This Week In Medicine: Stop Exercising and Eat Chocolate! 5

It’s been a terrific few days of medical news for lazy people and chocoholics.

First, a study in PLoS One provided ammunition to the exercise-averse crowd by claiming that exercise can actually be bad for some healthy people. As an added bonus, a story about the study was carried on the front page of the New York Times.

Less than a day later, in a moment that will be long treasured by chocoholics, a study in BMJ calculated that people with metabolic syndrome could reduce their risk of serious cardiovascular events like heart attacks and strokes by eating dar chocolate every day.

Let’s take a quick look at each study:

The exercise study used data from 1,687 people who participated in one of six different exercise studies and found that a surprisingly large percentage of people had a significant adverse change in one of several important risk factors:
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Fascinating Debate Over Statins For Primary Prevention 2

The recent guest post by David Newman has prompted several thought-provoking comments. Since most readers will likely miss the comments, I’ve moved these comments to a separate post.

Statin Island May 27, 2012, 3:35 PM:

Thank you. Clearly, this important commentary raises questions about the integrity of Lancet as well as the authors of the study.

But what is most discouraging, and dangerous, is that this kind of deception occurs so frequently. Meanwhile, major news outlets, television channels, etc. have reported the results as the authors intended. And so the gravy train has left the station.

Lancet should publish a clarifying editorial and send it everywhere they can. They are an accessory to any harm that has resulted, to patients and to the credibility of medical science.

Michael V Holmes (@mvholmes) (May 28, 2012, 10:10 AM:

I disagree with this critique. The authors weighed each RCT by the LDL-C lowering to be able to provide a standardized comparison across the studies (it’s in the Methods of the paper). By doing so, they didn’t break the randomization, and shouldn’t have introduced confounding, as suggested by this commentary piece. And being able to say “for each 1 mmol/L LDL-C reduced, the RR of CHD is 0.79, 95% CI 0.77, 0.81″ is very helpful metric.

Larry Husten (May 28, 2012, 12:31 PM:

I don’t claim to be an expert in meta-analysis but I’m not sure that Holmes is responding to the fundamental flaw in logic in the Lancet paper raised by Newman. The Lancet paper– correctly, as Newman acknowledges– identifies a benefit for statins in people who respond to statins, but it says nothing about the broader primary prevention population, some of whom will not respond to statins. The conclusion reached by the CTT authors, that statins should be more widely used in this primary population, is therefore unwarranted.

I am hopeful that Dr. Newman will respond in more detail and discuss the technical issues raised by Holmes.

MDinSTL (May 30, 2012, 11:32 AM):

Within any randomized group, some will do better than others. When targeting a lower LDL, those who achieve and maintain the target do better than those who do not. This phenomenon has been called dose targeting bias.

What is key to understand though is that an intervention may have NO benefit, yet this relationship of better LDL lowering to better outcomes can still be observed.

Therefore if the trials show no net benefit between statin vs placebo, it is not necessarily true that the subgroup analysis the Lancet group employs means some people benefited.

This is easiest to see by considering this point: If the statin-treated non-CAD patients had no overall reduction in mortality, and the subgroup with a large LDL drop did have lower mortality, then those without a large LDL drop must have been harmed by statins to account for the lack of overall effect compared to the placebo-treated patients.

If investigators really believe some benefit from statins accrues to those without apparent CAD provided LDL falls at least 40 pts, then the answer is to perform a trial where entry criteria include an ability to show a 40 pt drop in LDL, then randomize pts to statin vs no statin. That ain’t gonna happen because 1. few seriously believe that, and 2. this message is really a marketing message intended to promote use of statins in the general population.

DH Newman(May 28, 2012, 5:08 PM: 
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Guest Post: Data, Drugs, And Deception– A True Story 15

Editor’s Note: The following guest post by Dr. David Newman is reprinted with permission from his website and blog, Smartem.Org. Dr. Newman is an Emergency Physician and Director of Clinical Research at Mt. Sinai School of Medicine in the Department of Emergency Medicine.  He is the author of the critically-acclaimed Hippocrates’ Shadow: Secrets From the House of Medicine. CardioBrief readers might also enjoy watching his TED talk, Truth That Lasts.

Data, Drugs, And Deception– A True Story

by Dr. David Newman

Last week The Lancet published a meta-analysis of 27 statin trials, an attempt to determine whether patients with no history of heart problems benefit from the drugs — true story. The topic is controversial, and no less than six conflicting meta-analyses have been performed — also a true story. But last week’s study claims to show, once and for all, that for these very low risk patients, statins save lives — true story.

Actual true story: the conclusions of this study are neither novel nor valid.

