Little Difference In Chest Pain Between Men And Women 1

In recent years the medical community has grown increasingly concerned that women with heart attacks may be less likely to receive prompt and effective treatment. The difference between the sexes in the presentation of symptoms is thought to be a major barrier to better treatment for women. But now a new study published in JAMA Internal Medicine finds that a key aspect of these differences– the description of chest pain in the emergency department– may not play as big a role as previously suspected.

Click here to read the full post on Forbes.

 

JAMA Int Med

About these ads

No Support For Broad Screening Of Chronic Kidney Disease 1

Although taught in  medical school and widely used in clinical practice, broad screening of otherwise healthy people for chronic kidney disease (CKD) is unwarranted, according to new recommendations from the American College of Physicians published in the Annals of Internal Medicine. People with early kidney disease, who are classified as having stages 1 to 3 CKD, usually do not have symptoms and are generally diagnosed with labarotory tests or imaging. People who progress to advanced kidney disease are at greatly increased risk for dialysis, end-stage renal disease, and death.

The authors of “Screening, Monitoring, and Treatment of Stage 1-3 Chronic Kidney Disease” discuss the paucity of evidence in the field and highlight the absence of randomized, controlled trials evaluating the risks and benefits of screening for CKD or evaluating the sensitivity and specificity of screening tests.

Click here to read the full post on Forbes.

 

 

Clear! CPR in the Hospital Is Not Always Good for the Patient Reply

On TV it always seems clear and simple. A patient in the hospital goes into cardiac arrest and the medical team springs into action. After a few tense moments of furious activity, and only after all seems lost, the patient is successfully revived. A few scenes later the smiling and now fully healthy patient thanks the doctor and returns to his or her life as a professional athlete, parent of young children, or criminal mastermind.

Medical professionals know that in real life this is rarely the way it goes. Most patients who undergo cardiopulmonary resuscitation (CPR) are old, frail, and very sick. Many will die and many who survive CPR will die anyway before leaving the hospital. And many survivors will have severe neurological problems.

Now a physician states in JAMA Internal Medicine that hospitals need to change the way they view CPR.

Click here to read the full story on Forbes.

 

European Heart Guidelines Based On Disgraced Research May Have Caused Thousands Of Deaths 2

Despite a 2-year-old scandal discrediting key evidence, current guidelines relying on this evidence have not been revised. As a result of physicians following these guidelines, some researchers say, it is possible that thousands of patients may have died each year in the UK alone. It is unlikely that a true understanding of the damage will ever be known.

Current European Society of Cardiology guidelines recommend that beta-blockers be given to many patients having surgery for noncardiac reasons to protect the heart during surgery. (US guidelines are somewhat less aggressive in their endorsement of perioperative beta-blockade.) The guidelines, which were published in 2009, were based on analyses of the available trials. The strongest evidence came from the DECREASE family of trials, which appeared to strongly support perioperative beta-blockade, and one other large trial, POISE, which raised concerns that beta-blockers might lead to an increase in deaths. When the ESC committee combined all the data they found a neutral effect on mortality but a strong benefit due to significant reductions in non-fatal MI and stroke with beta blocker use. This was the basis for the strong recommendation in the ESC guidelines.

In 2011, however, faith in the reliability of the DECREASE trials was shattered as a result of a scientific misconduct scandal centering on the principal investigator of the studies, the now disgraced Dutch researcher Don Poldermans. The issue was further complicated because, in addition to his key role in the trials, Poldermans was the chairman of the committee that drafted the guidelines.

Now, a group of UK researchers, led by Darrel Francis, have published in the journal Heart the results of a meta-analysis of the remaining non-DECREASE trials that tested perioperative beta-blockade. With the removal of the DECREASE trials the findings were strikingly different from the earlier analyses. In a combined population of 10,529 patients taken from 9 trials there was a statistically significant increase in the risk of death in the group of patients randomized to beta-blockers…

Click here to read the full story on Forbes.

Don Poldermans
Darrel Francis

Paper Raises Hundreds Of Questions About The Integrity Of Stem Cell Research Group 2

Serious questions have been raised about the integrity and validity of research performed by a well-established German stem cell research group. A paper published in the International Journal of Cardiology exhaustively details a multitude of discrepancies and contradictions in papers from the researcher’s group. Further, the revelation of such widespread misconduct may lead to broader disturbing questions about the reliability of scientific publications and the ability of the clinical research system to police itself.

In “Autologous bone marrow-derived stem cell therapy in heart disease: Discrepancies and contradictions,” Darrel Francis and colleagues scrutinize 48 papers from the research group of Bodo-Eckehard Strauer. According to Francis et al, the 48 papers from Strauer’s group contained reports on only 5 actual clinical studies, or “families” of reports, and that duplicate or overlapping reports were common. The paper contains details about more than 200 errors in the papers, including contradictory descriptions of the design, protocol and results of the trials. Francis et al write:

“Readers cannot always tell whether a study is randomised versus not, open-controlled or blinded placebo-controlled, or lacking a control group. There were conflicts in recruitment dates, criteria, sample sizes, million-fold differences in cell counts, sex reclassification, fractional numbers of patients and conflation of competitors’ studies with authors’ own.

