FDA Approves Eliquis (Apixaban) For Stroke Prevention In AF 2

The FDA has finally approved apixaban (Eliquis, Bristol Myers Squibb and Pfizer) to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. The action comes after the widely-anticipated drug had been plagued by delays at the FDA but well before the PDUFA deadline of March 17, 2013. Eliquis is the latest member of the new generation of oral anticoagulants, which also includes dabigatran (Pradaxa, Boehringer Ingelheim) and rivaroxaban (Xarelto, Johnson & Johnson).

The FDA said that apixaban should not be taken by patients with prosthetic heart valves or by patients with AF caused by a heart valve problem. (Recently the FDA added a contraindication to the dabigatran label against using the drug in patients with mechanical heart valves.) The FDA said that the most serious risk associated with apixaban, as with other anticoagulants, is bleeding, including life-threatening and fatal bleeding. Patients taking apixaban will receive a patient Medication Guide. The FDA is advising health care professionals to counsel patients about the signs of symptoms of possible bleeding.

The FDA approval was based largely on the results of the highly positive ARISTOTLE trial which found that apixaban was superior to warfarin in AF patients. The FDA will likely allow BMS and Pfizer to claim that apixaban is superior to warfarin, as the press release states that “patients taking Eliquis had fewer strokes than those who took warfarin.”

Click here to download a PDF of the package insert.

Click here to read the FDA press release…

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Autopsy Studies Find Large And Dramatic Drop In Early Atherosclerosis Over 60 Years 1

Service members who died over the past decade were far less likely to have atherosclerosis than service members who died in Korea or Vietnam, according to a new study published in JAMA. Although it is impossible to fully understand the causes and implications of the finding, the results provide powerful new evidence pointing toward a very long term, enormous reduction in the prevalence of coronary disease, especially in younger people, though an aging population and disturbing trends in obesity and diabetes mean that cardiovascular disease will continue to be a major public health problem for the foreseeable future.

Micrograph of an artery that supplies the hear...

Bryant Webber and colleagues analyzed autopsy reports and available health data from 3,832 service members who died of combat or unintentional injuries in Afghanistan and Iraq and compared their findings to similar studies performed during the Korean and Vietnam wars. 8.5% of the newest group had evidence of coronary atherosclerosis, compared with 77% in the Korean War group and 45% in the Vietnam War group. The authors acknowledge that there are many reasons why the groups should not be directly compared but conclude that the overall trend   in the reduced prevalence of atherosclerosis is undoubtedly true.

As might be expected, service members with atherosclerosis were older and more likely to have dyslipidemia, hypertension, or obesity than service members without atherosclerosis. Surprisingly, cigarette smoking was not significantly associated with atherosclerosis in this study.

In an accompanying editorial, the Framingham Study’s Daniel Levy writes that “the main finding of this study is valid: the prevalence of atherosclerosis in young men today is much lower than the prevalence in the Korean or Vietnam War eras. If these findings are generalizable to the US population as a whole, then the cardiovascular health of the US population may have improved appreciably over the past 6 decades.”

Levy writes that the concurrent decline in mortality from cardiovascular disease is likely the result of advances in both prevention and treatment, but only advances in primary prevention can explain the trend found in the autopsy studies. Nevertheless, he notes, cardiovascular disease is still the leading cause of death in the US: “The national battle against heart disease is not over; increasing rates of obesity and diabetes signal a need to engage earlier and with greater intensity in a campaign of preemption and prevention.”
Click here to read the JAMA press release…

FDA Approves Lomitapide For Homozygous Familial Hypercholesterolemia Reply

Aegerion Pharmaceuticals said today that the FDA had approved lomitapide (Juxtapid) to help further lower cholesterol in patients with homozygous familial hypercholesterolemia. The approval comes with a box warning about the risk of hepatotoxicity and a Risk Evaluation and Mitigation Strategy (REMS) Program which will require certification of health care providers and pharmacies before the drug can be prescribed and dispensed. The drug is expected to cost between $200,000-$300,000 per year.

The novel drug, which is a microsomal triglyceride transfer protein inhibitor is indicated, according to the label, “as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available, to reduce low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), apolipoprotein B (apo B), and non-high-density lipoprotein cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH)” The label notes that the safety and effectiveness of the drug has not been established in hypercholesterolemia patients who do not have homozygous FH and that the effect of the drug on cardiovascular morbidity and mortality has not been determined.