The Lancet meta-analysis, authored by the Cholesterol Treatment Trialists group, examines individual patient data from 27 statin studies. Their findings disagree with an analysis published in 2010 in theArchives of Internal Medicine, and with analyses from two equally respected publications, theTherapeutics Letter and the Cochrane Collaboration.* Despite this history of dueling data the authors of last week’s meta-analysis, in a remarkable break from scientific decorum, conclude their report with a directive for the writers of statin guidelines: the drugs should be broadly recommended based on the new analysis.

As an editorialist points out, if implemented, the CTT group recommendations in the United States would lead to 64 million people, more than half of the population over the age of 35, being started on statin therapy — true story.

Where is the magic, you ask, in this latest effort? What is different? In some ways, nothing. Indeed just a year and a half earlier The Lancet published a meta-analysis of 26 of the same 27 studies, with the same results, by the same authors (true story, and an odd choice on the part of the journal). So the findings aren’t new. They are, however, at odds with other meta-analyses. Why? It is the way they calculated their numbers. This meta-analysis, like the earlier one from the same group, reports outcomes per-cholesterol-reduction. The unit they use is a “1 mmol/L reduction in low density lipoprotein (LDL)”, in common U.S. terms, a roughly 40-point drop in LDL.

That’s the magic: each of the benefits reported in the paper refers to patients with a 40-point cholesterol drop. Voilá. One can immediately see why these numbers would look different than numbers from reviews that asked a more basic question: did people who took statins die less often than people taking a placebo? (The only important question.) Instead, they shifted the data so that their numbers corresponded precisely to patients whose cholesterol responded perfectly.

Patients whose cholesterol drops 40 points are different than others, and not just because their body had an ideal response to the drug. They may also be taking the drug more regularly, and more motivated. Or they may be exercising more, or eating right, and more health conscious than other patients. So it should be no surprise that this analysis comes up with different numbers than a simple comparison of statins versus placebo pills. Ultimately, then, this new information tells us little or nothing about the benefits someone might expect if they take a statin. Instead it tells us the average benefits among those who had a 40-point drop in LDL.
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Aspirin Found To Prevent Recurrent Venous Thromboembolism 1

Aspirin can help prevent the recurrence of venous thromboembolism (VTE) after discontinuation of anticoagulation therapy, according to results of the WARFASA (the Warfarin and Aspirin) study published in the New England Journal of Medicine.

Following 6 to 18 months of oral anticoagulation, 403 patients with first-time unprovoked VTE were randomized to aspirin (100 mg daily) or placebo for two years. Aspirin therapy resulted in a significant reduction in VTE but did not cause an increase in the risk of bleeding:

  • VTE recurrence: 6.6% per year in the aspirin group versus 11.2% in the placebo group (hazard ratio 0.58, CI 0.36 to 0.93, p=0.02).
  • Major bleeding occurred in one patient in each treatment group.

In an accompanying editorial, Richard Becker writes that the results of WARFASA “are compelling and may signal an important step in the evolution of care” but calls for additional studies to more precisely define the role of aspirin in preventing recurrent VTE. The results of a larger trial, the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) study, will be reported this year, according to Becker, and, in conjunction with WARFASA, “may provide more reliable evidence of the effect of aspirin in patients with first unprovoked venous thromboembolism.”

FDA Advisory Committee Recommends Against ACS Indication For Rivaroxaban 1

The FDA’s Cardiovascular and Renal Drugs Advisory Committee voted against adding an indication for acute coronary syndromes (ACS) to the label  of the anticoagulant rivaroxaban (Xarelto). The vote was 6 to 4 against approval, with 1 abstention.

The advisory panel spent most of the day trying to reconcile diametrically opposed views of the pivotal ATLAS ACS 2-TIMI 51 trial. On the one hand, the sponsor (Johnson & Johnson) and the TIMI investigators (Jessica Mega, C. Michael Gibson, and Eugene Braunwald) portrayed a robustly positive trial that strongly demonstrated the beneficial effects of low dose rivaroxaban in ACS when added to dual antiplatelet therapy. On the other hand, one FDA reviewer, Medical Team Leader Tom Marciniak, raised multiple questions about the validity of the trial and its conclusions because of an alarming amount of early withdrawals and missing data. His view was largely endorsed by several committee members, including Steve Nissen and Sanjay Kaul.

In a press release, J&J said it “will ensure the questions raised today are addressed with the FDA.”

See my previous post for a detailed live account of the advisory committee meeting.

Live Blog: The FDA Advisory Panel For Rixaroxaban for ACS 1

Here’s my live-blogg of the FDA’s Cardiovascular and Renal Drugs Advisory Committee meeting to consider the supplemental new drug application (sNDA) for rivaroxaban (Xarelto, Johnson & Johnson) for use in patients with acute coronary syndrome (ACS) already taking dual antiplatelet therapy. Here is a link to the FDA briefing documents.


