The Dangers Of Going Too Fast 5

Updated– According to an editorial published online in the BMJ journal Heart, running too hard, too fast, and for too long can be dangerous. The same holds true in publishing. The editorial was hastily released ahead of its scheduled publication time after portions of it were quoted in Wall Street Journal article on the dangers of endurance sports. A BMJ representative told me that Heart had not yet found out how the WSJ article gained early access to the editorial, although in the article it appears that the Heart editorialists spoke at length with the WSJ reporter.

In the editorial, cardiologists James O’Keefe and Carl Lavie marshall the evidence suggesting that “extreme endurance exercise may exact a toll on cardiovascular (CV) health.” The authors acknowledge that runners have only a very small risk of dying during a marathon, but “chronic extreme exercise” can induce “adverse structural and electrical remodeling, which offsets some of the CV benefits and longevity improvements conferred by moderate physical activity.”

The authors cite data showing that “improvements from unfit to moderately fit confer dramatic reductions in morbidity and mortality” but that “fitness levels above 12 metabolic equivalents do not seem to translate into additional gains in CV health and longevity.” The authors posit a U-curve, with “couch loungers” on one side and “extreme exercise aficionados” on the other side. They recommend moderate exercise as “the safe and comfortable zone at the bottom of the U curve, which, they say, is the sweet spot for most people. They conclude with a “take home message” recommending that most people limit vigorous exercise to 30-50 minutes per day.

In the WSJ article both O’Keefe and Lavie, former elite athletes with years of intense training, discuss their current moderate exercise regimens. The article also includes an old quote from Kenneth Cooper, the sports physician who helped launch the original aerobics movement: “If you are running more than 15 miles a week, you are doing it for some reason other than health.”

Update– I asked Heart editor Adam Timmis to comment on this episode and whether he thought the Ingelfinger rule (which forbids prepublication publicity about a forthcoming paper) applied in this case. Here is the response I received:

“Embargo breaks are always regrettable, of course. But while the Ingelfinger rule is a worthy one, to apply it in this case would be like taking a mallet to a walnut.

The article in question was a review article- albeit in editorial format-not original research. And there is little or nothing in the piece that is not already in the public domain. Therefore, we think that it would be excessive to withdraw it from publication.”

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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…

Statins and Exercise, Independently Beneficial, Even Better In Combination 2

It’s no secret that statins and exercise are good for people with cholesterol problems. Now a new study published in the Lancet offers fresh evidence that the two appear to be independently beneficial, and that adding the two together may result in greater benefits than either alone.

US researchers analyzed data from 10,043 people with dyslipidemia treated at 2 Veterans Affairs Medical Centers. Participants were followed for a median of 10 years, during which time nearly a quarter of them died. After adjusting for baseline characteristics and other risk factors, mortality was separately and independently reduced by statins and by fitness level, with the greatest benefit found in the group of patients who were taking statins and were highly fit (>9 MET). The researchers further reported that only a moderate and achievable amount of exercise produced an effect similar to that of statins in people not taking statins. “Improved fitness,” they wrote, “is an attractive adjunct treatment to statins or an alternative when statins cannot be taken.”

“The fitness necessary to attain protection that is much the same or greater than that achieved by statin treatment in unfit individuals is moderate and feasible for many middle-aged and older adults through moderate intensity physical activity such as walking, gardening, and gym classes,” said lead researcher Peter Kokkinos, in a Lancet press release.

In an accompanying editorial, Pedro Hallal and I-Min Lee write that “the undervaluation of physical activity in clinical practice” is “unacceptable.” “Prescription of physical activity should be placed on a par with drug prescription.”

Photo by T-Rex Runner (click on the the picture for more background)

Click here to read the Lancet press release…

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.

The Doctor At The Center Of The Insider Trading Scandal 2

Last week’s big insider trading case offers fresh evidence that financial interests often clash with medical ethics. Of course, the news stories were all about the juicy details of insider trading at a hedge fund based on information leaked by a key academic investigator. This is an important and shocking story. But there’s another story buried here. Though far less dramatic than the insider trading part of the story, the DOJ complaint paints a rare portrait of the inner workings of the pharmaceutical industry and its dysfunctional relationship with academic leaders. And it ain’t a pretty picture.

Dr. Sidney Gilman

The key medical figure in the case is Dr. Sidney Gilman, an 80-year-old neurologist with expertise in neurodegenerative disorders, including Alzheimer’s disease. According to his biography on the University of Michigan website, Gilman first served on the faculty at Harvard and Columbia and then had a long and distinguished career at the University of Michigan, where he was the chair of the department of neurology for many years. He is a member of the Institute of Medicine of the National Academy of Sciences and a past president of the American Neurological Association. In other words, he’s a bigshot.

Gilman moonlighted as a consultant, working for an expert networking firm, where he provided advice to the financial industry (and which eventually led to the insider trading case), and for Elan Pharmaceuticals. In addition to his consulting for Elan, he also served as the chair of the Safety Monitoring Committee for a phase II clinical trial of a highly promising (at the time) Alzheimer’s drug, bapineuzumab, under development by Elan and Wyeth.

The bottom line of the DOJ and SEC investigation is that Gilman provided confidential information about that trial to the hedge fund. While serving on the Safety Monitoring Committee of the trial, from the summer of 2006 through mid-July 2008, Gilman had access to the safety (but not the efficacy) data from the trial. Throughout this period he leaked the positive safety information to his contact at SAC (the enormous hedge fund), which then began to accumulate a large position in both Elan and Wyeth.

On June 17, 2008, about six weeks before the first results of the trial were presented, Elan and Wyeth issued a press release announcing “encouraging top-line results” from the phase 2 trial. Although it disclosed that the trial had not met its primary endpoint, the press release focused on promising subgroup analyses and comments from company officials expressing optimism about the drug. The companies announced that full results of the trial would be presented on July 29, 2008 at ICAD (International Conference on Alzheimer’s Disease). The stock of Wyeth and Elan rose in response to the press release.
Click to continue reading…

Model Finds High Cost For ECG Screening Of Athletes 2

A national program of ECG screening for U.S. athletes would save almost 5,000 lives over 20 years but would cost more than $50 billion dollars, according to a paper published in the Journal of the American College of Cardiology. The advisability of routine ECG screening for athletes has divided the experts: currently the ESC recommends ECG screening while the American Heart Association does not.