Contradictory results were also common. These included arithmetical miscalculations, statistical errors, suppression of significant changes, exaggerated description of own findings, possible silent patient deletions, fractional numbers of coronary arteries, identical results with contradictory sample sizes, contradictory results with identical sample sizes, misrepresented survival graphs and a patient with a negative NYHA class.”

Click here to read the full post on Forbes.

Bodo-Eckehard Strauer

Unconventional Analysis Finds Threshold For LDL Reduction With Statins Reply

Using an unconventional mathematical approach, a group of Japanese researchers say there may be no good reason to reduce LDL cholesterol more than 40 mg/dl. Their research letter has been published online in JAMA Internal Medicine.

According to the authors, members of the ALICE (All-Literature Investigation of Cardiovascular Evidence) Group, most meta-analyses use linear models that assume “a constantly increasing or decreasing risk as the exposure increases or decreases.” Linear models, however, can be “misleading,” they write, because they assume a specific dose-response relationship. By contrast, their new analysis utilizes “flexible” models that can more readily uncover “threshold effects.”

Click here to read the full post on Forbes.

 

More Reasons Why Health Hype Stories Are Bad Reply

In response to my post yesterday about why health stories should nearly always be received with caution, I received the following comment from a distinguished cardiovascular researcher:

One lost point is the role of the investigators and media in hyping their research. Hazen (principal investigator of the first study) is a bright and thoughtful guy, but through the Cleveland Clinic PR department, his nice hypothesis-generating research got turned into the missing link between red meat and heart disease, which obviously is a huge leap. The paper itself is much more measured than the press release and subsequent coverage. Same for the carnitine meta-analysis It is a meta-analysis of small studies published in a 3rd tier medical journal. I haven’t read the original article, but I bet it is pretty measured in its discussion and conclusion. But then comes the press release and the media, and boom, we have a cure for heart disease that conflicts with a cause for heart disease. Both studies are hypothesis-generating and non-conclusive. They are important additions to our medical knowledge base, but offer nothing for the public right now.

So here I blame the PR departments, but the investigators go along with this, so they get some of the blame, as well as the media who hype it. By the way, from the standpoint of the investigators, the institutions, and the journals they published in, this media frenzy was considered a huge success. For the rest of the medical community and the patients, it was a nuisance, a distraction, led to confusion, and then phone calls to doctors.

Hype shot glass

I’d like to offer one additional caveat about the L-carnitine metaanalysis. This is a perfect example of a topic that might be seriously distorted by publication bias. In other words, a potentially important finding– in this case, a result showing that carnitine is beneficial after a heart attack– is much more likely to be published than a negative finding. This doesn’t mean that the metaanalysis is necessarily wrong, but it does provide yet another reason why we should always be careful when looking at studies like these.

 

 

The Best Doctor Blog On The Internet 1

Let me say it right away: the best blog written by a doctor, at least that I’ve ever read, is by a provincial South African general surgeon who calls himself Bongi. He doesn’t write about complex medical policy, and he doesn’t worry too much about appropriate use criteria or whether a patient who needs anticoagulation should get warfarin or Xarelto. Instead, he writes about his astonishing experiences as a front-line surgeon (and, for many years, as a medical trainee) in a country on the border between first and third world medicine.

His stories will blow your head off. One minute you’ll be laughing. The guy is seriously funny, possessing a keen sarcastic wit with an edgy South African accent. But then, suddenly, just when you’re enjoying the antics of his colleagues and countrymen,he’ll turn deadly serious, and leave you breathless or in tears.

Read the rest of this post on Forbes.

Becoming Your Own Doctor In The Brave New World Of Personalized Medicine Reply

Lately there’s been a lot of talk about personalized medicine. There’s a bold idea going around that people should take control of their own healthcare and manage the flood of new data stemming from a whole bunch of new technologies, including, but hardly limited to, personal genomes, biomarkers, wireless sensors, and iPhone ECGs.

Would most should people would benefit if they took a more active role in obtaining this information (for example, by ordering a personal genome from 23andme.com), and then interpreting and acting upon the information?

It seems like a great idea, after all….

…boutique-style healthcare is a lot like organic food, which may taste better and may help a few privileged people feel better about themselves, and may possibly yield a small individual health benefit (though there is absolutely no evidence to show this). However, there is absolutely no chance that organic food can be used to actually feed the vast majority of the 7 billion or so people currently living on this planet.

Similarly, taking control of individual health data will almost certainly allow a few privileged and obsessed people to feel they’re better off than most. It may even improve their health. But, again, more importantly, there is no possibility in the foreseeable future that this self-management of extremely complex personal health data will improve the overall public health of the planet.

Read my entire post on Forbes.