4:48: Meeting adjourned! J&J has just issued a press release saying they will “ensure the questions raised today are addressed with the FDA.”

4:45: Temple is raising the possibility that the FDA might ultimately approve rivaroxaban for ACS. I would not be shocked if this were to happen.

4:38: Now discussing whether the FDA should say about the use of rivaroxaban with thienopyridine. All agree that people should be on a thienopyridine. What about prasugrel and ticagrelor? Nissen says the reality is that rivaroxaban will be given with these drugs, even though there’s no evidence. This was part of his reasoning in voting no. Sager said he would be more concerned about prasugrel, because of the excess risk of bleeding associated with prasugrel. But he notes there is no evidence to support use with either drug.

4:33: Moving on to questions about what to do if rivaroxaban is approved. Everyone agrees that the 2.5 dose is the dose that would get approved.

4:30: Kaul said he wished he had had the courage to abstain (to general laughter) and said he agrees with Fleming that he’d rather advise than vote, and that there was a very fine line between yes and no today.

4:24: Nissen thinks the decision to use mITT– which is counting events at 30 days after stopping treatment– is what doomed ATLAS. With mITT, he says, you’re telling the investigators and the patients that you don’t care so much about what happens to them long term. Nissen thinks the drug could be approvable if there were a second trial, but he also says its possible that the mortality benefit would not be replicated. He’s worried about exposing hundreds of thousands of patients to a three-drug regimen and causing lots of bleeding complications.

4:18: Results: Yes 4, No 6, 1 Abstain!

Voting breakdown:
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Studies Probe Effect Of CPAP And Sleep Apnea On Hypertension Reply

Two studies published in JAMA provide additional but not surprising information about the relationship between obstructive sleep apnea (OSA), hypertension, and the role of continuous positive airway pressure (CPAP).

In the first study, Ferran Barbé and colleagues randomized 725 people with OSA but no daytime sleepiness to either CPAP or no active treatment. Although there were fewer cases of systemic hypertension or cardiovascular events in the CPAP group than in the control group after a median followup of 4 years, this difference did not reach significance.

Incidence of hypertension or cardiovascular events:
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Rivaroxaban For ACS Gets Positive FDA Review, But Questions About ATLAS Trial Conduct Persist 2

The FDA will offer generally positive but also highly mixed advice to the FDA’s Cardiovascular and Renal Drugs Advisory Committee  when it meets on Wednesday to consider the supplemental new drug application for rivaroxaban (Xarelto, Johnson & Johnson) for use in patients with acute coronary syndrome (ACS) already taking dual antiplatelet therapy. The FDA posted the briefing documents on its website this morning.

Although the primary clinical review and the statistical review support approval for the new indication (the drug is already approved for venous thromboembolism prophylaxis and stroke prevention in AF), one reviewer, Thomas Marciniak, the Medical Team Leader, issued a blistering memorandum suggesting that the supporting data, plagued by missing and inconsistent records in the pivotal ATLAS ACS 2-TIMI 51 trial, “may not support the favorable statistical results.”

The primary clinical reviewer, Karen Hicks, recommended approval for the 2.5 mg BID dose (but not the 5 mg dose) of rivaroxaban for ACS. She noted that the lower dose reduced the combined endpoint of CV death, nonfatal MI, or nonfatal stroke  in the ATLAS trial, with most of the benefit driven by a reduction in CV death, with little or no difference in MI or stroke. The higher 5 mg dose increased bleeding risk in the trial without providing additional efficacy, she concluded. She did not recommend a mortality indication for the label. Her views generally coincide with the reception of the ATLAS trial following its presentation and publication in the New England Journal of Medicine.

It should be noted that Hicks hedged her endorsement with a potentially significant caveat:
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You Know Nothing, Dr. Snow: Why Medicine Can’t Be More Like Facebook 3

Medicine can never be like Facebook, despite what Matt Herper argues over at Forbes. Perhaps he was just trolling for hits on a day when everyone is thinking about the Facebook IPO, but Herper proposed, with apparently seriousness, that medicine needs to model itself on the tech world in order to match the kind of progress– and profits– of a Facebook. But the medical news this week provided ample evidence why this will never happen. Biology is much more complex and resistant than the digital world.

For a medical journalist like myself this was a frustrating week. There were a whole bunch of large, major studies on important subjects published in top journals. But the take-away message from these studies, both individually and combined, is that achieving any kind of real progress in medicine is incredibly hard.