Israeli investigators developed a cost-projection model using data from a retrospective Italian study and based on population data derived from high school and college athletic associations and expense assumptions from Medicare. Currently there are more than 8.5 million student athletes. Over 20 years, the investigators predicted that a national screening program would result in 170 million ECG screenings and, based on an estimated 2% disqualification rate, 3.4 million disqualifications. This would cost between $51 and $69 billion dollars and save 4,813 lives, yielding a cost per life saved in the range of $10.6 to $14.4 million.

In an accompanying editorial comment, Antonio Pelliccia takes issue with the cost assumptions in the paper and maintains that pre-participation screening “should be priced as a package of preventive medicine program” rather than the more expensive individual diagnostic testing. He acknowledges that this “will require a change in the cultural attitude and current medical policy” in the U.S.

In a statement, the ACC said that automatic external defibrillators (AEDs) can be life saving “if used quickly on stricken athletes.” However, although AEDs are now commonly placed at sports venues and other public places, they “are only effective if actually used” and bystanders are often afraid to use them. “AEDs are life-saving,” said Joanne Foody, in the ACC statement. “While many fear they may cause more harm than good, it is not the case.”

Click here to read the ACC press release…

Yet Another Look At The Transcendental Meditation Paper 85

Editor’s note: Below are two responses to Robert Schneider’s defense of his Transcendental Meditation paper, which Schneider wrote in response to my earlier article about the publication of his paper.  In the first part I respond to some of the general issues raised by Schneider. The second part, from Sanjay Kaul, addresses the statistical issues discussed by Schneider.

I’m grateful for Kaul’s highly technical analysis of the statistical issues raised by Schneider, but I don’t think this case really requires a terribly high level of technical expertise. Common sense actually works pretty well in this case. A trial with barely 200 patients can not be expected to provide broad answers about the health benefits of a novel intervention. As Kaul and others have stated on many other occasions, “extraordinary claims require extraordinary evidence,” and it is quite clear that the evidence in this trial is not extraordinary, at least in any positive sense.

Questions About Trial Reliability And Data– In his response Schneider tries to skate away from the inevitable questions raised about this paper when Archives of Internal Medicine chose to withdraw the paper only 12 minutes before its scheduled publication time. Schneider can pretend that this incident never occurred, but outsider readers can not help but wonder what sparked this extraordinary incident, and will not be satisfied  until the details are fully explained.

There are additional red flags about the trial. Schneider told WebMD that since the Archives incident “the data was re-analyzed. Also, new data was added and the study underwent an independent review.” Said Schneider:

“This is the new and improved version.”

This is an extraordinary claim, because a clinical trial can not be “new and improved” unless there were serious flaws with the earlier version. What exactly does it mean to say that a paper published in 2012 about a trial completed in 2007 is “new and improved”? (According to ClinicalTrials.Gov the study was completed in July 2007, while June 2007 was the “final data collection date” for the primary endpoint.)
Click to continue reading…

From Barack To Rupert, A Thanksgiving Message 2

Sorry for this off-topic post, but I couldn’t resist sharing this email message forwarded from a friend in Washington, DC:

Thanksgiving Day, The White House

Dear Rupert,

I thought on this day in particular it would be appropriate for me to send a brief note expressing my gratitude for all that you did for us over the last year. It’s clear to me that without your tireless help the outcome would have been very different. For obvious reasons I can’t acknowledge your help in public, but I want you to know that I will never forget your help, and Michelle and I will be thinking of you during our Thanksgiving Dinner in a few short hours.

Please let Roger know that his work was particularly indispensable. I hope you encourage him to give big Xmas bonuses to  O’Reilly, Hannity, Kelly, and the rest of the bunch (I’m sorry but I just don’t have enough time to mention all the amazing players on the great Fox News bench). Of course they are unaware of their contribution, but their tireless efforts in pursuit of their simple-minded ideology really demonstrated to America the sad, bankrupt state of the Republican party. (Maybe next year I’ll propose a TARP-style plan to rescue the Republican Party, just like the auto industry– LOL.) I have to admit that I almost felt sorry for Mitt, the way they held his feet to the fire during the primaries.

But of course your efforts went way beyond Fox News. I really think that the Fox entertainment network was equally valuable. After all, after watching shows like Glee, The Simpsons, and American Idol the vast majority of Americans were far less susceptible to the homophobic, racist, pseudo-patriotic and pseudo-religious rantings of the right. And I know that a super smart businessman like yourself would never allow so-called “conservative” family values to get in the way of the vast profits you earn from popular music and culture.

There’s so much more for which I would like to thank you but I don’t have time! Let me just touch on the great work you’ve done with the Wall Street Journal. Of course, no one really reads newspapers these days, but those complete knuckleheads on the editorial page still haven’t figured out that all the great reporting in the rest of the paper vaccinates most readers against all their ridiculous editorial positions. (As a side note, I particularly admire your business acuity here, since you’re clearly able to get such first-rate work from all those reporters at bargain-basement prices.)

Let me just finish by wishing you a Happy Thanksgiving. Please pass on my thanks and regards to the Kochs, Karl, and all the rest. I wish I had time to thank them all.

All my best,

Barack

What’s The Best Treatment For Abdominal Aortic Aneurysm? Reply

Endovascular repair of AAA (abdominal aortic aneurysm) gained enthusiastic acceptance after initial results from three trials (EVAR 1, DREAM, and OVER) found an early survival advantage for endovascular repair compared to open repair. Some of the enthusiasm waned, however, after long-term results from the first two trials found no difference in survival between the groups after the first two years. Now the results of the third trial, the Open versus Endovascular Repair (OVER) Veterans Affairs Cooperative Study Group,  have been published in the New England Journal of Medicine. and these confirm the pattern found in the other trials.

The trial randomized 881 patients with asymptomatic AAA who were eligible for either approach. Although in the early years of the trial endovascular repair was superior to open repair, after a mean followup of  5.2 years there were no significant differences in mortality between the two groups, with the same number of deaths (146) deaths occurring in each. Here are the hazard ratios for endovascular repair:

  • at 5.2 years: 0.97, CI 0.77 – 1.22, p=0.81
  • at 3 years: 0.72, CI 0.51 – 1.00; p=0.05
  • at 2 years: 0.63, CI 0.40 – 0.98, p=0.04

Summarizing their findings, the OVER investigators wrote that the two procedures “resulted in similar long-term survival. The perioperative survival advantage with endovascular repair was sustained for several years, but rupture after repair remained a concern. Endovascular repair led to increased long-term survival among younger patients but not among older patients, for whom a greater benefit from the endovascular approach had been expected.”

