TAVI: Belgian Researchers Slam Evidence Base And Overuse In Europe 1

The growing and enthusiastic adoption of transcatheter aortic valve implantation (TAVI) in Europe has no justification, according to three researchers who performed a health technology assessment for the Belgian government. In a paper published in BMJ, the authors from the Belgian Health Care Knowledge Centre conclude that TAVI should only be used in patients “who are deemed inoperable for technical reasons,”  which is about 10% of patients “of those currently considered for treatment.”

In their paper the writers do not identify any new concerns about TAVI, but they weave together the various threads of criticism that have been directed at the dissemination of TAVI. Hans Van Brabandt, Mattias Neyt, and Frank Hulstaert also charge that the evidence base for TAVI is deeply flawed as a result of an unpublished negative trial, serious baseline imbalances between controls and TAVI patients in the PARTNER trial, and unreported conflicts of interest by the principal investigator of PARTNER.

By the end of 2011 approximately 40,000 TAVI procedures had been performed, they write. Nearly all of the procedures were performed in Europe, where devices do not undergo the same regulatory scrutiny as drugs, needing only a CE mark to go on the market, “putting them on the same footing as domestic appliances such as toasters.” They note that TAVI was used in Europe for four years before the FDA approved its use in the US, but only for patients who were not surgical candidates and only when the transfemoral approach was used.

Despite the greater rigor of the US regulatory process, the authors write that after their careful review of all the available evidence “we remain far from convinced that it is adequate” and that “the arguments supporting the widespread use of TAVI do not stand up to scrutiny.”

Although in  the PARTNER A trial TAVI met the predefined criteria for non-inferiority when compared to surgery, the authors write that strokes, TIAs, and major vascular complications occurred more often with TAVI. TAVI performed better in the PARTNER B trial, which studied patients who were not eligible for surgery, but TAVI was still associated with a higher rate of stroke and vascular events. Results of the two trials “suggest that TAVI can be justified for inoperable patients on clinical grounds,” but, write the authors, this conclusion is weakened because the FDA, Edwards (manufacturer of the Sapien TAVI device), and trial investigators have failed to provide data to the authors, despite repeated requests, about a follow-up study comparing TAVI to standard therapy in 90 patients. The failure to share the data, they write, “is both ethically and scientifically unacceptable and should be legally regulated in future.”

The authors also maintain that  the principal investigator of the PARTNER trial, Martin Leon, did not fully disclose his financial interest in TAVI. Although it was disclosed in the NEJM papers that Leon had received $6.9 million from Edwards when it purchased Percutaneous Valve Technologies, which Leon had co-founded, the articles did not mention that Leon “was to receive three further payments on the achievement of three milestones: successful treatment of 50 patients, regulatory approval in Europe, and limited approval in the US.”
Click to continue reading, including a comment from Sanjay Kaul…

USPSTF Maintains Recommendation Against ECG Screening Of Asymptomatic Low-Risk Adults Reply

The  US Preventive Services Task Force (USPSTF) has reaffirmed its 2004 recommendation against ECG screening for asymptomatic adults who are already at low risk for coronary heart disease (CHD). The Task Force also concluded that there was insufficient evidence to assess the risks and benefits of ECG screening in asymptomatic people at intermediate- or high-risk for CHD. The report has been published in Annals of Internal Medicine.

For asymptomatic people at low-risk, the report concludes that additional information obtained from resting of exercise ECG tests would be unlikely to change their risk assessment or to improve their health outcomes. By contrast, the tests are associated with “significant possible harms,” most importantly related to “exposure to potential adverse effects of invasive tests.”

The USPSTF weighed the evidence of the risks and benefits of ECG screening, but it did not include the cost of ECG screening as part of its analysis. The Task Force also recommends that physicians “individualize decision making to the specific patient or situation.”

The USPSTF notes that their recommendations differ slightly from current ACCF/AHA guidelines which state that resting ECGS are “reasonable for cardiovascular risk assessment in asymptomatic adults with hypertension or diabetes.” In addition, an exercise ECG “may be considered for cardiovascular risk assessment in intermediate-risk asymptomatic adults (including sedentary adults considering starting a vigorous exercise program), particularly when attention is paid to non-ECG markers such as exercise capacity.”

Authors Retract Article About Websites That Sell Statins Without Prescriptions Reply

An article in Pharmacoepidemiology and Drug Safety about websites that advertise statins to consumers has been retracted by the authors after one company mentioned in the article disputed the authors’ assertion that the company sold statins to patients who did not have a prescription. The news was reported on Retraction Watch.

Here’s the notice:

The following article from Pharmacoepidemiology and Drug Safety, “Direct to consumer Internet advertising of statins: an assessment of safety”, by Bethan Williams and David Brown, published online on 2nd February 2012 on Wiley Online Library (wileyonlinelibrary.com) and in Volume 21, Issue 4, pages 352–365, April 2012, has been retracted by agreement between the authors, the journal Editor-in-Chief, and John Wiley & Sons Ltd. The retraction has been agreed due to the inability to verify the accuracy of the data in Appendix 1.

According to Retraction Watch, Appendix 1 contained a list of 184 websites that appeared to have sold statins without a prescription.The journal’s editor told Retraction Watch:

A lawyer for a company specified in the appendix threatened a suit, claiming they never dispensed meds without a prescription.  We told the author we would back them, but we needed to see proof the website ever said that.  The authors had no evidence to back up their statement.