Let’s take a quick look at these studies:

1. Coffee in the New England Journal of Medicine: Despite some of the breathless news reports, some of which erroneously claimed that the study proved that drinking coffee can extend your life, this large study added little or nothing new to our knowledge about coffee. Even the editor of the journal, Jeff Drazen, acknowledged the limitations of this sort of study. The simple truth is this: although coffee is ubiquitous and has been the subject of hundreds of different studies of all different types and designs, we will almost certainly never learn to any degree of certainty whether coffee is good or bad for us. An enormous, decades-long randomized controlled clinical trial, which is the only possible way to ascertain the truth about coffee with any degree of certainty, would be nearly impossible to perform, for multiple reasons.

I don’t want to overstate my pessimism here. I think there is a much more limited lesson that can be derived from this NEJM study and the rest of the coffee literature. From the totality of the evidence it seems highly unlikely that coffee has any large effect, either positive or negative, on important outcomes like mortality or cancer. But we’ll never know for sure about small effects, and we will certainly never know if there are small populations or individuals who are particularly likely to derive benefit or harm from coffee.

2. HDL Cholesterol in the Lancet. In some respects the HDL cholesterol story is exactly the opposite of the coffee story. Unlike coffee, the epidemiology of HDL is clear-cut, and therefore the reverse association of HDL with cardiovascular disease is among the best established facts in all of medicine. But association is not causation, and despite more than a generation of intense research we still don’t know how– or even if– HDL works. In fact, as its name implies, high density lipoprotein is not so much a biological entity as an artificial construct of something that we can measure easily.
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FDA Approves Generic Clopidogrels As Plavix Loses Patent Protection 1

For the second time in the past six months, a cardiology mainstay drug has lost patent protection and gone generic. Today the FDA announced that it had approved several generic versions of clopidogrel (Plavix), the antiplatelet drug that for many years was the second best-selling drug in the world. Last November the best-selling drug of all time, Lipitor (atorvastatin), another cardiology mainstay, went off patent, though it wasn’t until earlier this month that multiple generics became available.

The FDA said that it had approved 300 mg formulations of clopdiogrel from Gate Pharmaceuticals, Mylan Pharmaceuticals, and Teva Pharmaceuticals and 75 mg formulations from Apotex Corporation, Aurobindo Pharma, Mylan Pharmaceuticals, Roxane Laboratories, Sun Pharma, Teva Pharmaceuticals, and Torrent Pharmaceuticals.

In recent years the FDA approved two newer antiplatelet drugs that had been designed to take over the central role of Plavix in treating acute coronary syndromes. However, these drugs, prasugrel (Effient) and ticagrelor (Brilinta) have been struggling in the marketplace, and at this point appear very unlikely to command a significant share of the market.
Click here to read the FDA press release…

Large Metaanalysis Finds Statins Effective in Low Risk Patients Reply

A very large metaanalysis provides strong evidence that the relative reduction in risk of statins is at least as great in low-risk patients as in high-risk patients. The finding, write the authors, provides evidence that expansion of guidelines to lower risk populations should be considered.

In their paper in the Lancet, the  the Cholesterol Treatment Trialists’ (CTT) Collaborators analyzed data from 134,537 patients in trials comparing statins to control therapy and 39,612 patients in trials comparing low and high dose statins. They examined the impact of statin therapy according to the baseline 5-year risk of a major vascular event on control therapy.  Statin therapy caused a consistent reduction in the relative risk of major vascular events and all-cause mortality independent of other factors, including age, sex, baseline LDL cholesterol, or established CV disease.

Here is the rate ratio for major vascular events across five levels of risk at baseline (note that 1 mmol of LDL cholesterol is equivalent to about 39 mg/dl of LDL):

        5 Year Risk         Rate ratio per 1.0 mmol/L of LDL reduction

  • <5%                          0·62 [99% CI 0·47–0·81]
  • ≥5% to <10%          0·69 [99% CI 0·60–0·79]
  • ≥10% to <20%       0·79 [99% CI 0·74–0·85]
  • ≥20% to <30%       0·81 [99% CI 0·77–0·86]
  •  ≥30%                       0·79 [99% CI 0·74–0·84]

The metaanalysis found no evidence for harm associated with statin therapy, including cancer or other non-vascular mortality.

The authors noted that people in the lowest two categories of risk in the study, who are expected to have a 5 year event rate lower than 10%, are not recommended for statin therapy in current guidelines. As generic statins are highly cost-effective, the result “suggests that these guidelines might need to be reconsidered.”