FDA Safety Review Finds Small, Nonsignificant Increased Risk With Chantix (Varenicline) Reply

The FDA today updated its safety review of the smoking cessation drug varenicline (Chantix, Pfizer). A large meta-analysis, which the FDA had required Pfizer to perform, found a higher rate of major adverse cardiovascular events (MACE) in patients taking varenicline than in patients taking placebo. However, the increase in risk was very small and did not achieve statistical significance. The FDA concluded that “it is uncertain whether the excess risk for the Chantix group was due to the drug or due to chance.”

The FDA said the results of the meta-analysis are consistent with findings of an earlier trial described in a previous FDA communication. The new meta-analysis utilizes data from 7,002 patients who were randomized to placebo or varenicline in one of 15 double-blind trials.

The FDA reported a low MACE rate for both groups. Although varenicline-treated patients had nearly double the risk of an event as the placebo-treated patients, there was a wide range in the confidence interval. The FDA noted that cardiovascular mortality and all-cause mortality was slightly lower in the varenicline-treated group, though the difference was of course not statistically significant.

Here’s the data from the meta-analysis:

MACE: varenicline 0.31% [13/4190] vs. placebo 0.21% [6/2812]

  • Adjusted hazard ratio: 1.95 (CI: 0.79-4.82)

Cardiovascular mortality: varenicline 0.05% [2/4190] vs. placebo 0.07% [2/2812], p=ns

All-cause mortality: varenicline 0.14% [6/4190] vs. placebo 0.25% [7/2812], p=ns

Following Earlier Recall, Ranbaxy Halts Manufacturing Atorvastatin Reply

Ranbaxy, the often-troubled manufacturer of generic drugs, will temporarily stop manufacturing generic atorvastatin. On November 9, 2012 the company announced a voluntary recall of some lots of atorvastatin because of possible contamination with glass particles. An FDA statement today said that Ranbaxy will discontinue making the drug “until it has thoroughly investigated the cause of the glass particulates and remedied the problem.”

To date, no reports of harm from the contamination have been received by the FDA. Both FDA and Ranbaxy believe there is only a low likelihood that there will be adverse events related to the problem.

The FDA said it does not anticipate a shortage of atorvastatin because of the recall, but that it “is working with other manufacturers of atorvastatin to ensure adequate market supply.”
Click to read the FDA statement…

Longer Warfarin Therapy After Bioprosthetic Aortic Valve Replacement May Be Beneficial Reply

Three months of warfarin is the usual standard of care following bioprosthetic aortic valve replacement (AVR),  although the supporting evidence base for this practice is limited. Now a large new registry study published in JAMA suggests that more prolonged warfarin therapy may be beneficial.

Danish researchers identified 4,075 patients who underwent bioprosthetic AVR. As expected, warfarin treatment between 30 and 90 days after AVR was associated with significant reductions in stroke, thromboembolic events and cardiovascular deaths compared with patients not taking warfarin. The benefits continued between 3 and 6 months, though the reduction in stroke was no longer statistically significant. The authors calculated that for every 23  patients not being treated with warfarin between 3 and 6 months, there was one additional cardiovascular death, at a cost of 1 bleeding complication requiring hospital admission for every 74 patients.

“With no randomized trials to guide the length of warfarin treatment, our results call for a review of guidelines in the field to consider an extension of the treatment to 6 months after surgery, especially in patients with an increased risk of cardiovascular death,” the authors wrote.

In an accompanying editorial, Shamir Mehta and Jeffrey Weitz write that, despite the limitations of an observational study, the results support a change in clinical practice in favor of prolonged warfarin therapy for as long as 6 months. They observe that the trial does not provide information about the possible role for the newer oral anticoagulants or about the role of adjunctive aspirin.

Here is the press release from JAMA:

Anticoagulation Treatment For Longer Than Three Months After Aortic Valve Replacement Associated With Decreased Risk of Cardiovascular Death

 CHICAGO – Although current guidelines recommend 3 months of anticoagulation treatment after bioprosthetic aortic valve replacement surgery, a study that included more than 4,000 patients found that patients who had warfarin therapy continued between 3 and 6 months after surgery had a lower rate of cardiovascular death, according to a study in the November 28 issue of JAMA.

“Biological prostheses are preferred to mechanical valves for aortic valve replacement (AVR) surgery in elderly patients older than 65 years because of shorter life expectancy and lack of a need to use anticoagulation treatment in the long-term. Especially in these patients, the tradeoff between thromboembolic complications due to the valve implant and bleeding events as adverse effects from anticoagulation therapy must be balanced. Nevertheless, appropriate duration of anticoagulation treatment postoperatively is yet to be established because the risk of complications when the treatment is discontinued is unknown,” according to background information in the article. The current recommendation of 3 months of warfarin treatment after bioprosthetic AVR surgery is primarily based on results from 1 retrospective study with a limited number of events.