The corresponding author, of the paper, David Brown, of the University of Portsmouth in the United Kingdom, told Retraction Watch:

We conducted our study in good faith; however, on publication, it was brought to our attention by one of the editors that the producers of one of the websites listed in the Appendix to the paper had indicated that the site was listed in error as offering statins for sale without a prescription.

We did not keep the original screen-dumps of websites at the time of our study (19th November – 23rd December 2010) and as we could not verify the inclusion of the website, we immediately agreed to retract the paper in accordance with the editor’s wishes.

I must stress that this was an honest error on our part; there never was any intention to mislead the journal or its readership. This stance was accepted by the journal editor.

FDA Approves Vascepa, A New Fish Oil Pill From Amarin 1

The FDA has approved a new prescription formulation of fish oils for the treatment of very high levels of triglycerides. The news was  first reported by The Street reporter Adam Feuerstein.

The drug will be sold under the brand name Vascepa. According to the company, it will be indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe hypertriglyceridemia (TG > 500mg/dL).

Vascepa contains ultra-purified ethyl EPA, an omega-3 fatty acid. Vascepa will be the second prescription fish oil formulation, following GlaxoSmithKline’s Lovaza, which Feuerstein said generates about $1 billion in annual sales.

The triglyceride-lowering efficacy of Vascepa has been studied in two 12-week, placebo-controlled phase 3 studies: ANCHOR, in patients with triglyceride levels between 200 and 500 mg/dl, and MARINE, in patients with triglyceride levels between 500 and 2000 mg/dl. Last year Amarin announced the commencement of REDUCE-IT (Reduction of Cardiovascular Events with EPA – Intervention Trial), a trial designed to evaluate the efficacy of Vascepa when given in addition to  a statin in reducing major cardiovascular events in a high-risk population.

A recent meta-analysis of studies with various preparations of fish oils found no evidence of a reduction in cardiovascular events with fish oil supplements in patients with a history of cardiovascular disease.

Click here to read the press release from Amarin.

Click here to read prescribing information for Vascepa.

ESC Position Paper Advocates Population-Based Strategies To Reduce Cardiovascular Deaths Reply

About half of all cardiovascular deaths could be prevented by implementing population-level changes, according to a position paper from the European Society of Cardiology published in the European Journal of Preventive Cardiology. Torben Jørgensen and colleagues maintain that population-level interventions are much more effective than current strategies that seek to reduce individual risk.

Population-based strategies include taxation, legislation, and environmental changes. The authors call the move away from individual risk and toward a population-based strategy “a paradigm shift in CVD prevention.”

The authors argue that the change is necessary because “societal changes during the last decades have led to the present harmful environment with high calorie intake, low degree of physical activity, continuous smoking, and high alcohol intake.” Further, they note, efforts to promote a healthy lifestyle “routinely face opposition by commercial vested interest from corporations (e.g. food, tobacco, alcohol).”

Addressing a common criticism of population-based strategies, the authors counter the allegation that the “‘nanny state’ hinders the free choice of people” with the observation that “people today are nudged in the wrong direction by corporations’ de facto setting of the default option. Yet corporations do not have responsibility for population health – this is the responsibility of governments.”

”Population interventions make the environment healthier and change happens automatically whereas with an individual approach you need an active response,” said Professor Simon Capewell, a co-author of the paper, in an ESC press release.

Here are several of the paper’s major recommendations:

•    Healthy dietary habits will be supported by changes in agricultural policies, tax on products with free sugar and saturated fat and subsidies for fruit and vegetables, reduction of salt and trans-fatty acids in processed foods, clear labelling of foods, and limiting advertising for junk food.
•    Completely smoke-free environments are the only way to protect non-smokers. Smoking and second-hand smoking can be regulated by taxation, restrictions in sale and use, banning advertising, plain packaging, and warning labels.
•    Physical activities should be integrated in daily life by subsidies to public transport and re-allocating of road space to cycle and footpath lanes. Changes in schools, worksites, and built environment can make physical activity a more natural part of daily life.
•    Alcohol intake can be reduced by taxation, low availability, regulation of advertising, and low social and legal tolerance of drink driving.

Click here to read the press release from the ESC…

ROMICAT-II Provokes Opposing Views On CT Angiography In The Emergency Department 1

For patients with suspected acute coronary syndromes (ACS) CT angiography (CTA) compared to standard treatment can reduce the time in the emergency department (ED), according to results of the ROMICAT-II (Rule Out Myocardial Infarction/Ischemia Using Computer-Assisted Tomography) trial published in the New England Journal of Medicine. However, CTA resulted in more tests being performed and increased radiation exposure.

1000 patients with possible ACS but without ECG signs of ischemia or a positive troponin test were randomized to either CTA or standard treatment. The primary endpoint of the study, the mean length of hospital stay, was reduced from 30.8 hours in the standard evaluation group to 23.2 hours in the CTA group, a highly significant reduction of 7.6 hours (p<<0.001). In addition, many more patients in the CTA group were discharged directly from the ED (47% vs 12%, P<0.001). There were no cases of undetected ACS in either group and very few major adverse cardiovascular events (2 vs 6, p=0.18). Half of the patients in the CTA group were discharged within 8.6 hours, compared with only 10% of the controls.