In an accompanying comment, Shah Ebrahim and Juan Casas ask whether everyone over the age of 50 should take statins. They calculate that, in the UK, adoption of a threshold of 10% would result in 83% of men over 50 years of age and 56% of women over the age of 60 as needing statins.
Click here to read the Lancet press release…

Robert Hauser, ICD Watchdog, Offers Viewpoint On Riata Controversy At HRS Reply

Editor’s Note: The following guest post is published with the permission of its author,  Edward J. Schloss, MD, (Twitter ID @EJSMD) the medical director of cardiac electrophysiology at Christ Hospital in Cincinnati, OH.

Robert Hauser, ICD Watchdog, Offers Viewpoint On Riata Controversy At HRS

by Edward J Schloss MD

The St. Jude Riata ICD lead controversy took center stage at last week’s Heart Rhythm Scientific Sessions in Boston, as previously reported here.  Near the end of the meeting a leading figure in the field, Dr. Robert Hauser, of the Minneapolis Heart Institute, summarized the current state of the Riata crisis and discussed its broader implications. Hauser has played key roles in the Riata and several other similar, highly disturbing cases, including those involving the Sprint Fidelis ICD leads and the Prizm 2 DR ICD device malfunction.

In a troubling revelation near the end of his talk, Hauser suggested that St. Jude’s problems may not end with the now discontinued Riata leads, and that the company’s Durata leads may have failure mechanisms not previously reported.

Hauser first discussed an abstract from Steinberg and associates from Quebec.  These investigators used chest x-rays rather than fluoroscopy to detect Riata externalizations:

They, like others, found a far higher incidence of externalized conductors than what has been reported by St. Jude Medical.  And frankly, this and other reports presented at this meeting raise serious questions about the accuracy of the data that the manufacturer has communicated to us.  What we learned today is that this externalized cable process is time dependent.  It seems to be occurring more frequently in the 1580 leads, particularly in the 8 French, and that with time we are going to see progression.  The fact that these investigators were able to use special chest radiographs to identify externalized conductors is interesting and deserves further study by comparing the sensitivity and specificity of their technique to high-resolution cine-flouroscopy

Hauser then discussed the Riata extraction experience from Royal Victoria Hospital in Belfast, and then offered some practical advice:
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No Benefit Found For Exercise Echocardiography In Asymptomatic Patients Following CABG Or PCI 1

Routine exercise echocardiography in asymptomatic patients after revascularization does not lead to better outcomes, according to a new study published in Archives of Internal Medicine. Although guidelines generally discourage the practice, post-revascularization stress tests are still commonly performed.

Serge Harb and colleagues performed exercise echocardiography on 2,105 patients following CABG surgery or PCI and followed them for a mean of 5.7 years. 13% of the subjects were found to have ischemia. One-third of these underwent repeat revascularization. Nearly half (49%) of the patients without ischemia on the initial test underwent further exercise testing. Overall, 17% of patients in the study underwent repeat revascularization. However, revascularization had no significant impact on mortality.

Mortality was higher in patients who had ischemia at any time than in patients with no ischemia (8% versus 4.1%, p=0.03). However, the authors reported that “clinical and stress testing findings, but not echocardiographic features, were associated with both all-cause and cardiac mortality.” This finding, according to the authors, suggests “that risk evaluation could be obtained from a standard exercise test rather than exercise echocardiography.”

The authors write that “careful consideration is warranted before the screening of asymptomatic patients is considered appropriate at any stage after revascularization.”

In an accompanying commentary, Mark Eisenberg writes that the study makes “a compelling argument that routine periodic stress testing in asymptomatic patients following coronary revascularization is of little clinical benefit.”

Click here to read the press release from Archives…

Xience Stents Gain European Nod For Three-Month Dual Antiplatelet Therapy Reply

The biggest drawback to drug-eluting stents has been the requirement for prolonged dual antiplatelet (DAPT) therapy following stent implantation to prevent stent thrombosis and other potential complications. The precise length of DAPT has been the subject of considerable discussion and research.

Now the Xience Prime and Xience V everolimus-eluting stents have received the CE Mark in Europe for a DAPT length of only three months, according to an Abbott press release. The manufacturer of the stents, Abbott, said this was the “shortest duration  for any major drug eluting stent (DES) in Europe.”

Abbott said that data presented this week at the EuroPCR congress found no cases of stent thrombosis in more than 10,000 patients who received a Xience stent and who discontinued DAPT after three months.

An Abbott spokesperson told CardioBrief that the company is “currently exploring our filing strategies with the FDA for a three-month DAPT indication.”
Click here to read the press release from Abbott…

Returning To Detroit, William O’Neill Heads To Henry Ford Hospital Reply

Interventional cardiology leader William O’Neill is leaving the University of Miami Miller School of Medicine to become the medical director of the new Center for Structural Heart Disease at Henry Ford Hospital in Detroit. The new center will focus on new minimally-invasive treatments for heart failure and heart valve disease.

