Category Archives: cardiology
Two studies on the PCSK9 inhibitors evolocumab and alirocumab were recently published in the New England Journal of Medicine (see here and here). See this story by Larry Husten for the details. Evolocumab and alirocumab are monoclonal antibodies that are in development and are seeking FDA approval based on LDL-cholesterol reduction this year. The two studies were not designed to answer the question of whether evolocumab and alirocumab prevent cardiovascular events. Rather, the studies measured LDL reduction and tabulated adverse events over a 52- or 78-week time period. Among the adverse events being tabulated were cardiovascular events and there were fewer cardiovascular events in the patients who were in the evolocumab and alirocumab groups, as compared to patients who received placebo or usual care. One of the studies had prespecified an exploratory analysis of cardiovascular events. For the other study the investigators did a post hoc analysis of certain cardiovascular events. Neither study was powered (i.e., big and long enough) to provide a reliable estimate of the benefits of these drugs in reducing heart attacks, strokes and deaths. In other words, statistically speaking the studies were pretty thin gruel and the companies as well as the investigators acknowledge that fact. So, as of now, we really do not know that these drugs reduce the risk of cardiovascular events, let alone by how much. Nor do we really know how safe the drugs are. All these studies tell us is that as of now these drugs appear to be progressing satisfactorily along the path to approval and we just have to be patient for a couple of years until the results of the outcomes trials are available.
Fortunately, the sponsors have started large cardiovascular outcomes trials in high risk patients (e.g., the alirocumab trial will involve 18,000 patients and a minimum of 1613 primary endpoint events and a minimum two year followup — see here for a description of the trial).
I suggest taking a look at this short video of Harlan Krumholz speaking from the conference — I completely agree with his comments (website registration may be required). I also agree with the editorial by Donald Lloyd-Jones and Neil Stone, in which they state:
The ODYSSEY LONG TERM and OSLER studies whet our appetites for further results that show cardiovascular benefit and documented safety, even at substantially lower LDL cholesterol ranges than achieved before. However, it would be premature to endorse these drugs for widespread use before the ongoing randomized trials, appropriately powered for primary end-point analysis and safety assessment, are available. Reports from several lipid treatment trials provide important object lessons in this regard. Two trials of niacin revealed lower levels of LDL cholesterol and lipoprotein(a) when niacin was added to statin therapy but no net clinical benefit and very worrisome signals of harm. A randomized, controlled trial of torcetrapib reminds us that “off-target” effects can scuttle a promising drug. And the recent long-awaited presentation of results of a trial in which ezetimibe was added to moderate-intensity statin therapy in high-risk patients showed only modest benefit, though with excellent safety.
Advanced heart failure is a debilitating and lifethreatening disease that has become increasingly common as our population ages. Patients who have reached a point where their disease threatens their survival are not always candidates for heart transplantation. Even for those that are, only a limited number of donor hearts are available. In the last two decades, implantable pumps to supplement the heart’s function have become available. A left ventricular assist device (LVAD) is a mechanical pump that is implanted in heart failure patients to help the heart’s left ventricle pump blood throughout the body. An LVAD can be used as either a “bridge-to-transplant” to help a patient survive until a donor heart becomes available, or as “destination therapy,” to provide long-term support in patients who are not candidates for a transplant. An LVAD can in some cases prolong the life of heart failure patients whose symptoms can no longer be controlled with medications.
As with any other medical intervention, there are risks and burdens associated with LVAD implantation. The medical risks of the procedure include bleeding, development of blood clots, infection, respiratory failure, kidney failure, stroke, and device failure. LVAD patients must be connected to electricity at all times and are advised not to drive. Each LVAD patient must have a dedicated caregiver to assist with batteries, changing dressings, transportation, and activities of daily living. Heart failure patients often suffer from other medical problems that are not alleviated by LVAD placement. Quite a bit of emotional stress and in some cases financial stress is involved. In addition to heart failure cardiologists and cardiac surgeons, social workers and in some cases bioethicists and palliative medicine specialists meet with the patient to ensure that he or she understands the risks, benefits and alternatives to device placement. The patient must be in a position to make a well-informed decision as to whether to have an LVAD implanted, and it is not uncommon for patients to decline the procedure.