Charlotte Merie, M.D., of the Copenhagen University Hospital Gentofte, Copenhagen, Denmark and colleagues investigated whether discontinuation of warfarin treatment within prespecified periods after bioprosthetic AVR surgery was associated with increased risk of thromboembolic complications, cardiovascular death, and bleeding incidents. Through a search in the Danish National Patient Registry, 4,075 patients were identified who had bioprosthetic AVR surgery performed between January 1997 and December 2009. The researchers determined the incidence rate ratios (IRRs) of strokes, thromboembolic events, cardiovascular deaths, and bleeding incidents by discontinuing warfarin as opposed to continued treatment at 30 to 89 days, 90 to 179 days, 180 to 364 days, 365 to 729 days, and at least 730 days after surgery. Average age of the patients was 75 years; 41 percent were women.

Overall, 361 patients (8.9 percent) experienced a stroke, 615 (15.1 percent) had a thromboembolic event, and 364 (8.9 percent) encountered a bleeding incident after the date of surgery. During the observation period, 1,156 patients (28.4 percent) died, with 879 (76.0 percent) of these deaths related to cardiovascular disease. The IRRs for patients not treated with warfarin compared with those treated with warfarin were 2.46 for stroke; 2.93 for thromboembolic events; 2.32 for bleeding incidents; and 7.61for cardiovascular deaths within 30 to 89 days after surgery; and 3.51 for cardiovascular deaths within 90 to 179 days after surgery.

“Our study demonstrates that discontinuing warfarin therapy within the first 3 months after surgery is associated with a significant increase in the risk of stroke, thromboembolic complications, and cardiovascular death. The novelty of our study is the finding that discontinuing warfarin therapy within 90 to 179 days after surgery is associated with a significant increase in the risk of cardiovascular death,” the authors write.

“International guidelines on anticoagulation after a bioprosthetic AVR have been written with limited data on the appropriate duration of warfarin treatment after surgery. Consequently, our study challenges current guidelines on the duration of antithrombotic treatment after AVR surgery with biological valves by presenting results suggesting that these patients will gain from an additional 3 months of warfarin treatment in terms of reduced cardiovascular death without risking a significant increase in bleeding events.”

(JAMA. 2012;308(20):2097-2107)

Editor’s Note: This work was supported by the Research Fund of the Department of Cardiology at Copenhagen University Hospital Gentofte, Gentofte, Denmark. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, etc.

Expert Consensus Document Offers Advice On Troponin Tests Reply

A newly published document provides practical advice on the use of the popular and potent troponin tests. The Expert Consensus Document on Practical Clinical Considerations in the Interpretation of Troponin Elevations was developed by the American College of Cardiology Foundation in collaboration with several other societies to help address the many complex issues raised by the introduction of the tests in clinical practice.

Sanjay Kaul, a co-author of the document, said the document does not contain new information, but was written to respond to the request of clinicians “for help regarding the considerations for ordering, interpreting, and using troponin as a decision aid in the management of patients with ACS and non-ACS conditions.” The document provides “a roadmap for the proper use of troponin in the setting of appropriate clinical context. The hope is to avoid unnecessary testing and referral as well as inappropriate utilization of downstream diagnostic and therapeutic interventions.”

The document helps physicians understand when they should order troponin tests and how to interpret the results. The recommendations are designed to work in coordination with the recently updated universal definition of MI, and provide detailed information about the use of troponins in acute coronary syndromes, PCI, CABG, and a variety of nonischemic clinical conditions.

“There are many things that can cause damage to the heart muscle that would allow troponin to leak in the circulation where we can measure it, and it’s not always due to heart attack,” said L. Kristin Newby, the co-chair of the writing committee, in an ACC press release. “So if we are indiscriminate in how we order these tests or we aren’t paying attention to the clinical scenario before us, we may miss something important.”

“We need to be thinking about why we are ordering the troponin test before we order it,” said Newby. “We hope this document provides a road map to help clinicians be more deliberate when ordering these tests and interpreting the results.”
Click here to read the ACC press release…

L.A. Confidential: Preview Of AHA Scientific Sessions 2012 Reply

The American Heart Association scientific sessions, which start next weekend in Los Angeles, will be bigger than ever, with 853 separate sessions– 111 more than last year– and 27 late-breaking clinical trials– 6 more than last year. Elliott Antman, chair of the scientific sessions program committee, provided a preview of some of the highlights of this year’s late-breakers.

Two of the most interesting trials will be presented at the first late-breaking session on Sunday afternoon. Perhaps the most eagerly anticipated trial of the entire meeting is the NIH’s FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial, which will be presented by Valentin Fuster. The trial will evaluate the relative worth of CABG and PCI in patients with diabetes.

Immediately preceding FREEDOM on the program is another NIH-sponsored trial, TACT (The Trial to Assess Chelation Therapy), testing the potential value of chelation therapy, a controversial alternative therapy. “We ought to take our hat off to the NIH for doing this trial, since industry was never going to fund this trial,” said Antman. Although most physicians have a skeptical view of chelation therapy, patients often express interest in it. TACT will finally provide real data about this approach.