Click here to read the press release from Aegerion…

2012 In Review: A Bad Year For Conventional Wisdom 3

This was a really grim year for anyone who thought we had things pretty well figured out. Time and again conventional wisdom was thrown out the window. 2012 forced the cardiology community to reconsider what it thought it knew about HDL cholesterol, platelet function tests, aspirin resistance, triple therapy, IABP, and more.

One device company, with a lot of help, did just about everything right when it introduced a radical, highly disruptive new technology. Another device company did just about everything wrong in handling a series of crises. The new generation oral anticoagulants continued to make gains– slowly– but also failed to achieve the early blockbuster success that some had thought they might achieve.

And it was another bad year for scientific integrity.

Conventional Wisdom Isn’t

Raising HDL cholesterol had to be great. Then the evidence arrived. Just last week HPS2-THRIVE put the final  nail in the niacin coffin. (I wonder what all the critics of AIM-HIGH have to say now?) And another CETP inhibitor bit the dust. The HDL hypothesis is far from dead, but any claim of benefit due to raising HDL will need to be rigorously demonstrated in a large, well-designed clinical trial.

Platelet function tests just had to be useful in guiding therapy. Then ARCTIC came along and blew a cold wind on the idea.

On a related note, many believed that testing for aspirin resistance might be a good idea. Then a paper in Circulation presented strong evidence that the entire concept of aspirin resistance might be a myth.

Triple therapy for PCI patients already receiving anticoagulation was standard clinical practice, endorsed by the guidelines. Now, after WOEST, we know that what we knew was wrong. Drop the aspirin.

Intraaortic balloon counterpulsation (IABP) has a class 1 recommendation for patients in cardiogenic shock following myocardial infarction for whom early revascularization is planned. Until IABP-SHOCK II was presented at the ESC and published in NEJM.

Depending on your perspective the FREEDOM trial either confirmed or denied conventional wisdom. We now know with near certainty that diabetics with multivessel disease have better outcomes with CABG than with PCI. An important lesson from an important trial.

Conventional wisdom had it that chelation therapy was worthless. The conventional wisdom may still be valid, but the NIH’s TACT trial means the debate will continue. It’s hard to imagine a satisfactory result to this controversy, despite the good intentions of the NIH and at least some of the TACT investigators. In general I support the concept of testing alternative therapies, especially if they gain traction in clinical practice, but it’s not clear yet whether we really learned anything from TACT (except that doing trials like this is extraordinarily hard). A trial like TACT should only be performed if it has a good chance of actually answering the big clinical question. Unfortunately, TACT didn’t do this.

TAVR: Bright Spot in a Dark Year

Click to continue reading…

2012 In Review: Social Media In Cardiology 5

For a whole variety of reasons most cardiologists are not really comfortable diving into social media. For some reason they’re more comfortable remaining poolside, reading Braunwald or the latest mini JACC or Circulation than writing a blog or interacting with each other or their patients on Facebook or Twitter. Most cardiologists who do get their feet wet send out a few isolated tweets or posts and then disappear into the great digital void. So here’s a special shout out to a few brave cardiologists who are at least making an effort (feel free to add to this list in the comments section):

twitter

Cardiologists Chris Cannon and Herb Aronow,  and cardiology fellow Michael Katz, regularly tweet about cardiology. Some big names like Harlan Krumholz and Bob Harrington are sporadic tweeters, providing behind the scene glimpses at events like a PCORI meeting or an ACC Board of Governors meeting. Electrophysiologist John Mandrola didn’t just get his feet wet but took a big belly dive into the social media pool, actively tweeting, blogging on his own and over at that other cardiology website, and contributing to newspapers and big sites like KevinMD. Eric Topol is a prolific tweeter, but he rarely seems interested in cardiology these days.

Jay Schloss deserves special mention for live-tweeting a closed Riata symposium and then keeping CardioBrief readers fully informed about each major development of this important case as it slowly unfolded this past year. Westby Fisher is the great grandfather of all cardiologists in the blogosphere and twitterverse, though lately he’s pulled back a bit, foolishly deciding that his medical practice and family life are somehow more important than his social media standing.

Finally, though he’s not a cardiologist, Lancet editor Richard Horton deserves special mention. He took to Twitter like a duck to water, though not everyone was so pleased by all his preening. As I wrote earlier this year, it was impossible not to be fascinated by the occasional glimpses he provided of the dark underside of medical publishing. He’s toned this down a lot lately, but on occasion he still has some amusing comments on the rivalry (real or imagined?) between his journal and the New England Journal of Medicine. But if you’re not interested in the politcs of the World Health Organization or the British medical establishment you may not want to follow him these days.