ED and hospital costs were similar in both groups. Radiation exposure was increased in the CTA group (13.9 mSv vs 4.7 mSv) and more diagnostic tests were performed  in the CTA group.

The authors concluded that their “data should allow providers and patients to make informed decisions about the use of this technology as an option for evaluation when symptoms are suggestive of an acute coronary syndrome.”

Schrödinger’s ROMICAT

In contrast to the neutral presentation of the authors in the NEJM paper, strikingly different positions about the utility of CT angiography were taken in an accompanying editorial by Rita Redberg and a press release issued by the National Heart Lung and Blood Institute, which sponsored the study.

In her editorial, Redberg writes:

 Although shorter lengths of stay in the hospital are highly desirable, especially from the patient’s point of view, the ROMICAT-II study reveals a deeper flaw in the approach to chest pain in the emergency department. The underlying assumption… is that some diagnostic test must be performed before discharging these low-to-intermediate-risk patients from the emergency department. This assumption is unproven and probably unwarranted. The rationale for any test, as compared with no testing, should be that it will lead to an improved outcome, and here there is no evidence that the tests performed led to improved outcomes.

Redberg points out that the very low (under 1%) rate of patients who actually had an MI in the study means “that it is impossible to know whether the CCTA groups received any benefit whatsoever.” Further, factoring in radiation doses  both from CTA and nuclear stress tests and adverse reactions to contrast dye, “clinicians may legitimately ask whether the tests did more harm than good.”

For patients like those in ROMICAT II, with normal ECG findings and negative troponin tests, “multiple studies show no evidence that any additional testing further reduces that risk.”Although CTA can reduce length of stay in the hospital compared to standard care, “it is even faster to discharge these patients without any additional diagnostic test after determining that their ECG findings and troponin levels are normal.” She concludes:

In short, the question is not which test leads to faster discharge of patients from the emergency department, but whether a test is needed at all.”

By contrast, the NHLBI press release focuses exclusively on the benefits of CTA and lacks any significant discussion of its potential limitations, as presented in the NEJM paper and as discussed in detail by Redberg. The press release quotes Susan Shurin, the acting director of the NHLBI:

Identifying the underlying cause of chest pain more quickly with CT scans could allow medical care providers to better allocate limited resources to the patients who are most in need of treatment.

The principal investigator of the study, Udo Hoffmann, says that ROMICAT II can “help health care providers and patients make better informed decisions by knowing the risks and potential benefits of using CT scans to more quickly diagnose acute coronary syndrome,” but he glosses over the risks and then focuses on the benefits:

“It can be a relief to patients with chest pain to quickly know they are not having a heart attack and that they can spend the night at home, instead of in a hospital bed.”

Finally, the press release gives short shrift to the radiation issue:

Participants in the CT group were exposed to more radiation than those in the standard screening group, though the study authors suggested that future CT scans could be done using less radiation, which could help lower exposure without sacrificing accuracy.

Click here to read the NHLBI press release…

St Jude CEO Spills The Beans On PFO Closure Trial 1

(Updated at bottom with statement from St. Jude Medical)

Dan Starks, the CEO of St Jude Medical, stated during a quarterly earnings call last week that results of the RESPECT trial of PFO closure for crytpogenic stroke were “favorable” and that the full trial results will be presented in October at the TCT meeting in Miami. But his statement raises more questions than it answers.

It should be noted that it is impossible to ascertain the actual results of the trial from his remarks. He did not even state whether the trial had met its primary endpoint, and there are always potential dangers when the full data from a large trial are analyzed. Further, when asked to confirm whether RESPECT was indeed scheduled for presentation at TCT, TCT’s Gregg Stone told CardioBrief that “the submission deadline [for late-breaking clinical trials] has not even been reached yet.”

Jonathan Tobis, an expert in PFO closure at UCLA, told CardioBrief that any evaluation of the trial should await the full presentation of the data: “this is anybody’s guess until the data is presented,” he said.

Here is the transcript of the relevant portions of the conference call:

Dan Starks (CEO): Earlier this year, we announced that we completed enrollment in our landmark RESPECT clinical trial, evaluating the benefit of PFO closure in patients who suffer from cryptogenic stroke. As a reminder, the RESPECT trial enrolled 980 patients and generated more than 2,700 patient years of experience. We expect the results of this trial to be presented at a late-breaking clinical trial session during the TCT meeting later this year.

In stark contrast to prior randomized trials of competitive PFO devices for mitigation of risk in cryptogenic stoke patients, we are confident our trial will demonstrate greater benefit and less risk in the device arm of the trial.

Michael Weinstein (JP Morgan analyst): …Dan, you mentioned that the PFO closure for stroke RESPECT trial, can you just update us on the filing of that data and that PMA with the FDA? …

Dan Starks: On the PFO closure, the submission to FDA is being prepared as we speak and there is a lot of data to analyze and prepare and organize. And so, I would be confident that the PMA submission will be in during the fourth quarter and I suspect that we would be unlikely to get that submission in before the end of the third quarter. So timing wise that’s our update.