Directly following the first session, the second late-breaking session will focus on economic and quality-of-life studies, including a quality of life TACT substudy and a cost-effectiveness FREEDOM substudy.

On Monday, two Italian trials will look at the role of omega-3 fatty acids for recurrent atrial fibrillation (FORWARD) and for the prevention of post-operative AF (OPERA). The Physicians Health Study II will examine the effect of multivitamins for cardiovascular endpoints. The UMPIRE study will test the feasibility of giving the polypill in 2,000 patients for a period of 15 months.

The second late-breaker session on Monday will present the results of three phase 2 trials of PCSK9 inhibitors. The session will include a panel discussion and an overview of this fast-moving and much-anticipated new therapeutic area. Also at this session will be the results of the  dal-OUTCOMES phase 3 trial of the CETP inhibitor dalceptrapib. Although the drug is no longer in clinical development, many observers are eager to see if the results will have implications for other CETP inhibitors.

A Tuesday morning session will be entirely devoted to stem cell regeneration trials. Antman said this was a “promising avenue of investigation” but acknowledged that we still don’t know if this whole approach might fail.

Later on Tuesday, Arthur Moss will present the results of the MADIT Randomized Trial to Reduce Inappropriate Therapy, comparing customized programming to standard programming for the reduction of ICD-induced inappropriate shocks. At the same session the results of RELAX-AHF will be presented, testing the novel agent relaxin in acute heart failure. Finally, the CARRESS-HF  study will offer insight into the role of ultrafiltration in patients with acute decompensated heart failure and worsening renal function.

Research And Denial At St Jude Medical 2

Research and development is the cornerstone of medical progress, but sometimes R&D turns into its evil twin brother, research and denial.

Yesterday I reported on the the RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) trial presented at the TCT meeting in Miami. The trial missed its primary endpoint, and although there were definite hints of possible benefit in the trial, most outside observers seemed to agree that the trial did not establish a firm basis for the routine clinical use of PFO closure devices in stroke. FDA approval of the device based on RESPECT seems unlikely.

This wasn’t the first we’d heard of RESPECT. Last summer, as I reported here, during an earnings call, St. Jude CEO Dan Starks gave a preview of the RESPECT results: “we are optimistic that these will be favorable results,” he said. Then, yesterday, the company doubled down on its position and issued a press release stating that the trial “provides clinical evidence of risk reduction” and offers “compelling evidence” for use of the St. Jude device “over conventional medical management alone.” A St Jude spokesman told me that the company “absolutely intends to move forward with our regulatory process and will file our PMA submission” in the fourth quarter of 2012.

Deepak Bhatt, an influential interventional cardiologist at Harvard’s Brigham and Women’s hospital, offered a very reasonable assessment of the trial in an interview with Bloomberg News: “We need a definitive trial of this approach if it’s going to be broadly used for PFO closure. Anecdotally, there are patients who seem to benefit. It’s unfortunate that none of the trials have been able to absolutely nail that down.”

The stock market provided further evidence that St. Jude’s view of the trial was not the prevailing view. Despite what the company called “compelling evidence,” St. Jude’s stock price dropped 3.6% when the news of RESPECT was released.

In contrast to St. Jude, Gore, which is conducting REDUCE, a separate study of its own device for PFO closure, said that the RESPECT data “suggest [my emphasis] closure therapy for PFO may be beneficial, but further research is required.” Gore reaffirmed its intent to complete the REDUCE trial and pursue the indication for PFO closure. Of course, by the time REDUCE is completed there’s no guarantee that Gore won’t enter its own reality distortion field. Commercial pressures can be a heavy burden on the objective assessment of reality. But for now Gore’s perspective is sensible.

Closing the Hole in Medical Progress

The mutation of research and development into research and denial has worse consequences than a drop in stock price. It can paralyze medical progress. For more than a decade the value of PFO closure in stroke has been an unanswered question. Trial enrollment has been notoriously slow and difficult. The main reason is that many interventional cardiologists don’t want to randomize their patients because they strongly believe, despite the lack of evidence, in the value of PFO closure. So expensive procedures continue to be performed, despite a lack of evidence, and despite the likelihood that good evidence will ever emerge. It’s a frustrating siutation.

Earlier this year, in an editorial in the New England Journal of Medicine, S. Claiborne Johnston wrote about the harmful effect that off-label use of PFO closure devices has on research. He recommended that reimbursement for PFO closure be limited to patients participating in a clinical trial. Seems like a good idea to me.

During the 9 years it took for the results of this trial [CLOSURE 1] to be reported, approximately 80,000 patients have had a patent foramen ovale closed with the use of a device at an average cost of $10,000 per procedure. Even if only half these patients were treated by this method for the purpose of preventing stroke, it would suggest that during that period of time $400 million was spent on a procedure that had no apparent benefit, to say nothing of the potential clinical risks involved. By limiting the use of device closure to within the remaining clinical trials, such an expense could be curtailed and completion of these trials might be accelerated. In this setting, a strategy of withholding reimbursement for unproven device therapy unless such treatment is part of a randomized trial seems justified.