Prior to going to Miami in 2006, where he had been the executive dean for Research, Research Training and Innovative Medicine, O’Neill had spent 20 years in the Detroit area as the director of the division of cardiovascular medicine at William Beaumont Hospital. Prior to that he was the director of the cardiac catheterization laboratory at the University of Michigan.

O’Neill told the Detroit Free Press that he considers research in heart failure and valve problems to be his new career passion. “I’ve come to realize I love doing it,” said O’Neill.

Click here to read the press release from Henry Ford Hospital…

Revascularization In New York State: High Questionable Rates For PCI But Not CABG Reply

A large study looking at real world usage of elective coronary artery bypass surgery (CABG) and stenting (PCI) in New York State finds that nearly two-thirds of PCI procedures have inappropriate or uncertain indications. By contrast, 90% of CABG procedures were deemed appropriate and 1.1% inappropriate.

In a paper published in the Journal of the American College of Cardiology, Edward Hannan and colleagues analyzed data  from NY State patients who received CABG or PCI in 2009 and 2010 and applied appropriate use criteria (AUC) from the ACC, the AHA, and other organizations. (The study only included patients without an acute coronary syndrome (ACS) or previous CABG, as these indications have not generally been the subject of previous concern. By contrast, a large, controversial study last year, that found a significant percentage of nonacute PCIs were performed for inappropriate or uncertain indications, included patients both with and without ACS.)

Here are the main findings of the study:
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FDA Advisory Panel Recommends Approval For Weight Loss Drug Lorcaserin Reply

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted to recommend approval of lorcaserin (Lorqess, Arena). The result signals a remarkable turnaround for the drug, which the same panel had rejected in September 2010. The vote was 18 in favor of approval, 4 against, and 1 abstention.

Committee members seemed less disturbed this time around about the issues that concerned them at the earlier meeting. The theoretical risk of an increase in cancer was discussed at length but did not appear to bother the panel. Valvulopathy and cardiovascular adverse events were the major obstacles. For valvulopathy, although the data from Arena did not allow the FDA reviewers to rule out an increased relative risk of 1.5 with lorcaserin, the absolute incidence of valve problems was low. A few panel members raised the idea of requiring echocardiograms prior to prescribing lorcaserin.

An increased risk of cardiovascular adverse events could not be ruled out by the committee, but members felt that it would be unfair to change the rules in midstream and require a CV events study prior to approval. It appears likely that the FDA will require a post-approval outcomes study if the drug is approved, however.

Committee members wrestled for much of the day with questions about the drug’s modest efficacy in producing weight loss, a problem that was exacerbated by the high rate of dropouts in clinical trials. Ultimately, however, Arena was able to demonstrate that the drug met one of the predefined FDA criteria for efficacy.

Sanjay Kaul, a panel member who was one of the four negative votes, provided the following comment:
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Guest Post: Shedding Light On Riata At The Heart Rhythm Society Meeting 2

Editor’s Note: The following guest post is published with the permission of its author,  Edward J. Schloss, MD, (Twitter ID @EJSMD) the medical director of cardiac electrophysiology at Christ Hospital in Cincinnati, OH.

Shedding Light On Riata At The Heart Rhythm Society Meeting

by Edward J Schloss MD

This morning in Boston, HRS 2012 sessions began with a state of the art session on St. Jude ICD leads.  Riata, Riata ST and Durata are being discussed at the first large electrophysiology meeting since this lead came under FDA recall.

It was obvious at the outset, that this is a vital topic to the EP community.  Those who didn’t arrive early were relegated to a remote viewing station.  Even there, the crowd was very large and engaged.

Kenneth Ellenbogen started the presentation with updated data on the VA Riata and Riata ST leads.  Interestingly, this data actually showed an increased failure rate of Riata ST as compared to Riata.  This stands in distinction to data from the Minneapolis Multicenter Data presented later in the late breaking trials session.

Things got interesting with the discussions of the clinical aspects of Riata lead management.  Dr. Larry Epstein of Boston highlighted potential management strategies.  He advised against placement of a sensing lead alone if the lead is failed.  In explaining why “I’m scared about Riata,” he gave the account of a patient with completely normal lead parameters that fortuitously suffered a cardiac arrest in his hospital.  The ICD was ineffective at terminating the arrhythmia and the patient had to be externally defibrillated.  To screen for these sort of silent lead failures, he performs fluoroscopy and high-energy shock delivery on his Riata leads before scheduled generator changes.