It must be recognized that cardiac surgery, including LVAD implantation, is big business for many medical centers. I was reminded of this when I received the Fall 2014 edition of Center Scope, the newsletter sent to patients and former patients of Medstar Washington Hospital Center (WHC), Washington, DC. I have embedded the newsletter below. The cover story focuses on a 66-year-old patient named Alberto Gomez, who received an LVAD at Washington Hospital Center. Mr. Gomez appears to be a somewhat atypical patient, in that he had enjoyed excellent health up until suddenly developing extreme fatigue and being diagnosed with advanced heart failure. In any case, Mr. Gomez seems to be a great guy, and I want to make clear that I do not intend to criticize him at all. Rather, my beef is with the way the public affairs & marketing department of WHC, which produces Center Scope, has used Mr. Gomez’s story to spin a happy tale in which “hope,” “determination,” and “faith” are the only things a person needs to manage serious illness.
Alberto’s mental strength and determination served him well. He did not need a blood transfusion during surgery, an often needed measure, and declined pain medication in recovery. And when a stroke he suffered after discharge initially left him with weakness and speech deficits, Alberto overcame them with hard work and perseverance. Currently, Alberto is on a transplant list for a new heart, which doesn’t stop him from living life. “I stay very busy,” he shares. “And I have no time for complaining.”
While Alberto’s heart now requires a LVAD to ensure proper function, his heart needs no assistance in dispensing generosity, kindness and faith. Since recovering from surgery, Alberto has made it a priority to return to the Hospital Center to visit with patients facing similar procedures. “I share my experiences,” Alberto says. “I pray with them and I cry with them. I tell them to trust in the doctors and the technology.”
I’m very glad that Mr. Gomez is doing well. However, I couldn’t help thinking that the message (from WHC, not Mr. Gomez) that a positive attitude can conquer all is a bit insulting to the many LVAD patients who don’t do well. Were their complications — or their need for pain medication — due to lack of determination?
At the end of the story is the following sentence: “For more information on our heart failure services, visit MedStarHeartInstitute.org/Trust.” I thought to myself that even though the story consisted of one long human interest anecdote, at least at this link I can find some more objective information. On going to the indicated webpage, however, I was disappointed to find only a shortened version of Mr. Gomez’s story and a link to the full version. (The WHC website does have some information on heart failure and LVADs, but I had to click around a bit in order to find it.) I get that hospitals want to advertise their services, but my message for Washington Hospital Center is, how about a little more objective information and a little less schmaltz.
The long-awaited IMPROVE-IT trial was presented last month at the American Heart Association Scientific Sessions. Here are the presentation slides:
IMPROVE-IT was a trial that tested the ability of ezetimibe (Zetia) to lower the risk of heart attacks and strokes when added to simvastatin. See Larry Husten’s background post here, and if you type “ezetimibe” in the search box on this blog or on the Gooznews blog, you will find some previous posts of mine relating to ezetimibe. I admit I was a bit surprised that the trial was positive. I was expecting it to be negative, based on the negative results of the ENHANCE trial. Still, the benefit was small, a 6.4% reduction in risk of the primary endpoint (composed of cardiovascular death, heart attack, unstable angina requiring hospitalization, coronary revascularization, and stroke). In the high-risk trial participants — all patients who had been hospitalized for acute coronary syndrome within the 10 days before randomization — this translated to a 2% absolute benefit over 7 years. Of note, there was no reduction in all-cause or cardiovascular mortality.
I only want to make a few comments now, but I intend to write more when the trial is published. First, a 6.4% reduction is risk is a very small benefit, and many people would only consider that reduction in risk meaningful in a high risk population. Second, it is regrettable that we had to wait 12 years after the drug’s approval to find out whether it improves outcomes.