In an accompanying editorial, Joshua Beckman places OVER within the context of EVAR 1 and DREAM, and points out that “the results of these three clinical trials” have been “incredibly consistent.” All three trials found “an upfront reduction in mortality with catch-up later.” With no significant differences in mortality between the procedures, “patients can weigh the value of open repair, a major operation with greater upfront morbidity and mortality, against that of endovascular repair, with its lower early-event rate but the need for indefinite radiologic surveillance.”

Investigator Defends Controversial Transcendental Meditation Paper 5

Editor’s Note: Here is a response by Dr. Robert Schneider to my story last week about his controversial paper on Transcendental Meditation that appeared in Circulation: Cardiovascular Quality & Outcomes. I will respond to Dr. Schneider’s post later this week.

Response from Dr. Robert Schneider

We appreciate the interest in our article published in Circulation: Cardiovascular Outcomes and Quality, November 2012.  However, there are several errors and inaccuracies in the blog. Many of these points were addressed in the Circulation Outcomes publication.  Below are highlights.

Robert Schneider, MD, director of the Institute for Natural Medicine and Prevention and dean of Maharishi College of Perfect Health in Fairfield, Iowa. Courtesy MAPI

1.     This was a prospective, randomized, controlled, single-blinded clinical trial.  This report is the first publication of data from the trial. It was revised in response to extensive peer-review over the past months.  Whatever unpublished version of the manuscript the bloggers had access to previously did not have the benefit of the most current peer review and revision.

2. There were a range of check and balances built into the study to ensure veracity.  For example:

  • data were collected blindly at the clinical site in Milwaukee
  • the trial was monitored by independent data safety and monitoring board
  • end point events were adjudicated by an independent reviewer using standardized criteria
  • results were confirmed by independent data analysis
  • limitations are enumerated and discussed in the publication

3. Regarding the hypothesis testing capacity of the study, according to the Consolidated Standards of Reporting Trials (CONSORT) guidelines,

“Randomised clinical trials (RCTs) are generally considered to produce the most solid evidence for the effectiveness of medical interventions”  (Keech 2007).  The CONSORT guidelines are recommended by the International Committee of Medical Journal Editors (ICMJE). The design, implementation, analysis and reporting of this trial followed CONSORT guidelines.  Thus this clinical trial was an experimental study that tested an hypothesis.  By contrast, observational studies, which this was not, generates hypotheses (http://en.wikipedia.org/wiki/Observational_study).

4.  The total number of primary end point events is within one of an earlier, unpublished version of the manuscript (noted in blog update November 18).  In preparation for the revised manuscript, one additional event was identified.  However, this had no meaningful effect on the results or statistical significance. That is, the main results are essentially unchanged.
Click to continue reading…

HeartWare LVAD Approved By FDA For Transplant Patients Reply

The FDA said today that it had granted approval to the HeartWare Ventricular Assist System for use in heart failure patients waiting for a transplant. Approval of the device had been expected after the FDA’s Circulatory System Devices panel recommended approval of the device earlier this year.

HeartWare was approved based on data from the pivotal ADVANCE trial, in which 140 patients received the Heartware device and were compared to historical controls who had received Thoratec’s HeartMate II device. The FDA said this was the first time it had approved an LVAD using registry data as a control. Unlike Thoratec’s HeartMate II VAS, which is surgically implanted in an abdominal pouch, the HeartWare VAS is implanted next to the heart.

The FDA said that surgical outcomes were comparable in the two groups. Because of the risk of stroke associated with the device, the FDA said patients and clinicians should “discuss all treatment options before deciding to use the device.”

HeartWare said that the FDA was requiring the company to perform a post-approval study in the form of  a registry consisting of 600 HeartWare patients  and an additional 600 control patients. The FDA will also require sites that implant the device to undergo training with an approved program.

Click here for the HeartWare press release.
Click here to read the FDA press release…

Comprehensive Guidelines for Stable Ischemic Heart Disease Released Reply

Stephan D. Fihn, MD

New comprehensive guidelines for the diagnosis and treatment of stable ischemic heart disease have been released by the American College of Cardiology (ACC)/American Heart Association (AHA) Task Force on Practice Guidelines, along with the American College of Physicians (ACP), American Association for Thoracic Surgery (AATS), Preventive Cardiovascular Nurses Association (PCNA), Society for Cardiovascular Angiography and Interventions (SCAI), and The Society of Thoracic Surgeons (STS). The guidelines are being published in the Journal of the American College of Cardiology and Annals of Internal Medicine and will be available on the ACC Cardiosource website and the SCAI website.

The chairman of the writing committee, Stephan Fihn, provided the following summaries of the key points of the document for professionals and for patients:

For professionals:

a. Management of SIHD, including diagnosis, risk assessment, treatment and follow-up should be based upon strong scientific evidence and the patient’s preferences.

b. All patients who present with angina should be categorized as stable vs. unstable angina. Those with moderate or high risk unstable angina should be treated emergently for acute coronary syndrome.

c. For patients with an interpretable ECG and who are able to exercise, a standard exercise test should be the first choice test for diagnosis of IHD, especially if the likelihood is intermediate (i.e., 10 to 90%). Those who have an uninterpretable ECG and are able to exercise, should undergo an exercise stress with nuclear MPI or echocardiography, particularly if the likelihood of IHD is intermediate to high. For patients unable to exercise, nuclear MPI or echocardiography with pharmacologic stress is recommended.

d. Patients diagnosed with SIHD should undergo assessment of risk for death or complications of IHD. For patients with an interpretable ECG and who are able to exercise, a standard exercise test is also the preferred choice for risk assessment. Those who have an uninterpretable ECG and are able to exercise, should undergo an exercise stress with nuclear MPI or echocardiography, while for patients unable to exercise, nuclear MPI or echocardiography with pharmacologic stress is recommended.

e. Patients with SIHD should generally receive a “package” of Guideline-Directed Medical Therapy (GDMT) that include lifestyle interventions and medications shown to improve outcomes which includes (as appropriate):

  • Diet, weight loss and regular physical activity;
  • If a smoker, smoking cessation;
  • Aspirin 75-162mg daily;
  • A statin medication in moderate dosage;
  • If hypertensive, antihypertensive medication to achieve a BP <140/90;
  • If diabetic, appropriate glycemic control.

f. Patients with angina should receive sublingual nitroglycerin and a beta-blocker. When these are not tolerated or are ineffective, a calcium-channel blocker or long-acting nitrate may be substituted or added.