Within that, though, one can see that we have a number – since our organization is strongly focused on preparing that submission, obviously we’re no longer blinded to the data and that was the basis for the level of confidence we’ve expressed that when the full trial results are reported at the TCT, we are optimistic that these will be favorable results.

Comment: The statement that the “trial will demonstrate greater benefit and less risk” for St. Jude’s PFO closure device is highly unusual. One danger is that the company’s initial evaluation of the results may clash with the eventual evaluation of the academic investigators, peer reviewers, other experts, and, ultimately, FDA reviewers and consultants. Companies are in no position to be objective about their own products or trials. This is why academic investigators, peer reviewers, editors, FDA reviewers and consultants, and other interested experts play important roles in discussing and ultimately judging the value of new therapies. Taking the word of a company is simply not acceptable any more.

Many companies in the past have released highly positive press releases of trials that ultimately have  been received in a far harsher light. In some of these cases, there have also been suspicions that the premature release of results could be used to affect a stock. Indeed, Starks’ statement was first reported by an analyst for Merrill Lynch, who wrote that the statement by Starks was “a major disclosure” and concluded that the statement suggests that the trial “hit its primary endpoint.” Ultimately, he wrote, the PFO closure market represents a $500 million “annual market opportunity.” Maybe. But that’s an awfully long way to go on the basis of few vague words spoken in the heat of a conference call.

Caution is warranted especially because of the sorry history of negative trials in this area. It’s possible of course that the St. Jude device is superior to the failed STARFlex Septal Closure System from the now-defunct NMT Medical, but until it can be convincingly demonstrated otherwise the burden of proof lies with those who advocate the continued use of these devices. But the Merrill analyst believes that positive results from RESPECT could spark greater usage in Europe (where the device is already available, despite the complete absence of evidence supporting its use) and greater usage in the US of “other STJ closure technologies,” since many US physicians “believe in the mechanism and the technology as a valid tool to prevent strokes.”

But let’s remember the NEJM editorial by S. Claiborne Johnston that accompanied the Closure 1 trial earlier this year in which he outlined some of the troubling issues raised by the trial. Because of off-label use of closure devices, enrollment in the trial took 5 years and forced a reduction in the sample size of the trial. He continued:

During the 9 years it took for the results of this trial 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.

There are more reasons to be skeptical. Although Starks was quick to bring up RESPECT, he was silent about another St. Jude PFO Closure trial, the European-based PC-Trial, which was finished and had completed its followup before the RESPECT trial. To date the company has yet to release any information about the results of the trial.

The entire case, I think, highlights the importance of restoring the system whereby trial investigators, and not companies, present the results of clinical trials. It’s not a perfect system by any means. But it’s a lot better than the alternative offered here by St. Jude’s CEO.

I’ve asked for comments from St. Jude, the RESPECT trial investigators, and other experts. I’ll update this story as necessary.

Click here for a full transcript of the St. Jude conference call.

Update: Shortly after publication of the above story I received the following statement from St. Jude in response to an earlier request. I will leave it for my readers to decide whether this adequately addresses the issues I’ve raised.

St. Jude Medical has previously expressed confidence in our RESPECT program because of fundamental differences in clinical trial design, patient selection, and device design compared to competitive programs. Mr. Starks was reiterating this confidence and optimism that because of these differences, the outcomes of the RESPECT trial would be different than prior randomized trials. We have also publically indicated our intention to file the PFO PMA before the end of this year which, of course, requires the Company to have visibility into the data in order to perform the required analysis.  Mr. Starks’ statement that we are now unblinded to the data is intended to be nothing more than a reflection of the fact that we are analyzing the data for the PMA submission. In his comments, there was no specific data or endpoint information disclosed.  It would be our intention to issue a press release, including formal statements by the Steering Committee membership, at the same time the RESPECT clinical trial results are presented or published, which, as Mr. Starks indicated, will likely occur during the TCT meeting.

The PC Trial is an investigator-sponsored trial, funded by St. Jude Medical. You would need to contact the trial sponsors for further information about the presentation of results.

Elevated Risk of Acute MI Following Total Hip And Knee Replacement Surgery 1

A large study reports a high increased risk for acute MI (AMI) in the first 6 weeks after total-hip replacement (THR) or total-knee replacement (TKR) surgery. Analyzing a nationwide cohort from Denmark that included 95,227 patients who underwent THR or TKR and matched controls, Arief Lalmohamed and colleagues calculated the adjusted hazard ratios (HR) for AMI. Their results are published in the Archives of Internal Medicine.

The risk for AMI was significantly higher in the first two postoperative weeks for both THR and TKR, but the risk was higher only in the THR group for weeks 2 through 6.

Adjusted HR, Weeks 1 to 2:

  • THR: 25.5 (95% CI, 17.1-37.9)
  • TKR: 30.9 (95% CI, 11.1-85.5)

Adjusted HR, Weeks 2 to 6:

  • THR: 5.05 (95% CI, 3.58-7.13)
  • TKR: 0.81 (95% CI, 0.37-1.77)

At 6 weeks, the absolute rate of AMI was 0.51% in the THR group and 0.21% in the TKR group. The only significant effect modifier identified by the investigators was age, with the greatest excess risk found in patients age 80 or older. By contrast, no increase in risk was found in patients younger than 60 years.