The following is reposted from e-patients.net.
The American Heart Association journal Circulation: Cardiovascular Quality and Outcomes has announced a new Patient or Caregiver Viewpoint section in the journal. Viewpoints will be authored by patients or their caregivers and will discuss the patient’s experience of heart disease, stroke, or other cardiovascular disease and their interactions with the healthcare system.
As Harlan Krumholz and I explain in an Editor’s Note, the editors of the journal hope that Viewpoints “will contain insights from the patient’s perspective along with suggestions on how to improve clinical care and healthcare delivery.”
The first Viewpoint, by a heart disease patient, discusses how he experienced interactions with his physicians over whether he should start a blood pressure medication and his thoughts on how physicians and patients could work together in a manner consistent with the patient’s values and goals.
Viewpoints will contain a minimum of medical jargon and will be freely accessible to the public. The journal hopes to make these articles a regular feature. If you are a patient living with or at risk of cardiovascular disease, or a friend or family member of such a patient, please consider submitting a Viewpoint. Instructions for authors are posted on the journal’s website.
Circulation: Cardiovascular Quality and Outcomes will be publishing a new series of articles called narratives, which will be written by patients or by their family, friends or caregivers.
Narratives: The purpose of this series is to further understanding of patients’ experience of cardiovascular disease. These articles will be written by patients, or by their family members, caregivers, or friends. The articles will explore the effects of illness and treatment on patients’ lives and on their relationships with family, friends, caregivers, and health care providers. They will often discuss aspects of a condition that are important to patients but may not be fully appreciated by clinicians. We are especially interested in publishing narratives that contain lessons on the strengths and weaknesses of our health care system. They may, for example, be designed to help health care providers become aware of problems in communication of information, decision making, care coordination, access, cost, timeliness, safety, equity, and quality of care.
Recently, I joined the editorial board of Circulation: Cardiovascular Quality and Outcomes, the American Heart Association journal that focuses on quality of care and outcomes research. As my readers know, I became interested in cardiovascular disease because my daughter has heterozygous familial hypercholesterolemia, a genetic disease that cause high LDL-cholesterol and can lead to premature heart disease. I wrote this perspective for the November issue on how engaged patients can help bring about positive change in health care.
Last week, the American College of Cardiology announced that it had named Shalom Jacobovitz as its CEO. Since 2004, Jacobovitz has served as president of Actelion Pharmaceuticals U.S., Inc., the U.S. subsidiary of Swiss pharmaceutical company Actelion Pharmaceuticals Ltd. Prior to that, Jacobovitz held positions at F. Hoffman La Roche, Abbott Canada, Nordic Labs and Marion Merrill Dow (now known as Aventis), according to the ACC press release.
A little background on Actelion. The company has several approved drugs but 90% of its revenue comes from its drug for pulmonary arterial hypertension (PAH), Tracleer (bosentan). Tracleer’s patent will expire in a few years, so the company will need a replacement drug to avoid a drastic decrease in revenues when generic versions of Tracleer become available. The company has a drug in development for PAH and other indications called macitentan. In April 2012, the company announced that the phase III trial for macitentan in PAH met its primary endpoint. In the fourth quarter of 2012, the company filed applications with the FDA and EMA requesting approval for macitentan for the PAH indication. The trial, called SERAPHIN, has not been published but the results were presented at a conference and an abstract was published in CHEST.
I did a little googling to find out more about Actelion. One of the first things I found was this 2010 FDA warning letter. The letter, addressed to Jean-Paul Clozel, M.D., CEO of Actelion Pharmaceuticals U.S., Inc. (Shalom Jacobovitz is cc’d), states that the company had failed to comply with Postmarketing Adverse Drug Experience reporting requirements relating to Tracleer and two other Actelion drugs.