Dr. Roger Carillo of Miami outlined his approach to Riata lead management as well.  He expressed concern over the potential for thrombus formation on externalized leads.  He advocated routine fluoroscopic exams on all Riata leads.  He then performs transeophageal echo on externalized leads and anticoagulates those with thrombus.  He presented a step-by-step account of the unique challenges of Riata lead extraction.  Warning of a variety of pitfalls and complications, he added, “if you fail to follow any of these steps, the lead will not forgive you.”

The session ended with more calming words from Charles Love of Columbus.  In his talk on Durata leads, he repeatedly emphasized “it is a very, very different lead.”  He spent some time going over the design of all St. Jude leads and pointed out the potential benefit of the Optim insulation coating added to Durata and Riata ST Optim leads.  Active registries on these newer leads continue to show robust performance approaching 5 years.  He did acknowledge the small numbers of leads in late follow up.  But in the question and answer section, not all were convinced.  Dr. Larry Epstein stated, “I still have issues with trust.”

Atorvastatin Lifts Ranbaxy While Pfizer Abandons Its Lipitor Marketing Efforts Reply

Pfizer will no longer aggressively market Lipitor (atorvastatin), its former crown jewel and the most lucrative pharmaceutical product ever. At the same time, generic drug manufacturer Ranbaxy posted record revenue for the last business quarter, growth fueled largely by sales of generic atorvastatin in the United States.

Pfizer told the Wall Street Journal that it was abandoning efforts to market Lipitor. It said it was no longer selling Lipitor to health plans, that it had stopped using drug reps to promote the drug to physicians, and that it had ceased all Lipitor advertising. The Pfizer move comes after the expiration of the Lipitor patent last fall but immediately prior to May 31, when a host of new generic versions of atorvastatin are expected to enter the marketplace.

Pfizer mounted an aggressive campaign to retain as much of the atorvastatin market as possible in the early days after the loss of market exclusivity. In the first quarter, according to the Journal, Lipitor revenues for Pfizer were $383 million. This was more than most analysts had originally anticipated, until Pfizer rolled out its aggressive campaign, but paled in comparison to the $12.9 billion annual sales of the drug at its peak. Pfizer said it had spent $87 million marketing Lipitor in the quarter.

Also in the first quarter, Ranbaxy sales in the US doubled to $375 million. This was the first full quarter in which the company sold generic atorvastatin. In March, for the first time, Ranbaxy had a greater share of the atorvastatin market than Pfizer, according to Fierce Pharma.


Persistent Concerns About Lorcaserin (Lorqess) From FDA Reviewers Reply

The FDA has posted briefing documents for Thursday’s meeting of the Endocrinologic and Metabolic Drugs Advisory Committee to reconsider the new drug application for lorcaserin (Lorqess, Arena). The same panel recommended against approval of the drug in September 2010, citing weak efficacy and safety concerns.

The FDA reviewers do not appear to have substantially altered their view of lorcaserin. There are no major new safety concerns, but the limited efficacy of the drug gives little reason for panel members to take a risk.

The same safety signals– in particular, lingering concerns about heart valve problems– remain. It is unclear whether new, previously unpublicized data submitted by Arena on the effect of lorcaserin on the serotonin receptor (the source of previous heart valve problems with phen/fen) will move the dial on this issue. One important note of caution here: although no statistically significant increase in risk of valve disease was found by the FDA (relative risk 1.16, 95% CI 0.81-1.67), the reviewer noted that the “upper bound exceeds the 1.5 upper bound requested by FDA to rule out an excess risk of VHD.”

The cancer issue seems less important this time, although its earlier significance may have been overstated.

Although the draft discussion questions for the committee mostly focus on the safety issues, I suspect that the efficacy data will actually play a more important role in determining how the committee votes. The efficacy data has not substantially changed since the previous meeting. A new trial, BLOOM-DM, is consistent with the previous trials, demonstrating a modest effect that meets some but not all of the FDA predefined criteria for efficacy.

Here’s how the FDA’s statistical reviewer summarized the efficacy findings:
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All Dressed Up And No Place To Go: False-Positive Activation Of The Cath Lab For Primary PCI Reply

Primary PCI is widely recognized as the best early option for patients with  ST-segment elevation myocardial infarction (STEMI). However, efforts to deliver primary PCI to the broadest possible population inevitably result in an increased number of false-positive activations of the cardiac catheterization laboratory. Now, a new studypublished in the Archives of Internal Medicine finds that the rate of false-positive activations is higher than expected.