 

FDA Panel Recommends Approval Of Mipomersen For Familial Hypercholesterolemia 1

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 Strategies (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.

 

 

UK Study Casts Doubts On Value Of Type 2 Diabetes Screening Reply

The dramatic growth in type 2 diabetes has resulted in increased interest in screening programs. Now a new study published in the Lancet raises concerns that screening programs may not result in long-term improvement in outcomes.

In the ADDITION-Cambridge study, investigators in the UK randomized general practices to either screening or no screening.  The practices allocated to screening were further divided to either intensive cardiovascular risk reduction or standard care. The study population included more than 20,000 adults 40-69 years of age at high risk for undiagnosed diabetes.

3% of patients in the screening groups received a diagnosis of diabetes. After a median followup of 9.6 years, there were no significant differences between the screened population and the control group.

Rate per 1,000 person-years and hazard ratios for the no-screening and the screening group:

  • Mortality: 9.89 versus 10.50, 1.06 (CI 0.90-1.25)
  • CV mortality: 3.25 versus 3.30, 1.02 (0.75-1.38)

The authors proposed several explanations for the lack of benefit associated withs screening, including ad-hoc screening outside the practice setting in the unscreened group, patients who did not follow the screening program, and concurrent gains in identifying and managing other cardiovascular risk factors during the study period. In addition, the patient population in the study may have been a relatively healthy population with a lower prevalence of undiagnosed diabetes.

The authors concluded that “if population-based screening for diabetes is to be implemented, it should be undertaken alongside assessment and management of risk factors for diabetes and cardiovascular disease and population level preventive strategies targeting underlying determinants of these diseases.”

In a Lancet press release, senior author Simon Griffin said that “the benefits of screening might be smaller than expected and restricted to individuals with detectable disease.  However, benefits to the population could be increased by including the detection and management of cardiovascular risk factors alongside the assessment of diabetes risk, performing repeated rounds of screening, and improving strategies to maximize the uptake of screening.”

In an accompanying comment, Michael Engelgau and Edward W Gregg write that prevention programs should screen not just for diabetes but for high-risk individuals as well, though they note that this strategy “assumes that effective prevention programs are available to high-risk cases.” Further, the value of screening depends “on more than just mortality as an outcome,” and will need to include morbidity, quality of life, and costs.
Click here to read the Lancet press release…

Stem Cell Therapy Company Hypes Preliminary Results 3

Update (July 6)–  I have heard from several investigators in the trial that the Osiris press release was issued without any input or consultation from the site investigators. In fact, the site investigators, including several who are  extremely experienced clinical trialists, have expressed frustration and disappointment because their input has not been sought at any point during the trial. In most multi-center trials it is common practice to consult with the sites, and in particular the top-enrolling sites. In this case, the highest enrolling sites have had no significant involvement in the trial design or conduct. One investigator said he “had never worked with a company like this.”

Another member of the steering committee told me that the committee had not met in a long time and has not seen the trial data. In fact, steering committee members were not even aware that Mark Vesely, an assistant professor at the University of Maryland, was the principal investigator of the study. One steering committee member said he’d never heard of him before reading the press release.

A biotech company has been accused of releasing preliminary and misleading information about a clinical trial. The company, Osiris Therapeutics, is the manufacturer of  a cultured mesenchymal stem cell therapy called Prochymal, which is being studied in a phase 2, placebo-controlled study in post-MI patients. Earlier this week Osiris issued a press release announcing preliminary results from the trial, in which 220 patients have been randomized, claiming that Prochymal “significantly reduces hypertrophy, arrhythmia and progression to heart failure in patients suffering a heart attack.” But Adam Feuerstein, a veteran biotech reporter for The Street, accuses the company of distorting the truth about the trial.

Osiris “disappeared” important data in its press release, Feuerstein writes in his detailed analysis of the press release. He quotes the press release:

Patients receiving Prochymal had significantly less cardiac hypertrophy, as measured by cardiac MRI, compared to patients receiving placebo (p [less than] 0.05). Patients treated with Prochymal also experienced significantly less stress-induced ventricular arrhythmia (p [less than] 0.05).

Feuerstein comments:

Sounds impressive except none of the Prochymal benefits disclosed by Osiris are predefined endpoints in the phase II trial.

Osiris appears to have thrown out the real endpoints called for in the phase II trial and replaced them with new endpoints which just happen to show Prochymal in the best light. Why would Osiris do this? Perhaps the pre-defined endpoints in the study all failed? That’s a pretty safe assumption when companies decide to swap out trial endpoints with no disclosure or explanation.