The Food and Drug Administration (FDA or “Agency”) inspected Actelion Pharmaceuticals’ (Actelion’s) facility located at the above address from June 24 through July 20, 2009. The inspection focused on Actelion’s compliance with Postmarketing Adverse Drug Experience (PADE) reporting requirements relating to the following drug products: Tracleer® (bosentan), NDA 21-290; Ventavis® (iloprost), NDA 21-799; and Zavesca® (miglustat), NDA 21-348. Both Tracleer® and Ventavis® are indicated for the treatment of forms of pulmonary arterial hypertension. Zavesca is indicated for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option. FDA’s inspection found that your firm failed to comply with the postmarketing reporting requirements imposed under 21 U.S.C. § 355(k) [Section 505(k) of the Federal Food, Drug, and Cosmetic Act (the Act)] and its corresponding regulations in Title 21 of the Code of Federal Regulations (21 C.F.R.) Section 314.80. Such failure to comply with Section 505(k) of the Act and its corresponding regulations is a prohibited act under Section 301(e) of the Act [21 U.S.C. § 331(e)]. Therefore, FDA concludes that Actelion has engaged in prohibited acts in violation of Section 301(e) of the Act.
The Agency is in receipt of your responses dated August 28, 2009, and September 11, 2009. It has been determined that the corrective actions you proposed are inadequate.
Actelion’s deviations from FDA’s reporting requirements observed during the inspection include, but are not limited to, the following: Failure to develop adequate written procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug experiences to FDA under 21 C.F.R § 314.80, and failure to report adverse drug experience information to FDA under 21 C.F.R. § 314.80, each of which is discussed, in turn, below. These deviations resulted in Actelion’s failure to report approximately 3,500 patient deaths reported to Actelion in connection with Tracleer® and Ventavis®, without an adequate basis for not reporting them. (emphasis added)
To be clear, the FDA is not saying that it has concluded that Actelion’s drugs caused these unreported deaths, but rather that Actelion failed to report these deaths without an adequate basis for not reporting them. The letter goes on to state that Actelion’s procedures for reporting postmarketing adverse drug experiences are in violation of the relevant FDA regulations in that they do not require reporting of death reports to FDA where there is a reasonable possibility that the drug caused the death. Without getting into all the details, the letter demolishes each of Actelion’s reasons for continuing to not report the deaths. The letter also requests a meeting with senior management to discuss the development of adequate procedures. There is also a link to a “close-out letter” dated June 13, 2012, in which the agency informs Actelion that it has evaluated Actelion’s corrective actions and determined that they are adequate.
To sum up the chain of events, the FDA inspected Actelion in 2009 and found inadequate procedures and failure to report patient deaths that were required to be reported. Actelion responded with various creative interpretations and rationalizations for why it shouldn’t have to change its way of doing things. FDA responded with a warning letter demolishing Actelion’s reasons for noncompliance and told them to comply or else. FDA then apparently met with senior management to walk them through basic regulatory requirements that they should have already been aware of. Two years later, FDA was finally able to conclude that Actelion was in compliance with its responsibilities. To be honest, I’m not impressed with Actelion’s performance here.
On to my next Google find. Not hard to find, actually, as it was recently discussed in the New York Times, on the Pharmalot blog, and on the FDA Law Blog here, here and here. The facts are that certain generic companies attempted to purchase samples of Tracleer and Zavesca (miglustat) from Actelion for the purpose of conducting bioequivalence studies in preparation for filing an application for FDA approval of generic versions of the drugs. Actelion refused to sell samples of the drugs to the generic companies and in September 2012 filed suit against the generic companies seeking declaratory relief that it is not required to sell them the samples. Tracleer was approved with a Risk Evaluation and Mitigation Strategies (REMS) program that limits distribution of the drug. Actelion argues that selling the samples to the generic companies would be inconsistent with the Tracleer REMS and certain distribution restrictions it has placed on Zavesca and that, in addition, it is not required to do business with anyone it doesn’t want to do business with. The generic companies argue that Actelion’s conduct violates antitrust laws. In an Amicus Brief, summarized here, the Federal Trade Commission supports the position of the generic companies, pointing out that Congress included language in the statute clarifying that REMS provisions may not be used to impede generic competition. The applicable statutory language states that no holder of a REMS-covered drug shall use an aspect of the REMS to “block or delay approval” of a generic drug application. The FTC explains that “If successful, conduct of the type alleged in this case threatens to undermine the careful balance created by the Hatch-Waxman Act and potentially preserve a brand firm’s monopoly indefinitely.” The FTC also supports the generic companies on the antitrust issues.
