospital Springfield in Springfield, Mo.
- Scott & White Memorial Hospital in Temple, Tex.
- Virginia Mason Medical Center in Seattle, Wash.
In a tweet, noted writer and surgeon Atul Gawande said, “This will change medicine.”
Walmart said that four of the hospitals — Cleveland Clinic, Geisinger Medical Center, Scott & White Memorial Hospital, and Virginia Mason Medical Center — will provide the cardiac procedures, including coronary artery bypass grafting, heart valve replacement/repair, closures of heart defects, thoracic and aortic aneurysm repair, and other complex cardiac surgeries. Three of the hospitals — Mercy Hospital Springfield, Scott & White Memorial Hospital, and Virginia Mason Medical Center — will perform the spine procedures. Mayo Clinic will continue to provide transplants.
“We devoted extensive time developing Centers of Excellence in order to improve the quality of care our associates’ receive,” said Walmart’s senior vice president of global benefits, in a press release. “We have identified six renowned health care systems that meet the highest quality standards for heart, spine, and transplant surgery. Through these hospital systems, our associates will have no out-of-pocket expenses and a greater peace of mind knowing they are receiving exceptional care from a facility that specializes in the procedure they require. This is the first time a retailer has offered a comprehensive, nationwide program for heart, spine, and transplant surgery.”