In an accompanying commentary, Arthur Wallace writes that the study “once again confirms that the perioperative period increases cardiac risk. Physicians must go further than establishing risk factors; physicians must actively work to reduce perioperative risk.” Risk can be reduced with the appropriate use of preoperative beta-blockers, clonidine, statins, and aspirin, he writes. Despite level 1 evidence supporting the use of antiischemic agents, many physicians discontinue their use in the perioperative period, he notes.
Click here to read the press release from Archives…

Guest Post: The BMJ’s Amazing Shock and Awe Assault on Sport Drink Science 3

Editor’s Note: The following guest post by Yoni Freedhoff is reprinted with permission from his blog Weighty Matters. Dr. Freedhoff is an assistant professor at the University of Ottawa the and founder of Ottawa’s Bariatric Medical Institute.

The BMJ‘s Amazing Shock and Awe Assault on Sport Drink Science

by Yoni Freedhoff

wow.

Wow, WOw, WOW!

What words would you use to describe a situation where one of the world’s most prominent medical journal publishes, not just one article critical of a specific category of food, but seven such articles, and where those articles come to the conclusion that the food is being marketing on the basis of food industry funded hype and collusion?

I’d use the words, “Thank You”!

You’ll definitely hear about it in the news today as the British Medical Journal has 7 incendiary pieces that are highly critical of sport and energy drinks, their Big Food parents and the researchers that are conflicted by them.

The first piece (Research: The evidence underpinning sports performance products: a systematic assessment) has researchers analyzing sport drink advertising and identifying an astonishing 431 performance enhancing claims for 104 different products. Those claims were “backed up” by references made on the products’ websites to 146 references. Of those 146, the authors could only actually find half of them, and of that half:

84% were judged to be at high risk of bias“,

while only 3 were deemed to be of high quality and of low risk of bias. Ultimately the authors not surprisingly concluded that:

The current evidence is not of sufficient quality to inform the public about the benefits and harms of sports products

Click to continue reading…

FDA Approves Another New Weight Loss Drug 1

The US FDA today approved a new weight loss drug that will be called Qsymia,the brand name for the combination of two previously approved drugs, phentermine and extended-release topiramate. The drug is manufactured by Vivus, Inc.

In a press release, the FDA said Qsymia had been approved for use in obese adults (BMI of 30 or above) or in overweight adults (BMI of 27 or above) with at least one other weight-related condition such as hypertension, diabetes, or dyslipidemia.

The label recommends a daily dose of Qsymia containing 7.5 mg of phentermine and 46 mg of extended-release topiramate. The drug will also be available at the higher dose of  15 mg of phentermine and 92 mg of extended-release topiramate.

According to the FDA, in clinical trials, at one year, patients taking the recommended dose had an average weight loss of 6.7%, while patients taking the higher dose had an average weight loss of 8.9%, when compared to patients taking placebo. People taking the lower dose of Qsymia who do not lose 3% of their body weight after 12 weeks are unlikely to achieve a sustained weight loss on the same dose. These patients should either discontinue the drug or move to the higher dose. After 12 weeks on the higher dose, people  who do not achieve a 5% weight loss should discontinue the drug.

The combination drug is contraindicated during pregnancy. Because of the high risk of oral clefts in fetuses exposed to topiramate, women should have a negative pregnancy test before starting Qsymia and every month while taking the drug, in addition to using contraception. The drug is also contraindicated in people with glaucoma or hyperthyroidism. Because the drug may increase heart rate, its use in people with recent unstable heart disease or stroke is not recommended. In addition, the FDA recommends that all patients taking Qsymia have their heart rate monitored regularly, in particular when starting the drug or increasing the dose.

FDA is requiring Vivus to implement a Risk Evaluation and Mitigation Strategy (REMS), consisting of a Medication Guide for patients and a plan to educate prescribers and patients to avoid the increased risk of birth defects associated with the drug. Pharmacies will need to obtain a special certification before dispensing Qsymia. The FDA is requiring the company to perform a long-term cardiovascular outcomes trial.

The drug had previously been known as Qnexa, but was forced to change the name by the FDA “because too many other drugs ended in the same letters and it would have caused confusion,” Vivus President Peter Tam told Bloomberg News.

The approval of Qsymia, along with the approval a few weeks ago of Arena’s lorcaserin (Belviq), are the first new weight loss drugs approved by the FDA since 1999.
Click here to read the FDA press release…

Still The One: Cleveland Clinic Retains Top Spot On US News & World Report Heart Hospital Rankings Reply

US News & World Report has published its annual “Best Hospitals” list. Once again, the Cleveland Clinic is the top hospital for heart and heart surgery. Massachusetts General was the top hospital overall, followed by Johns Hopkins, Mayo Clinic, and the Cleveland Clinic.

Here are the top 20 hospitals for heart and heart surgery:

Click to continue reading…

Ticagrelor Joins Clopidogrel And Prasugrel In Updated NSTEMI Guidelines Reply

Ticagrelor (Brilinta, AstraZeneca) gains equal standing with prasugrel (Effient, Lilly) and clopdiogrel in the newly released focused update of the ACCF/AHA guidelines for unstable angina and non-ST-elevation myocardial infarction (NSTEMI). The change had been widely anticipated since last year’s FDA approval of ticagrelor.