g. Coronary arteriography should be considered for patients with SIHD whose clinical characteristics and results of noninvasive testing indicate a high likelihood of severe IHD and when the benefits are deemed to exceed risk.

h. The relatively small proportion of patients who have “high-risk” anatomy (e.g., >50% stenosis of the left main coronary artery), revascularization with CABG should be considered to potentially improve survival. Most of the data showing improved survival with surgery compared to medical therapy are several decades old and based on surgical techniques and medical therapies that have advanced considerably. There are no conclusive data demonstrating improved survival following PCI.

i. For the vast majority of patients with SIHD, a trial of GDMT is warranted before consideration of revascularization to improve symptoms. Deferral of revascularization is not associated with worse outcomes.

j. Prior to performing revascularization to improve symptoms, coronary anatomy should be carefully correlated with functional studies to ensure the highest likelihood that lesions responsible for symptoms are targeted.

k. All patients with SIHD should receive careful follow-up to monitor for progression of disease, complications and adherence to therapy. Exercise and imaging studies need not be performed annually and should generally be repeated only when there is a change in clinical status or when clinical features suggest a significant change in risk of death or complications from IHD.

For patients:

a. Nearly 9 million persons in the U.S. have angina, the most common symptom of IHD and the prevalence is as high as 15-33% among persons over age 60.

b. If you develop chest discomfort or shortness of breath with activity, seek immediate medical attention.

c. The choice of tests to diagnose IHD is complicated and is based upon your symptoms, personal and health characteristics and preferences. If you able to exercise, a standard exercise test is often the first-choice test.

d. If you are found to have IHD, it is important for your physician to assess your risk of a heart attack or other undesirable outcomes. This may require additional exercise or imaging tests.

e. Most patients with IHD should adopt lifestyle changes that include a healthy, low-fat diet; regular exercise and when warranted, weight loss. Other important steps (when applicable): include smoking cessation; good control of high blood pressure; a statin medication to lower LDL (bad) cholesterol; good control of diabetes; daily aspirin; and medications to eliminate chest pain (angina) such as nitroglycerin and beta-blockers. This “package” of activities and medications is called Guideline-Directed Medical Therapy.

f. When angina does not respond to medications, patients may decide with their medical team, to undergo a procedure to improve circulation to the heart. This can be accomplished either with surgery (coronary artery bypass grafting) or with a catheter (PCI – percutaneous coronary intervention). The choice should be based upon the clinical characteristics of the patient and the results of testing including cardiac catherization. Both surgery and PCI are relatively safe and effective in eliminating chest pain BUT surgery improves survival only in a relatively small group of patients with very severe blockages of the left main coronary artery or several arteries, while PCI has not been conclusively shown to improve survival in any group of patients.

g. Patients with SIHD should receive regular medical follow-up from a primary care provider or cardiologist. The purpose is to answer any questions that arise, monitor therapy for effectiveness and possible adverse events, and check for any new complications related to IHD. Annual stress tests are usually not necessary and your provider should determine what tests are necessary and how often they should be performed based upon your personal clinical characteristics.

FDA Approves Zilver PTX Drug-Eluting Stent For Peripheral Arterial Disease Reply

The FDA today approved Cook Medical’s Zilver PTX stent. It is the first drug-eluting stent (DES) approved for the treatment of peripheral arterial disease (PAD) in the superficial femoral and proximal (i.e., above the knee) popliteal artery. The new stent will provide a new treatment option for treating patients with PAD. Current treatments include exercise, drug therapy, balloon angioplasty, bare-metal stents, and surgical bypass.

“The clinical study demonstrated that the Zilver is more effective than balloon angioplasty for the treatment of symptomatic peripheral artery disease in above-the-knee femoropopliteal artery,” said Christy Foreman, of the FDA’s Center for Devices and Radiological Health, in an FDA press release. “This approval expands the treatment options for patients suffering from symptomatic peripheral artery disease to include the Cook Zilver PTX drug eluting stent.”

The FDA said the Zilver PTX stent is contraindicated in people with “stenoses that cannot be dilated to permit passage of the catheter or proper placement of the stent, patients who cannot receive recommended drug therapy due to bleeding disorders, or women who are pregnant, breastfeeding, or plan to become pregnant in the next five years.” In clinical studies the most common major adverse event associated with the stent was restenosis requiring treatment to restore patency.

The FDA is requiring Cook Medical to perform a five-year post-approval study of 900 patients.

“This approval marks the start of Cook’s program to bring the benefits of drug elution to U.S. physicians treating the peripheral arteries,” said a Cook Medical executive, Rob Lyles. He said that Cook Medical intends by the end of 2013 to offer a “full suite of drug-eluting peripheral stents in the most commonly used lengths and diameters.” The Zilver PTX will be initially available in an 80 mm length in 6 mm and 7 mm diameters. The company has also received approval to market 40 and 60 mm length stents, though these will not be available until early 2013. Cook said that it expects to receive FDA approval for a 120 mm length stent next year.
Click here to read the FDA and Cook Medical press releases…

Mysterious Disappearing Paper Finally Reappears In Another Journal 34

Robert Schneider, MD, director of the Institute for Natural Medicine and Prevention and dean of Maharishi College of Perfect Health in Fairfield, Iowa. Courtesy MAPI

Updated– Last year, in what may have been an unprecedented action, a paper on the effects of Transcendental Mediation (TM) in African Americans was withdrawn by the editors only 12 minutes before the paper’s scheduled publication in Archives of Internal Medicine. No definitive explanation was ever provided, though the editors and authors said that the action was prompted by last minute questions from reviewers at the NIH, which helped fund the study. (The episode was covered in detail on CardioBrief  (here and here) and on RetractionWatch.)

Now a new version of the paper has been published in Circulation: Cardiovascular Quality & Outcomes. The first author is Robert Schneider, from the Institute for Natural Medicine and Prevention at Maharishi University of Management in Maharishi Vedic City, Iowa. The co-authors are from the same institution and from the department of medicine at the Medical College of Wisconsin in Wisconin. It is clearly the same study of 201 African American patients randomized to TM or health education (HE) and followed for 5.4 years, though some of the numbers have changed in important ways between the earlier and later publications. One change involves the primary endpoint: the new paper in Circ:CVQ&O reports  52 primary endpoint events (the composite of death, MI, or stroke). Of these, 20 events occurred in the TM group and 32 in the HE group. By contrast, in the previous Archives version there were 51 primary endpoint events: 20 in the TM group and 31 in the control group.