My next Google find on Actelion: several years ago, Actelion purchased CoTherix CoTherix had a preexisting contract with Asahi Kasei Pharma Corporation to develop and market Asahi’s drug fasudit for PAH and stable angina. Fasudil would most likely have been sold at a lower price than Tracleer, undermining Tracleer sales. In connection with the acquisition, Actelion frustrated contractual “change of control” provisions designed to assure continued fasudil development. After the acquisition closed, Actelion informed Asahi that it was no longer interested in developing and marketing fasudil. Asahi sued, asserting that the reason Actelion purchased CoTherix was to eliminate a potential competitor drug. A key document came to light during discovery — handwritten notes by an Actelion executive saying “buying both companies will leave the market for Tracleer free for Actelion.” Asahi won a large judgment against Actelion.
In 2010, Actelion disclosed that its U.S. subsidiary had received a subpoena from the U.S. Attorney’s Office for the Northern District of California “requesting documents relating, among others, to marketing and sales practices of Tracleer® in the United States.” I don’t know the status of this investigation. However, Jean-Pierre Garnier, former CEO of GlaxoSmithKline, is currently chairman of the board of Actelion. Garnier was singled out by DOJ for promoting GSK’s drug Advair for unapproved uses.
All of the above lead me to believe that Actelion is a very aggressive company, one that pushes the boundaries on what is permitted under the law.
Professional medical associations such as the ACC are under intense scrutiny with respect to their relationships with industry and conflicts of interest. The ACC has extensive ties to industry, with approximately 25% of its total consolidated revenues coming from industry. What message is the ACC sending by choosing someone with this kind of background? Perhaps that the ACC wants to become even cozier with industry? In my opinion, the ACC board of trustees should have looked elsewhere for their CEO.
Cardiologist Westby Fisher weighs in here.
Addendum 1/16/2014: Actelion announced that the Department of Justice declined to intervene in the qui tam action relating to the marketing of Tracleer. The qui tam plaintiffs voluntarily requested dismissal.
In March of this year, Larry Husten reported on CardioBrief that a review article in the Korean Circulation Journal by Chang Gyu Park and Ju Young Lee appeared to plagiarize from a review article in the Journal of the American College of Cardiology by Franz Messerli and Gurusher Panjrath. In April, Husten reported that the article was being investigated by the publishing committee of the Korean Society of Cardiology and Korean Association of Medical Journal Editors. It has just come to my attention that the KCJ article has been retracted. Here is the notice:
On July 31, 2011, Korean Circulation Journal (KCJ) published a review article by Park et al. regarding the J-curve in hypertension and coronary artery diseases. However, a possibility of plagiarism has been raised in this article.
The Editorial Board of KCJ has examined the review article and has requested the Committee for Publication Ethics of Korean Association of Medical Journal Editors (KAMJE) to provide an adequate conclusion. After thorough investigation, the Committee for Publication Ethics of KAMJE and the Editorial Board of KCJ have concluded that the article is seriously plagiarizing from an article by Messeri (sic) et al.
In this regard, on May 8, 2012, the Executive Committee of the Korean Society of Cardiology has finally decided to retract the article completely. We apologize for any inconvenience this may have caused.