Feuerstein points out that the primary endpoint of the trial, as listed on Clinicaltrials.gov, is left ventricular end systolic volume (ESV), while the secondary endpoints are  left ventricular ejection fraction (LVEF), infarct size and major adverse cardiovascular events (MACE). Writes Feuerstein: “Osiris’ silence on the outcomes of these two important endpoints (ESV and LVEF) should be deafening to investors — and not in a good way.”

The Osiris press release also claims “a statistically significant reduction in heart failure”:

In the study, seven patients who were treated with placebo have progressed to heart failure requiring treatment with intravenous diuretics, compared to none of the Prochymal patients (p=0.01). Furthermore, patients receiving placebo tended to require re-hospitalization for cardiac issues sooner than the patients receiving Prochymal (median 27.5 days vs. 85.5 days).

However, as Feuerstein writes, “these weren’t predefined endpoints”:

Importantly, Osiris doesn’t disclose the time point at which these purported benefits occurred, nor does the company tell us anything about the number of patients analyzed. How was heart failure defined? Osiris doesn’t say. What was the baseline incidence of heart failure in the study? Osiris doesn’t say. The study only allowed for a single infusion of Prochymal or a placebo immediately after the first heart attack but patients were followed for six months or a year, so how do follow-up therapies in each arm of the study compare? Were they balanced? Again, Osiris doesn’t say.

In the press release a company official announces an extension of the trials duration:

Given the quality of the data and highly encouraging results observed thus far, we are extending the trial’s duration to capture a better understanding of the long-term clinical benefits of MSCs.”

But the company offers no explanation for the extension. Writes Feuerstein:

Perhaps Osiris is extending the phase II study to delay the reporting of negative results? Again, that’s a pretty safe assumption absent a better explanation.

Note: I’ve requested comments from Osiris and from several trial investigators.

One Reader’s Negative View Of Mark Midei Reply

A few months ago I posted a lengthy piece about Mark Midei, the interventional cardiologist from Maryland who had his medical license suspended last year following a lengthy scandal in which he became the poster-boy (or scapegoat, depending on whom you ask) for all that’s wrong with interventional cardiology in the US. Although I was highly critical of Midei in my piece, I also expressed sympathy for his situation. Now a reader– Ohio MD– has written a response on the Forbes CardioBrief feed to my original post, taking me to task for being “entirely too sympathetic” to Midei. I think his position is worth bringing to more general attention, though I continue to believe that it is possible to simultaneously believe that Midei is guilty as charged and yet feel sympathy for his situation.

Here is the comment by Ohio MD:

I think the article is entirely too sympathetic to the doctor. As a physician myself, I am absolutely appalled at the acts perpetrated by this man upon his patients. It is all too easy to point at rates of success in terms of claimed lives saved and numbers who survived the intervention. Realistically, many of those who underwent procedures were destined to do well without cardiac interventional procedures. Testimony and review of the Maryland Board of Medicine and a review by Midei’s own institution suggest a systematic process of overstating severity of coronary disease to justify needless interventions. One must also consider that these interventions carry with them not only substantial cost, but the burden of carrying a needlessly implanted device, potential need for chronic medication to prevent device-related complications, and not-inconsequentially, the stigma of the diagnosis of severe coronary artery disease. How many of the affected patients went on to higher insurance costs, potential loss of job positions, limitations of lifestyle, etc.?
Click to continue reading…

Many CHF Patients Not Receiving– Or Getting Benefits From– High Dose ACE Inhibitors And ARBs Reply

Although current guidelines recommend that ACE inhibitors and angiotensin-receptor blockers (ARBs) be used in high doses in patients with congestive heart failure, many CHF patients currently receive lower than recommended doses of these drugs. In a research letter published online in Archives of Internal Medicine, investigators in Montreal analyzed data from 43,405 patients with a first hospital admission for CHF in Quebec, 73% of whom received an ACE inhibitor and 27% an ARB.

Patients were classified as receiving low-, medium- or high-dose drugs. 29% received a low-dose. The groups were not evenly matched: patients in the high dose group were more likely to have hypertension and diabetes, while patients in the low dose group were more likely to have renal disease.

After adjusting for other factors, the risk of dying or being readmitted to the hospital was significantly reduced in the high dose group. Here are the hazard ratios for ACE inhibitors and ARBs (medium dose serves as the reference):
Click to continue reading…

Good Science/Bad Science: Contrasting Papers On Dietary Compositon In JAMA And BMJ 3

Two studies published on Tuesday on dietary composition offer a striking contrast. One tackles the interesting question of whether different diets producing the same amount of weight loss might have different effects on energy expenditure. The investigators performed a rigorous, carefully designed experiment that advances our knowledge about diets and metabolism. The second tackled an even more important question– the long term cardiovascular (CV) impact of different diets. In this instance, however, the investigators relied on weak observational data and reached conclusions that went way beyond anything observational data can provide. One study represents good science. The other does not.