In both papers the difference in the primary endpoint did not achieve statistical significance until after the investigators adjusted for baseline differences. The unadjusted hazard ratio (HR) for the new study was 0.64, (confidence interval 0.3701.12, p = 0.12); after adjusting for age, gender, and lipid lowering medications the HR drops, presto-chango, to 0.52 (0.29-0.92, p=0.025) and achieves statistical significance..

Dome shaped building on MUM campus, for the group practice of the TM-Sidhi program and Yogic Flying (Photo credit: Wikipedia)

Here are some other key questions that I have asked AHA, Circulation editors, and other experts to address:

– Was the AHA or the Circulation staff aware at any time that an earlier version of this paper had been scheduled for publication in Archives of Internal Medicine and withdrawn only 12 minutes before the scheduled publication time? Should this information have been disclosed by the study authors when submitting the paper?

– As mentioned above, the original publication in Archives appeared to have been cancelled because of questions raised by NIH reviewers. Have the Circulation: Cardiovascular Quality & Outcomes editors received any assurance that these questions have been addressed in the new paper?

– This trial was started all the way back in 1998 but was not registered on ClinicalTrials.Gov until February 2011 (shortly before the intended Archives publication). Why was it not registered earlier than 2011?

– June 2007 is listed in ClinicalTrials.Gov as the final data collection date for primary outcome measure. Why are the primary endpoint numbers different between the Archives and new version of this paper?

Update, November 13-Harlan Krumholz, the editor of  Circulation: Cardiovascular Quality & Outcomes, sent the following statement:

“We had no prior knowledge of what transpired with the Archives of Internal Medicine.  The Schneider paper went through rigorous peer review, statistical review and editorial discussions and the authors of the article were responsive to the review process.  As a result, the paper was accepted for publication and we are going ahead as planned.  If you have any further questions, we suggest you contact the researchers directly.”

Update, November 18–  An earlier version of this article contained several mistakes. First, the difference in the number of primary endpoint events between the two papers is much smaller than I had stated. The original paper reported 51 primary endpoint events. The new paper reports 52 endpoint events. I am still unclear about why there should be any difference between the two, since, as mentioned above, June 2007 was the final data collection date for the primary endpoint. I also incorrectly claimed that some  data reported in the original Archives paper were not included in the new paper. In fact, as a reader pointed out in the comments section below, these data were reported in Figure 1. I apologize for this mistake and regret the error. –LH

I asked Sanjay Kaul for his perspective on the paper. Here are his points:
Click to continue reading…

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…

Nonfasting Lipid Testing Gains Growing Acceptance Reply

Although fasting before a lipid test has long been recommended, a new study and accompanying commentaries make the case that nonfasting lipid levels are acceptable and may even be superior to fasting levels for the assessment of cardiovascular risk.

Investigators at the University of Calgary analyzed data from laboratory tests obtained from more than 200,000 people and found that fasting time caused little variation in total cholesterol and HDL cholesterol levels, although LDL levels and triglycerides varied by as much as 10% and 20%, respectively. The finding, the authors write in their paper in Archives of Internal Medicine, “suggests that fasting for routine lipid level determinations is largely unnecessary,” though patients with triglyceride levels over 400 mg/dl may require a fasting lipid level or a direct measurement of LDL.

In an accompanying editorial, J. Michael Gaziano writes that “the incremental gain in information of a fasting profile is exceedingly small for total and HDL cholesterol values and likely does not offset the logistic impositions placed on our patients, the laboratories, and our ability to provide timely counseling to our patients. This, in my opinion, tips the balance toward relying on nonfasting lipid profiles as the preferred practice.”

In an invited commentary, Amit Khera and Samia Mora take note of some limitations of the study but conclude that “given the current lack of evidence for the superiority of fasting lipid testing, it is reasonable to consider nonfasting lipid testing in most individuals who present for a routine clinic visit.”  Fasting levels may be indicated in people with high triglycerides and in high-risk patients such as diabetics.
Click here to read the press release from Archives of Internal Medicine…

Nine Italian Cardiologists Arrested In Broad Investigation Of Research Fraud And Misconduct 2

The Arrest of Maria Grazia Modena, from Il Resto Del Carlino

Nine Italian cardiologists have been arrested as part of a broad investigation into serious medical misconduct at Modena Hospital, according to multiple reports in the Italian media. The investigation encompasses at least 67 other individuals and a dozen medical equipment companies, including 6 foreign companies. The charges include conspiracy, fraud, embezzlement, bribery, forgery and performing unauthorized clinical trials. Several news reports mentioned that stents and angioplasty balloons were involved.

According to one Italian website, the investigation started in 2011 in response to allegations by a group, Amici del Cuore (Friends of the Heart), that patients at the Modena Hospital (Policlinico di Modena) received treatments and procedures as part of unauthorized experiments. In some cases the procedures may have resulted in fatal outcomes. The accused physicians “performed experimental tests without making it known to patients for the sole purpose of writing about these trials in specialized magazines collecting money through bogus non-profit organization,” the website reported. [All translations in this story taken from Google Translate.]

“We wanted to ask questions about certain procedures that went far beyond the standard ones, and that seemed unusual to us,” the president of Friends of the Heart, Professor Giovanni Spinella, told Il Salvagente. “We were aware that invasive procedures were performed, often on peripheral organs, and sometimes had little to do [with] the heart. And unfortunately had caused discomfort and damage to several patients.”

Another Italian site quoted a police official who called it “a major operation” and said the accused “committed human clinical trials without authorization and installed medical devices and equipment defective in patients unaware of being subjected to an experimental treatment.” The accused physicians then “created false medical records to cover medical errors.” The Italian media said the investigation included recordings of telephone conversations between the suspects. The Italian police named the operation camici sporchi (“dirty gowns”).

The most prominent person arrested was Maria Grazia Modena, the chief of cardiology at Modena Hospital and a former president of the Italian Society of Cardiology. (Grazia Modena was the subject of a profile in Circulation European Perspectives (PDF) in 2007.) Modena, 60 years old, was trained partly at New York University and the Mayo Clinic. The second main focus of the investigation appears to be the head of the catheterization laboratory at the hospital, Giuseppe Sangiorgi. According to news reports, he is the only arrested physician who is still in jail.