For the past several years I have been following the ezetimibe controversy (see these posts on Gooznews and this blog here, here, here, here, here, here, here, here, here, here, here, here, here, here, and here). In my view, we continue to lack evidence of ezetimibe’s clinical benefit, or even safety, 10 years after FDA approval.
I have a Google Scholar Alert for ezetimibe, so often links to articles on ezetimibe arrive in my email inbox. Recently, two review articles on ezetimibe were published that were a study in contrasts. The first, by Sheila Doggrell, takes a skeptical view toward ezetimibe and reaches the following conclusion:
The comparison of clinical trials with simvastatin and ezetimibe alone and together has clearly shown that simvastatin decreases LDL-cholesterol and this is associated with improved clinical outcomes. Also, ezetimibe alone or in the presence of simvastatin lowers LDL-cholesterol. However, ezetimibe alone or in the presence of simvastatin has not been shown to have any irrefutable beneficial effects on clinical outcomes. Thus, until/unless the use of ezetimibe is clearly shown to improve clinical outcomes, its use should be largely restricted to clinical trials investigating clinical outcomes, and ezetimibe should not be used routinely in everyday practice.
The second, by Binh An Phan, Thomas Dayspring and Peter Toth, takes a much more optimistic view:
In the current treatment of cardiovascular disease, many subjects fail to reach LDL-C targets or remain at high risk for CHD events despite optimal statin and medical therapy. Ezetimibe inhibits intestinal cholesterol absorption and is effective in lowering cholesterol as monotherapy or in combination with statins in several populations, including those with FH, sitosterolemia, and insulin resistance. Significant controversy has been generated regarding the clinical effectiveness of ezetimibe, particularly after the publication of ENHANCE and ARBITER-6 despite both trials having significant methodological flaws that limited their ability to evaluate the benefit of ezetimibe. Growing data suggest that ezetimibe in combination with statin has a positive effect on the progression of atherosclerosis and reduces cardiovascular events in subjects at risk for CHD, including those with chronic kidney disease. Results from IMPROVE-IT are forthcoming and may help to guide better the use of ezetimibe in very high-risk CHD populations. Until that time and based upon the current available data, ezetimibe should remain a viable adjunct to statin therapy in the treatment of hypercholesterolemia.
Dr. Phan and colleagues find reasons to dismiss the negative results of ENHANCE and ARBITER 6-HALTS as due to “methodological flaws” and use copious amounts of hand-waving to find support for ezetimibe in the SEAS and SHARP trials, even though those trials compared the combination of simvastatin and ezetimibe with placebo and thus can tell us nothing about what, if anything, ezetimibe added to those results. Could the differing views of Doggrell and Phan et al. have anything to do with the fact that Dr. Doggrell declares no conflicts of interest relating to ezetimibe, while Phan, Dayspring and Toth declare the following conflicts:
Binh An Phan is a speaker for Abbott. Thomas Dayspring consults for Abbott, GSK, Health Diagnostic Labs, Kowa Company, Eli Lilly, Merck, Genentech, The Roche Group, Genzyme, and Omthera. He is on the Lecture Bureau for Abbott, GSK, Health Diagnostic Labs, Kowa, Eli Lilly, LipoScience, Merck. Peter P Toth is a speaker for Abbott, AstraZeneca, Amylin, Boehringer-Ingelheim, GSK, Kowa, Merck and consults for Abbott, Aegerion, AstraZeneca, Atherotech, Genzyme, Genentech, Kowa, and Merck.
It is not too surprising that authors who are consultants and on the speaker’s bureau for Merck would take a favorable view of ezetimibe. What is surprising is that anyone would take their word for it.
Doggrell SA. The ezetimibe controversy — can this be resolved by comparing the clinical trials with simvastatin and ezetimibe alone and together? Expert Opin. Pharmacother. (2012) 13(10):1469-1480.
Phan BAP, et al. Ezetimibe therapy: mechanism of action and clinical update. Vascular Health and Risk Management 2012:8:415-427.