In the first study, published in JAMA, Cara Ebbeling and colleagues carefully studied 21 overweight and obese young adults. After first reaching a 10-15% weight loss during the run-in period of the study, the 21 subjects then received 3 different diets, in random order, for 4 weeks each: a high carbohydrate, low fat diet; a low-glycemic index diet with moderate percentages of carbohydrates and fats; and a very low carbohydrate diet with a high proportion of fat.

Although the subjects received the same amount of calories with each diet, there were significant differences between the groups in the amount of energy burned with the different diets. (This may be an important question, because weight loss requires energy expenditure to be greater than energy intake. If, everything else being equal, diets differ in their effect on energy expenditure, this may lead to superior weight loss strategies.) When compared to baseline, total and resting energy expenditure decreased the most with the high carbohydrate diet and the least with the very low carbohydrate diet. Further, the investigators also found that the low fat diet resulted in an increase in serum leptin levels (which could predict future weight gain) and other factors associated with metabolic syndrome. These same factors decreased with the very low-carbohydrate diet, but were perhaps offset by an incase in CRP levels– a marker of inflammation– with the very low carbohydrate diet.
Click to continue reading…

Is Chronic Kidney Disease A CHD Risk Equivalent? Reply

A new study published in the Lancet provides new data about whether chronic kidney disease (CKD) should, like diabetes, be considered a coronary heart disease (CHD) risk equivalent.

Marcello Tonelli and colleagues analyzed data from a population of 1.25 million people in Alberta, Canada. During a median followup of 4 years, 11,340 people were admitted to the hospital for MI. People with a previous MI were at higher risk for MI admission than people with either diabetes or CKD:

  • MI history: 18.5 per 1000 person-years (CI 17.4–19.8)
  • Diabetes: 5.4 per 1000 person-years (5.2–5.7)
  • CKD: 6.9 per 1000 person-years (6.6–7.2)
After adjustment for other variables, the relative rate of MI was lower in the CKD group than in the diabetes group (rate and adjusted relative rate for MI admission):
  • Previous MI: 7.7%, RR 3.8 (CI 3.5-41)
  • Diabetes and CKD: 6%, RR 2.7 (2.5-2.9)
  • CKD: 2.8%, RR 1.4 (1.3-3.5)
  • Diabetes: 2.4%, RR 2.0 (1.9-2.1)
  • No diabetes or CKD: 0.5%, RR 1 (reference)

The authors write that their “data show that diabetes alone and chronic kidney disease alone… do not increase the rate of myocardial infarction to the same extent as does a history of coronary disease, and therefore do not support the use of the term coronary heart disease risk equivalent for either disorder.” However, they concluded that CKD should “be added to the list of criteria defining people at highest risk of future coronary events.”

In an accompanying comment, Tamar Polonsky and George Bakris write that “despite negative findings for the primary outcome, compelling reasons are provided to consider lipid-lowering therapy in patients with chronic kidney disease.”
Click here to read the Lancet press release…

Real World Bleeding Risk Of Aspirin In Primary Prevention Examined Reply

A new study published in JAMA provides substantial new evidence about the real world effects of aspirin, including the risk of  bleeding, in a broad  population. The study also sheds important new light on the effects of aspirin in a diabetic population.

Giorgia De Berardis and colleagues analyzed data from more than 4 million people in Puglia, Italy and compared 186,425 people taking low-dose aspirin with the same number of matched controls not taking aspirin.

Major bleeding events requiring hospitalization:

  • aspirin: 5.58 (5.39-5.77) per 1000 person-years
  • controls: 3.60 ( 3.48-3.72) per 1000 person-years
  • Incidence rate ratio (IRR) 1.55 (1.48-1.63)

Diabetics overall had an increased risk of major bleeding episodes but this increased risk was not significantly associated with aspirin use:

  • Hemorrhagic events in diabetics overall (compared with non diabetics): IRR 1.36 (1.28-1.44)
  • Hemorrhagic events in diabetics taking aspirin compared with diabetics not taking aspirin: IRR 1.09 (0.97-1.22)

The authors wrote that their findings demonstrate that bleeding events occur more frequently than had been observed in clinical trials. They calculated that for individuals with a 10-year risk of cardiovascular events between 10% and 20% the risks and benefits of aspirin therapy are similar, causing 2 excess bleeds, and preventing 2 CV events, for every 1,000 people treated each year.

In an accompanying editorial, Jolanta Siller-Matula writes that the benefits of aspirin in secondary prevention are “not disputed,” since aspirin can prevent 6 major vascular events at the expense of 1 major bleeding event. But there is no such consensus for primary prevention, and Siller-Matula writes that the findings of the Italian study reinforce current European guidelines which do not recommend aspirin for primary prevention.

The JAMA study provides far more information about aspirin use in diabetics than had been previously available. Nevertheless, writes Siller-Matural, the decision whether to use aspirin for primary prevention in this population is still not clear, and will require additional data from ongoing studies.

Click here to read the JAMA press release…

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:
Click to continue reading…

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.
Click to continue reading…