Here are the names of the nine physicians:

  • Maria Grazia Modena, chief of cardiology
  • Giuseppe Sangiorgi, head of the catheterization laboratory
  • Luigi Vincenzo Politi
  • April Alexander
  • Simona Lambertini
  • Giuseppe Biondi Zoccai
  • Fabrizio Clement
  • Alessandro Mauriello
  • Andrea Amato, 36

Statins Use Linked To Reduction In Cancer Mortality 1

A large new population study rasies the possibility that statin use may lead to a decline in cancer mortality. Researchers in Denmark utilized health data from the entire population of the country and analyzed the information from nearly 300,000 patients who were diagnosed with cancer between 1995 and 2007. The authors note that the relationship is biologically plausible, since cholesterol synthesis is required for cell proliferation and other critical cellular functions.

In their paper published in the New England Journal of Medicine, the researchers compared 18,721 cancer patients who were statin users prior to their diagnosis with 277,204 had never used statins: Here is the adjusted hazard ratios for statin users:

  • All cause mortality: 0.85 (0.83-0.87)
  • Death from cancer: 0.85 (0.82-0.87)

There was no dose response relationship observed in the study. A similar and consistent pattern was observed for different types of cancer, though these differences not always achieve statistical significance.

In an accompanying editorial, Neil Caporaso notes that despite the considerable strengths of the study, which used data from the entire country of Denmark, the researchers were nevertheless unable to account for residual confouding differences between statin users and nonusers. The “consistent and substantial declines in mortality across diverse diverse cancers”  need to be interpreted with caution, he wrote. Caporaso suggests a variety of different research directions for further study of the important question of the relationship between statins and cancer.

 

Ultrafiltration Fails To Show Benefit In Acute Heart Failure Reply

Although ultrafiltration (UF) in recent years has become increasingly popular as an alternative to intravenous diuretics for patients with acute decompensated heart failure with acute cardiorenal system (type 1), the first clinical trial to test its value shows that it is inferior to standard drug therapy.

The results of CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) were presented at the AHA scientific session in Los Angeles by Bradley Bart and published simultaneously in the New England Journal of Medicine. The study compared UF with standard drug care in 188 patients with acute decompensated heart failure, worsening renal function, and persistent congestion.

UF was inferior to standard pharmacologic therapy as assessed by the primary endpoint of the trial, which was the bivariate change in serum cretinine and weight measured at 96 hours. Weight loss was similar between the groups (5.5 kg in the drug treatment group and 5.7 kg in the UF group ((p=0.58) but creatinine was significantly higher in the UF group:

  • -0.04 mg/dl in the drug group versus +0.23 mg/dl in the UF group (p=0.003)

At 60 days there  was no difference in the rate of death or rehospitalization between the groups, but a serious safety signal emerged as more UF patients had a serious adverse event (57% versus 72%, p=0.03).

The authors concluded:

Given the high cost and complexity of ultrafiltration, the use of this technique as performed in the current study does not seem justified for patients hospitalized for acute decompensated heart failure, worsened renal function, and persistent congestion.

In an accompanying editorial. W.H. Wilson Tang writes that “it is difficult to argue that ultrafiltration provides ‘diuretic sparing’ benefits in patients with acute cardiorenal syndrome when a well-managed pharmacologic approach provided equivalent clinical outcomes with fewer serious adverse effects.” He left hope that “a slower but steady ultrafiltration rate” might yet prove beneficial. Further, it is possible that aggressive therapy in order to reduce length of stay “may actually result in an increased incidence of the acute cardiorenal syndrome and cause unwanted consequences. Perhaps slow and steady may ultimately win the race after all.”
Click here to read the AHA press release…

RELAX-AHF Stirs Interest In Novel Drug For Acute Heart Failure Reply

A new drug modelled on a hormone active in pregnancy may prove beneficial to patients with acute decompensated heart failure. Serelaxin is a recombinant form of human relaxin-2, which is known to mediate the hemodynamic changes that occur during pregnancy. The drug is under development by Novartis for use in acute heart failure.

In the RELAX-AHF trial, 1,161 patients were randomized to serelaxin or placebo in the first hours of acute decompensated heart failure. Results of the trial, presented by John Teerlink at the American Heart Association in in Los Angeles and published simultaneously in the Lancet, have sparked considerable interest in the heart failure community, since few options have proven successful in this setting.

RELAX-AHF had co-primary endpoints. For the first primary endpoint, dyspnea relief  through day 5 (as measured by the visual analog scale area under the curve), serelaxin was associated with a statistically significant 19.4% improvement, resulting in a mean difference of 448 mm per hour (p=0.0075). The trial therefore reached the prespecfied criterion for efficacy. However, there were no significant differences in the other primary endpoint, dyspnea relief at 24 hours. There were also no significant differences in the secondary endpoints of cardiovascular death or hospital readmission for heart failure or renal failure through day 60.

At six months, however, cardiovascular deaths were significantly reduced in the serelaxin group:

  • 9.5% (55) in the placebo group versus 6% (35) in the serelaxin group (HR 0.63, CI 0.41-0.96, p=0.028, NNT = 29)

The investigators also reported that serelaxin was associated with significant reductions in the signs and symptoms of congestion at day 2, fewer patients with worsening heart failure, and the use of lower doses of IV diuretics.

The results, concluded the authors, “provide supportive evidence for a beneficial effect of serelaxin improving symptoms and other clinical outcomes in selected patients with acute heart failure.” The trial discussant, John McMurray, said that he believed serelaxin “does improve dyspnea and other symptoms and signs of congestion” but wondered about the clinical significance of the magnitude of the improvement and, also, whether the single trial would be sufficient to gain marketing approval.

A Surprising Reduction In Mortality

McMurray, along with trial investigators and other heart failure experts present at the AHA, expended considerable energy thinking about the reduction in mortality. The Lancet authors acknowledged that the findings of a six month survival benefit “for a drug given for 48 h with a moderate number of death events (107 total) raises the question of whether this benefit is due to chance and whether another, confirmatory trial should be done.” McMurray noted that if only two deaths had moved from one group to the other then the mortality finding would not have been significant.

But at an AHA news conference Milton Packer emphasized that “if the mortality effect is true then this trial changes the way we do things.” If confirmed, he said, it would mean that cardiologists would need to treat acute heart failure patients like ACS patients and deliver immediate treatment. Other heart failure cardioloigsts, including Mariel Jessup and Greg Fonarow, agreed that the mortality finding, if confirmed, would mean that serelaxin treatment would represent a genuine breakthrough in the treatment of acute heart failure. But, said Packer, “the real question is whether the mortality difference seen in this trial is true and replicable.”

Click here to read the AHA press release…

BLOCK HF: A “Game Changer” For Cardiac Pacing 3

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. Dr. Schloss was an investigator in the BLOCK HF trial.