“We have put it on equal footing with two other antiplatelet medications, clopidogrel and prasugrel,” said Hani Jneid, the, lead author of the update, in a press release issued by the AHA.

As part of the standard of dual-antiplatelet therapy (DAPT), aspirin should be given immediately to patients with unstable angina and NSTEMI. Aspirin use should be continued for “as long as it is tolerated.”

The document offers a highly detailed, near-Talmudic analysis of the literature, with a great deal of attention devoted to analysis of the  TRITON-TIMI 38 trial of prasugrel and the PLATO trial of ticagrelor. Overall, the committee concluded:

This guideline explicitly does not endorse one of the P2Y12 receptor inhibitors over the other.

However, based on data from the trials, the document provide ssome advice about the selection of the P2Y12 receptor inhibitors in specific situations, and related issues involving clopidogrel resistance.

–Because prasugrel was administered only after PCI had been planned, the writing group “does not recommend that prasugrel be administered routinely to patients with UA/NSTEMI before angiography.”

–The writing group cautions “clinicians about the potential increased bleeding risks associated with prasugrel and ticagrelor compared with clopidogrel in specific settings and especially among the subgroups identified in the package insert and clinical trials.”

–The document reviews at length the issue of clopidogrel resistance, but concludes “there is little information about the use of strategies to select patients who might do better with newer P2Y12 receptor inhibitors.”

–On genotype testing for loss-of-function CYP2c19 alleles: “On the basis of the current evidence, it is difficult to strongly recommend genotype testing routinely in patients with ACS, but it might be considered on a case-by-case basis, especially in patients who experience recurrent ACS events despite ongoing therapy with clopidogrel.”

–On platelet function testing: “any strong recommendation regarding more widespread use of such testing must await the results” of ongoing trials…. the prudent physician should maintain an open yet critical mind-set about the concept until data are available…”

–On the use of proton pump inhibitors and clopidogrel: “The expert consensus statement does not prohibit the use of PPI agents in appropriate clinical settings, yet highlights the potential risks and benefits from use of PPI agents in combination with clopidogrel.”

Click here to read the press release from the AHA…

New ICD Lead Technology Creates New Set of Problems: A Perspective From One Electrophysiologist 1

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.

Why I Don’t Like DF-4: A Personal Perspective

by Edward J Schloss MD 

Since the first human implantable cardioverter defibrillator (ICD) implant in 1980, there have been a wealth of technological advances that have allowed these devices to become a standard therapy in the treatment of patients at risk for sudden cardiac arrest.  Some of these, such as non-thoracotomy lead systems and biphasic waveforms have revolutionized the industry.  Others, such as downsized lead caliber have added risk without clear benefits.

The DF-4 ICD lead is one of the latest technologies to be approved in cardiac rhythm management.  DF-4 refers to the type of pulse generator connector on these leads.  All three major US ICD vendors have FDA approved DF-4 ICD leads, and these have been generally been well received by the implanting physician community.  In this perspective, I endeavor to show that it may be appropriate to temper this enthusiasm.

Historical Background and Lead Design

Early ICDs required open chest surgery to implant and were offered only to high-risk cardiac arrest survivors.  In the early 1990s, transvenous lead ICD systems eliminated the need for thoracotomy or sternotomy. Soon thereafter, these leads were coupled with downsized ICD generators and advanced shock waveforms resulting in significant improvements in implant safety and success.  As device indications expanded into primary prevention after the MADIT and SCD-HeFT trials, ICD implantation exploded in the US.
Click to continue reading…

NY Times: FDA Officials Spied On Its Own Scientists 5

FDA officials developed “a wide-ranging surveillance operation” against a group of its own “dissident” scientists, according to a news report by Eric Lichtblau and Scott Shane in the New York Times. The surveillance program secretly recorded thousands of emails the scientists sent to each other as well as to members of congress, journalists, and, the Times notes, “even President Obama.”

Although the Washington Post reported earlier this year that several FDA scientists were suing the agency because their emails had been read by the agency,  the full extent of the program had been completely unknown. Now the Times reports that the surveillance effort was massive and possibly illegal. Although the government, like other employers, has the right to monitor activity on its own computers, the Times notes that “the F.D.A. program may have crossed legal lines by grabbing and analyzing confidential information that is specifically protected under the law, including attorney-client communications, whistle-blower complaints to Congress and workplace grievances filed with the government.”

Adding insult to injury, the new information about the program only became available when a “private document-handling contractor” for the FDA inadvertently posted on the internet 80,000 pages of computer documents related to the investigation. (The documents were discovered when one of the scientists performed a Google search on his own name. “I couldn’t believe what I was seeing,” the scientist told the Times.) The documents have subsequently been removed from public view.

The FDA officials initially asked the Health and Human Services inspector general to undertake a criminal investigation into possible leaks from the scientists, but the inspector general found no evidence of a crime and said that “‘matters of public safety’ can legally be released to the news media.”

 

 

The Name Game: Why Did “TAVI” Suddenly Become “TAVR”? 2

One of the great, unexplained mysteries of the cardiology world in recent years is the sudden name change from TAVI  (transcatheter aortic valve implantation), which had been the universally-used name for the procedure during most of its development period, to TAVR  (transcatheter aortic valve replacement) about the time when the procedure edged closer to US approval.