James McCabe and colleagues analyzed data from 411 STEMI activations at two primary PCI centers. More than one-third — 36% — were judged to be false-positive. Patients with high BMIs or with chest pain or pressure at presentation were less likely to have a false-positive activation. The following factors were independently associated with an increased risk for a false-positive STEMI activation:

  • Left ventricular hypertrophy on ECG: adjusted odds ratio (AOR) 3.15, CI 1.55- 6.40, p=0.001
  • History of coronary disease: AOR 1.93, CI 1.04-3.59, p=0.04
  • History of  illicit drug abuse: AOR 2.67, CI 1.13-6.26, p=0.02
The authors conclude:
While a certain percentage of false-positive STEMI activations are essential to ensuring adequate diagnostic sensitivity, the point of equipoise between necessary diagnostic sensitivity and patient safety requires further investigation, particularly in light of increasing resource limitations.
In an accompanying commentary, Fouad Bachour and Richard Asinger note that the higher-than-expected rate of false-positives in the study may be partly due to “the variability of definitions.” They recommend that primary PCI programs adopt “a systematic protocol for the diagnosis and emergent treatment of STEMI including pivotal medical history for comorbid features, patient preference, continuous review of clinical experience, and direct feedback.” They suggest that an “acceptable rate of inappropriate activations … is probably in the 15% to 20% range.”
     —CardioExchange News

In AF, Women Have A Bigger Risk Of Stroke Than Men Reply

When compared to elderly men with atrial fibrillation, elderly women with AF have a significantly elevated risk for stroke. This increased risk occurs regardless of warfarin use, according to a new study published in JAMA.

Meytal Avgil Tsadok and colleagues reviewed data from Quebec, Canada on more than 80,000 AF patients at least 65 years of age. Much of the increased risk occurred in women over the age of 75.

Overall crude stroke incidence:

  • Women versus men: 2.02 versus 1.61 per 100 person-years, p<0.001

The risk for stroke among women remained elevated after adjustment for baseline risk factors, individual components of the CHADS2 score, and warfarin treatment:

  • Adjusted hazard ratio: 1.14, CI 1.07-1.22, p<0.001

The authors wrote that “women older than 75 years represent the most important target population for stroke prevention in patients with AF, and the effectiveness of novel anticoagulants in this population in real-world practice will need to be closely monitored.”
Click here for the press release from JAMA…

Roche Terminates Development Of CETP Inhibitor Dalcetrapib 1

Roche announced today that it had ended development of dalcetrapib, its entry in the once-promising class of HDL-raising CETP inhibitors. A data and safety monitoring board recommended that the dal-OUTCOMES phase 3 trial be stopped due to a lack of clinically meaningful efficacy. The DSMB found no evidence of safety problems.
Click here to read the press release from Roche…

Politics and Transcatheter Aortic Valve Replacement 2

Scott Gottlieb, MD

From the first early stages of its development, the prospect of transcatheter aortic valve replacement (TAVR) provoked two broad and competing fears:

  1. Regulatory safeguards would kill a promising new technology, denying its life-saving benefits to many thousands of desperately sick people.
  2. The stampede to stake a claim in a promising, highly lucrative new territory would lead to the exploitation and mistreatment of many thousands of desperately sick people.

Remarkably, neither scenario occurred. Instead, at a very early stage, medical societies, regulators, and industry worked together to ensure the smooth introduction of TAVR in the US. The final decision earlier this week by the Centers for Medicare & Medicaid Services (CMS) to provide reimbursement for TAVR was the latest step in a long, ongoing process that, for once, didn’t appear broken, and, in fact, represented an unusual consensus among physicians, regulators, insurers, and other involved parties.

However, in an apparent attempt to inject politics where it’s neither needed nor wanted, Scott Gottlieb, a conservative activist who is a former FDA deputy commissioner and CMS adviser, concludes that the CMS ruling means “that for costly procedures, Washington will be making more of these choices for us.” In a posting on the American Enterprise Institute’s The Enterprise BlogGottlieb writes that the decision “is a vivid example of how our healthcare is going to get reimbursed now that Washington calls more of the shots.”

Gottlieb doesn’t make a clear statement that explains his hostility to the CMS decision. Instead, he cites several facts that he thinks makes his case for him. He’s wrong.

For instance, Gottlieb writes:

CMS is also restricting the number of doctors that can perform the new procedure.

Actually, CMS has done nothing of the sort. It has insisted that doctors who perform the procedure have adequate training and that the hospitals where the procedures are performed have sufficient experience and adequate facilities. Perhaps Gottlieb would be happy to send an elderly relative for TAVR  to a local community hospital with little experience in the procedure. It was precisely to avoid this scenario that the American College of Cardiology and the Society of Thoracic Surgeons supported CMS in this coverage decision. I fail to see how anyone would benefit by widespread proliferation of TAVR by novice operators at inexperienced centers.
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