In what has been described as a “game changer” for the field of cardiac pacing, the BLOCK HF trial was reported at today’s AHA Scientific Sessions showing benefit of biventricular pacing over conventional RV pacing in patients with AV block and LV dysfunction.

Since the development of pacemakers over 50 years ago, doctors have treated patients with AV block with right ventricular pacing. Until about 10 years ago, this was felt to be harmless and potentially beneficial.  Pacing algorithms were designed to force right ventricular pacing and create what was termed a “physiologic AV delay” in the hopes that controlling the timing of atrial and ventricular contraction would improve hemodynamics.

The DAVID trial, reported in 2003, turned the conventional wisdom upside-down, and first clearly showed the hazards of unnecessary RV pacing.  DAVID was designed with the hypothesis that dual chamber pacing in patients receiving ICDs without bradycardia indications would result in improved hemodynamics and therefore improved outcomes as compared to conventional backup ventricular pacing.  To the surprise of the investigators, the opposite proved true.  The group receiving dual chamber pacing had about a 40% increase in mortality and heart failure hospitalization as compared to the minimal pacing group over one year.  As this data was confirmed with additional trials, doctors moved to minimize right ventricular pacing in their patients and new minimal pacing algorithms were developed by industry.

Paralleling the movement to minimize right ventricular pacing, the technique of cardiac resynchronization therapy (CRT) for treatment of heart failure took off.  Here the benefit of pacing right and left ventricles together was established for patients with heart failure and evidence of dyssnchronous ventricular contraction.

The BLOCK HF trial was planned to test the hypothesis that biventricular pacing would be superior to right ventricular pacing in patients with left ventricular dysfunction and heart block requiring pacing.  Enrollment began in December 2003.

BLOCK HF enrolled patients indicated for ventricular pacing due to AV block who had at least mild LV dysfunction (LVEF <50% on optimal HF medical therapy) and NYHA functional class I-III.  All patients then received biventricular devices (pacer or ICD depending on clinical indication) and then were randomized in blinded fashion to conventional dual chamber (RA-RV) pacing vs. biventricular (RA-RV&LV) pacing.  Primary endpoint was the time to first event: total mortality, heart failure exacerbation requiring acute care or >= 15% increase in echocardiographic left ventricular end-systolic volume.

Enrollment and follow up continued with serial echoes and clinical assessments for over seven years with mean follow up just over three years.  The sample size was determined by a pre-specified adaptive statistical analysis that took into account the results of repeated interim analyses.  The study would complete for success, hazard or futility.  A total of 691 patients completed randomization and were included in the final analysis (with 102 exited or lost to follow up).  The study population was predominantly male with average age in 70s, and NYHA class II predominated.  LVEF was average 43% in the pacemaker group and 33% in the ICD group.

In the final analysis, biventricular pacing led to a 26% reduction in the combined endpoint of death, heart failure exacerbation or LV enlargement.  Excluding the echo endpoint, the clinical parameters remained favorable, with a 27% reduction in death or heart failure exacerbation.  The heart failure curves diverge early and remain parallel and the mortality curves diverge at about four years and continue to separate.

In last night’s investigator meeting, Dr. Anne Curtis, the study PI, called BLOCK HF a “game changer” that could lead to a new indication for biventricular pacing in patients with heart block and LV dysfunction.  She acknowledged the limitations of the trial including a high crossover rate (predominantly RV to BiV) and some missing echo data.  The very long follow up, however, could be interpreted as an advantage for the trial.

As an investigator in the trial, I was very eager to see this data and encouraged by the results.  The trial was slow to enroll with very long follow up and we were just happy to see it reach fruition.  Over the years, I’ve seen numerous patients develop heart failure after initiation of conventional pacing and it’s good to know that we may be able to prevent this if a new indication arises from the BLOCK HF data.

As in all trials, we will need to be cautious in the application of the data.  BLOCK HF should not spell the end for right ventricular pacing.  For those patients with normal LV function or those who get minimal ventricular pacing (such as sick sinus patients), conventional RV pacing is still appropriate and avoids the additional cost complexity and hazard of adding an LV lead.

Early Look: New Methods To Enhance Cholesterol Efflux Reply

Although clinical trials of HDL-boosting CETP inhibitors have so far failed to produce positive results, many other avenues of HDL-related research remain active.  A glimpse at the very early phases of two intriguing lines of research in this area was offered on Monday at the AHA.

Apo A-1 is thought to be the key HDL component that removes cholesterol from cells. Almost a decade ago a study demonstrating regression of atherosclerosis with apo A-1 Milano caused tremendous excitement, but the recombinant product has not yet undergone further research or commercial development. A somewhat similar approach is now being developed by by CSL Limited with a novel formulation of human apo A-1, known as CSL112. At the AHA, Andreas Gille and colleagues reported giving CSL112 to healthy volunteers and observing dramatic increases in the ability of the HDL in their blood plasma to remove cholesterol from cells.

Gille reported that the increase in cholesterol efflux capacity was higher and occurred faster than any previous therapy, more than doubling within two hours, as opposed to a 2.9% increase after 4 weeks with niacin or 6.8% after 24 months with dalcetrapib. “CSL112 may offer a novel means to rapidly remove cholesterol from plaque following a heart attack,” said Gille. To date two phase 1 studies have demonstrated a favorable safety profile, he reported. A phase 2 study of CSL112 in patients with an acute coronary syndrome is planned.

An even more unusual approach is being explored by Alan Fogelman and his team, who have genetically engineered a tomato to produce a small peptide, 6F, that mimics the action of apo A-1. They then fed the tomatoes to mice with high LDL levels. After consuming the tomatoes along with a high-fat and high-calorie diet, there were a number of signs suggesting a beneficial effect, including significantly lower levels of inflammation, higher levels of the antioxidant paraoxonase, higher HDL levels, and less atherosclerotic plaque.

“To our knowledge this is the first example of a drug with these properties that has been produced in an edible plant and is biologically active when fed without any isolation or purification of the drug,” Fogelman said in an AHA press release.
Click here to read the press releases from the AHA…

Dalcetrapib: Another HDL-Raising CETP Inhibitor Bites The Dust 1

Another HDL-raising CETP inhibitor has failed to demonstrate cardiovascular benefit in a large clinical trial. With the presentation of the dal-OUTCOMES trial at the American Heart Association in Los Angeles andsimultaneous publication in the New England Journal of Medicine, dalcetrapib joins torceptrapib on the list of once-promising CETP inhibitors.