Now, in a clever letter published in the Journal of the American College of Cardiology, Stacey Clegg and Mori Krantz “humbly suggest reversion to the archaic name transcatheter aortic valve implantation (TAVI).” When the procedure is explained to potential patients, they write:

We gracefully explain that we blow up a balloon, smash the old valve to the side, then implant a new one within their existing annulus. Their reaction is often one of bewilderment. This confusion is well founded. Webster’s dictionary defines replace as “to put something new in place of something else,” and implies filling a place once occupied by something removed. One does not have a muffler replaced at the local auto shop and expect to find the old one still in place. Technically, we are performing valve displacement. However, a valve displacement doesn’t sound like an advanced restorative therapy that marketing experts would embrace.

Clegg and Krantz write that TAVI was still in use in 2010 when the first PARTNER trial was published in the New England Journal of Medicine (“Transcatheter Aortic-Valve Implantation for Aortic Stenosis in Patients Who Cannot Undergo Surgery”) but the acronym had been somehow magically transformed by 2011 when the second PARTNER trial was published in NEJM (“Transcatheter Versus Surgical Aortic-Valve Replacement in High-Risk Patients”).

Clegg and Krantz argue that “TAVI” should be restored as “the acronym of choice”:

Why does this matter? We contend that this is not merely semantic, because an accurate name for high-risk expensive procedures is pertinent to healthcare stake holders. It facilitates uniform communication among researchers, payers, regulators, clinicians, and, most importantly, patients. In a clinical landscape cluttered with jargon, we should strive toward verbal precision. Politicians, poets, and pollsters know that words matter. Powerful words launch social movements and even cultural revolutions. The right catch phrase also can launch a new product. However, there should be truth in advertising, and our regulatory bodies should be critical in determining if advertising is misleading or fails to disclose all the relevant facts.

There is one issue about the name change not addressed by Clegg and Krantz, and here we leave the idealistic world of semantics and philosophy and enter the hard-edged world of economics and finance. At the time of the change from TAVI to TAVR there were numerous rumors and speculations about the real reason for the change. Reimbursement for the procedure, the theory goes, would be much higher if it were based on a comparison with surgical replacement rather than surgical repair.

Drug-Eluting Stents Often Used In Patients At Low Risk Of Restenosis 2

The chief advantage of drug-eluting stents (DES) over bare-metal stents is that they significantly reduce the risk of restenosis. The chief disadvantages of DES are their greater cost and the requirement for prolonged dual antiplatelet therapy after DES implantation.

In a study published in Archives of Internal Medicine,  Amit Amin and colleagues analyzed data from 1.5 million PCI procedures included in the National Cardiovascular Data Registry (NCDR) CathPCI registry to assess whether a higher risk for target vessel revascularization (TVR) is associated with greater DES use and to estimate the economic impact of lower DES use in patients who are at low risk for TVR.

The authors calculated that 43.0% of patients were at low risk for TVR, 43.8% were at moderate risk, and 13.2% were at high risk. DES was used 73.9% of the time in the low risk group (TVR risk <10%), 78.0% in the moderate risk group (TVR risk 10-20%), and 83.2% in the high risk group (TVR risk >20%). According to the investigators, cutting DES use by half in low-risk patients would lower US health care costs by $205 million each year, at the cost of an increase in the overall TVR rate of 0.5%.

The authors concluded that “a strategy of lower DES use among patients at low risk of TVR could present an important opportunity to reduce health care expenditures while preserving the vast majority of their clinical benefit.”

In an invited commentary, Peter W. Groeneveld writes that “the use pattern of DES during the past 9 years illustrates how far away the system is from consistently embracing value-based medical decision making, and it also enumerates the many barriers and inertial practices in US health care that must be surmounted to reach economic sustainability.”

Click here to read the Archives press release…

Coca-Cola, The Olympic Torch, And The American College Of Cardiology 3

William Zoghbi, the current president of the American College of Cardiology, today served as a torchbearer for the 2012 Olympic Games in London. The ACC, naturally, was proud of the honor and tweeted the event. Zoghbi himself wrote about it on his ACC blog.

 But I couldn’t help noticing one line in Zoghbi’s blog:

 I am one of 22 participants chosen by the Coca-Cola Company to carry the Olympic Flame as part of its Live Positively campaign.

An ACC spokesperson told me that Zoghbi was chosen by Coke because the company is a sponsor of the ACC’s CardioSmart initiative. Here’s a note at the end of the ACC announcement of the sponsorship.

Note: The ACC’s newly formed Patient Centered Care Committee and Board of Trustees carefully review each potential sponsor, its products and how well the organization and its brand fit with the ACC’s goals and values. The ACC will not endorse any product or service in connection with its CardioSmart National Care Initiative. In addition, the ACC maintains complete editorial independence over program materials and tools, which support guideline-based cardiovascular care and prevention.

 I wonder what criterial the ACC Board of Trustees used in determining that Coca Cola and “its brand fit with the ACC’s goals and values.”

I was particularly disturbed by the words that Zoghbi was “chosen” by Coca Cola. At first I thought I might made a snide comment about how Coca Cola might end up choosing the next president of the ACC, but that seemed a bit extreme and unfair. But then I wondered: given the financial ties between the ACC and Coca Cola, what is the likelihood that the ACC will choose a president in the future who takes a strong stand against a company like Coca Cola?