In dal-OUTCOMES, 15,871 patients with a recent acute coronary syndrome were randomized to dalcetrapib or placebo. At a prespecified interim analysis after a median follow-up of 31 months, the Data and Safety Monitoring Board recommended termination of the trial for futility. The primary endpoint — a composite of death from CHD, nonfatal MI, ischemic stroke, unstable angina, or cardiac arrest with resuscitation — occurred in 8.3% of dalcetrapib recipients and 8.0% of placebo recipients (HR, 1.04; 95% CI, 0.93-1.16; P=0.52).

As expected, dalcetrapib raised HDL (by about 30%) and had little effect on LDL. However, there was no correlation between baseline HDL level and clinical outcome. Furthermore, dalcetrapib treatment resulted in mean increases of 18% in CRP level and of 0.6 mm Hg in systolic blood pressure.

The chair of the trial, Gregory Schwartz, said that the small increases in blood pressure and CRP might explain the results. The discussant for the trial, Alan Tall, said that the decision to stop the trial prematurely was rational. In addition to the changes in blood pressure and CRP, he offered several additional possible reasons for the drug’s failure to improve outcomes:

  • Moderate HDL elevation in patients who are already well treated may have little impact. It is possible that much larger elevations in HDL will be required to alter the course of disease.
  • CETP inhibitors may produce a form of HDL that does not enhance reverse cholesterol transport.
  • Dalcetrapib is only a partial CETP inhibitor. Phase 3 trials of more-potent CETP inhibitors, such as anacetrapib and evacetrapib, may still demonstrate benefit.

NIH Trial Gives Surprising Boost To Chelation Therapy 3

With a result that is likely to surprise and baffle much of the mainstream medical community, a large NIH-sponsored trial has turned up the first substantial evidence in support of chelation therapy for patients with coronary disease.  Known as TACT (Trial to Assess Chelation Therapy),  the highly controversial trial was presented today at the AHA by Gervasio Lamas. The trial was sponsored by two NIH institutes, the National Center for Complementary and Alternative Medicine and the National Heart Lung and Blood Institute.

Chelation therapy with EDTA to remove heavy metals from the blood in order to treat coronary disease has been around– and provoked criticism– since the 1950s. Despite a lack of evidence and the skepticism of the medical community, passionate supporters have kept the therapy alive in alternative medicine circles.

TACT was funded by the NIH more than a decade ago as part of a much-publicized initiative to study the claims of alternative medicine. In 2008 enrollment in TACT was temporarily suspended in response to claims that the trial was unethical. The trial was additionally hampered by slow enrollment.

Now the results of TACT will likely provide ammunition to chelation defenders, but the trial investigators and other experts have expressed considerable caution about the proper interpretation of the results.

TACT was a double blind study testing active or placebo infusions of chelation in stable patients with a history of MI. Due to slow enrollment the trial was downsized, ultimately enrolling 1,708 patients instead of the planned 2,372 patients. To maintain the trial’s power to achieve a meaningful result the follow-up time was increased. Because of the this change, and because the data and safety monitoring board reviewed the data multiple times over the course of the study, the threshold for statistical significance was lowered to 0.036.

The primary endpoint of the trial– the composite of death, MI, stroke, coronary revascularization, or hospitalization for angina– was significantly lowered in the chelation group:

  • 26.5% in the chelation group versus 30% in the placebo group (HR 0.82, 0.69-0.99, p=0.035)

There were no significant differences in any of the individual components of the primary endpoint. Most of the difference between the groups was due to a lower rate of coronary revascularization in the chelation group:

  • 15.5% versus 18.1% (HR 0.81, CI 0.64-1.02, p=0.076)

Nearly all the benefit in the trial was found to occur among the one-third of patients in the trial who had diabetes:

  • 102 events versus 67 events (HR 0.61, CI 0.45-0.83, p=0.002)

The investigators were cautious in their interpretation, noting that the trial barely achieved statistical significance, most of the difference was found in the softer endpoint of revascularization, and the finding is less reliable since there was a high withdrawal rate (17%) of patients in the trial.

The authors said their findings were “unexpected and additional research will be needed to confirm or refute our results and explore possible mechanisms of therapy.” TACT, they concluded, “does not constitute evidence to recommend the clinical application of chelation therapy.”

At an AHA press conference, Paul Armstrong said that TACT was a response to an unusual situation. On the one hand, most physicians and scientists have dismissed chelation therapy as lacking any evidence or rationale. On the other hand, chelation therapy is strongly supported by the alternative medicine community and more than 100,000 people receive chelation therapy each year. Armstrong said the results of the trial were “hypothesis generating, not practice changing.”
Click here to read the AHA press release…

ARCTIC Blows A Cold Wind On Platelet Function Tests 1

The use of platelet-function tests to monitor and guide antiplatelet therapy in PCI patients has sparked heated debate. Cardiologists have sought to reconcile biological plausibility with the absence of clinical evidence. Now the ARCTIC (Assessment by a Double Randomization of a Conventional Antiplatelet Strategy versus a Monitoring-guided Strategy for Drug-Eluting Stent Implantation versus Continuation One Year after Stenting) trial brings cold comfort to supporters of the monitoring strategy.

The ARCTIC investigators randomized 2440 PCI patients either to a strategy in which antiplatelet therapy was guided by platelet-function monitoring, or to conventional therapy without monitoring. The VerifyNow P2Y12 and aspirin point-of-care assay was used in the monitoring group. Results of the trial were presented at the American Heart Association scientific sessions in Los Angeles on Sunday and published simultaneously in the New England Journal of Medicine.

The primary endpoint was the composite of death, MI, stent thrombosis, stroke, or urgent revascularization at 1 year:

  • 31.1% in the conventional group and 34.6% in the monitoring group (HR 1.13, CI 0.98-1.29, p=0.10)

The ARCTIC investigators also reported a main secondary endpoint consisting of stent thrombosis, revascularized or not, or any urgent revascularization:

  • 4.6% and 4.9% (HR 1.06, CI 0.74-1.52, p=0.77)

In the monitoring group, 7.6% of patients were found to be poor responders to aspirin and 34.5% were poor responders to clopidogrel. The authors conclude that platelet-function testing with antiplatelet therapy adjustment does not improve clinical outcomes as compared with standard treatment and that their results “do not support the routine use of platelet-function testing in patients undergoing coronary stenting.”

A second arm of the trial, studying whether clopidogrel therapy should be continued after 1 year, is ongoing. In addition, a follow-up study, ANTARCTIC, is evaluating the value of platelet-function testing in an elderly population “with a paradigm shift towards safety.”