But why get all worked up about this? Coca Cola already pays the NHLBI so that it can put a red dress on Diet Coke cans, the AHA accepts money from Subway and Nintendo, and Victor Dzau, the cardiologist who serves as the Chancellor for Health Affairs at Duke, sits on the board of Pepsi. It’s all just business as usual.

AHA And ADA Cautiously Endorse Non-Nutritive Sweeteners 1

In a newly released scientific statement the American Heart Association and the American Diabetes Association offer a cautious endorsement of the use of non-nutritive sweeteners in the diet. But the statement notes that the products are not “magic bullets” and that there is no strong evidence demonstrating beneficial effects of the products.

Sugar in the diet has been linked repeatedly to obesity, type 2 diabetes, and cardiovascular disease, leading to recommendations that sugar intake should be limited. However, the evidence to date is “inconclusive” that non-nutritive sweeteners (including aspartame, acesulfame-K, neotame, saccharin, sucralose, and stevia) can reduce caloric intake, lower body weight, or help prevent diabetes or cardiovascular disease.

“Determining the potential benefits from non-nutritive sweeteners is complicated and depends on where foods or drinks containing them fit within the context of everything you eat during the day,” sad Christopher Gardner, one of the authors of the report, in an AHA press release. “For example, if you choose a beverage sweetened with non-nutritive sweeteners instead of a 150-calorie soft drink, but then reward yourself with a 300-calorie slice of cake or cookies later in the day, non-nutritive sweeteners are not going to help you control your weight because you added more calories to your day than you subtracted.”

“However, if you substitute the beverage with non-nutritive sweeteners for a 150-calorie sugar-sweetened soft drink, and don’t compensate with additional calories, that substitution could help you manage your weight because you would be eating fewer calories,” said Gardner.

The following text is taken from the summary and recommendations of the report:

At this time, there are insufficient data to determine conclusively whether the use of NNS to displace caloric sweeteners in beverages and foods reduces added sugars or carbohydrate intakes, or benefits appetite, energy balance, body weight, or cardiometabolic risk factors…. There are some data to suggest that NNS may be used in a structured diet to replace sources of added sugars and that this substitution may result in modest energy intake reductions and weight loss. Successful reduction in energy intake requires that there is incomplete compensation of energy reduction from the use of NNS containing beverages and/or foods. The impact of incorporating NNS and NNS-containing beverages and foods on overall diet quality should be included in assessing the overall balance of benefits and risks.

Addressing the negative perception of non-nutritive sweeteners that many people have developed,  weight loss expert and blogger Yoni Freedhoff sent the following comment to CardioBrief:

Likely consequent to the natural fallacy many readily assume that the consumption of NNS carries risk, included among them a risk towards increased consumption and weight gain.  It’s refreshing then to see the analysis of actual evidence on the use of NNS in people rather than animal models concludes that if anything there’s a suggestion of benefit to weight management, rather than risk, with the consumption of NNS.  Given the complexity of weight regulation and human behavior, no intervention will work in a vacuum and my clinical experience definitely suggests a synergy between their use and true caloric literacy and may help to explain the lackluster results.  Hopefully future studies will shine more conclusive light on the situation.”

(Editor’s note: The publication of this statement had been embargoed until 4 PM ET today. However, the AHA appears to have published the statement ahead of schedule and then tweeted it.)

Click here to read the AHA 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…

Severe Blood Conservation Appears Safe In Cardiac Surgery For Jehovah’s Witnesses Reply

Severe blood conservation in conjunction with cardiac surgery is not associated with long-term adverse consequences, according to a new study published in Archives of Internal Medicine.

Investigators from the Cleveland Clinic and the NHLBI compared 322 patients who were Jehovan’s Witnesses with an equal number of matched controls. Due to their religious beliefs Witnesses do not receive blood transfusions, and therefore “provide a unique natural experiment in severe blood conservation,” according to the authors.

Compared to patients who had transfusions, Witnesses had better  short term and long term outcomes. They had fewer complications in the hospital and better survival out to 15 years.

  • Perioperative MI: 0.31% for Witnesses versus vs 2.8% for controls (p = .01)
  • Operation for bleeding: 3.7% vs 7.1% (p = .03)
  • Prolonged ventilation: 6% vs 16% (p < .001)
  • Hours in the ICU (15th, 50th, and 85th percentiles): 24 versus 24, 25 versus 48, and 72 versus 162 (p < .001)
  • Survival at 5 years: 86% versus 74%
  • Survival at 10 years: 69% versus 53%
  • Survival at 15 years: 51% versus 35%

The investigators concluded that although they “found differences in complications among Witnesses and control groups that received transfusions, current extreme blood management strategies do not appear to place patients at heightened risk for reduced long-term survival.”

In an accompanying editorial,  Victor Ferraris points out that “Witnesses who undergo cardiac surgery are likely a healthier subgroup of Witnesses because those who are believed by their surgeons to require blood transfusion to survive cardiac surgery presumably never go to the operating room.” Nevertheless, “the finding that the Witnesses who did not receive transfusions did at least as well as, if not better than, those who received a transfusion raises questions about whether more patients might benefit from surgical strategies that minimize transfusion of blood products.”
Click here to read the press release from Archives…