Late entries:

 

 

New York Post Disavows Portions Of Article About Jeffrey Moses Reply

The New York Post has substantially disavowed significant portions of an October 22 news story about Jeffrey Moses. The story contained allegations that the well-known interventional cardiologist had tested positive for cocaine but was allowed to continue performing procedures at New York-Presbyterian Hospital. Now, the Post says, allegations of cocaine use were “subsequently proven to be conclusively false by two identical tests which were negative” and by “a court-ordered examination of Dr. Moses in May 2006 by a forensic psychiatrist who opined that he had no cocaine addiction problem.” The Post said its article gave a “false impression” about Moses and that it “regrets” any misunderstanding caused by that part of the article and “any harm it may have caused Dr. Moses personally and professionally.”

Here is the entire Editor’s Note, which was placed at the top of the story on December 20:

EDITOR’S NOTE: On October 22, 2012, The Post published an article about Dr. Jeffrey Moses, a world-renowned interventional cardiologist. Dr. Moses believes that the article gave readers the false impression that he is currently a cocaine user who is, and was for years, allowed by his hospital to operate on patients while under its influence. As the article reported, allegations of cocaine use were made by Dr. Moses’ ex-wife in their 2005 divorce case and the positive test referred to in the article was, according to Dr. Moses, a “false positive” which was subsequently proven to be conclusively false by two identical tests which were negative. The decision by New York Presbyterian Hospital not to discipline Dr. Moses and to allow him to continue to operate was made in light of the negative tests and a court-ordered examination of Dr. Moses in May 2006 by a forensic psychiatrist who opined that he had no cocaine addiction problem. Any understanding readers may have taken from the article that Dr. Moses was performing cardiovascular surgery while under the influence of cocaine was not intended. The Post regrets if any readers so misunderstood this part of the article and any harm it may have caused Dr. Moses personally and professionally.

The original Post story was summarized here on CardioBrief. As previously reported on CardioBrief, Moses is among the highest paid interventional cardiologists in the country. In 2010 he was reported to be earning at least $3 million a year. Long affiliated with the Cardiovascular Research Foundation and the annual TCT interventional cardiology meeting, Moses played a key role in bringing CRF leaders Martin Leon, Gregg Stone, and others to Lenox Hill from the Washington Hospital Center. The group subsequently moved to Columbia University.

HPS2-THRIVE: No Benefit, Signal Of Harm For Niacin Therapy 3

The largest-ever study of niacin has failed to show a clinical benefit for niacin and even found a strong signal of harm. Merck announced today that the HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) study did not meet its primary endpoint. In that study, the combination of a statin and Merck’s niacin compound, Tredaptive, a combination of extended-release niacin and laropiprant, an anti-flushing agent, was compared to statin therapy alone in 25,673 patients at high risk for cardiovascular events.

After a median followup of 3.9 years, the combination of niacin and laropiprant “did not significantly further reduce the risk of the combination of coronary deaths, non-fatal heart attacks, strokes or revascularizations compared to statin therapy,” according to Merck. Even more troubling, the company reported that there was “a statistically significant increase in the incidence of some types of non-fatal serious adverse events in the group that received extended-release niacin/laropiprant.”

Ball-and-stick model of the niacin molecule, a...

Merck said it was now no longer planning to seek approval of Tredaptive in the United States. The drug’s initial application for approval in the US was rejected in 2008. HPS2-THRIVE was designed to answer criticism from the FDA and other experts about the lack of any evidence demonstrating clinical benefit.

Tredaptive (also known as Cordaptive in some places) is approved in some countries outside the US. Merck said it is “recommending that providers not start new patients” on the drug. It is unclear whether the drug will remain on the market in these places.

Although niacin, a natural vitamin, has been used for decades to raise HDL, a clinical benefit has never been demonstrated. In 2011 the NIH’s  AIM-HIGH trial found no benefit for extended-release niacin. Critics said the trial was underpowered and otherwise flawed. HPS2-THRIVE, most agreed, would provide a more definitive test of the effect of niacin.

HPS2-THRIVE adds to the string of failures associated with trials of HDL-related therapies, although some hope remains for CETP inhibitors, despite the failure of two large clinical trials. It appears likely that the results of HPS2-THRIVE will also impact the use of existing niacin products. Bernstein analyst Timothy Anderson said it may “cause some collateral damage to AbbVie’s Niaspan.”

Responding to the breaking news, Steve Nissen said he had three initial thoughts about the trial:

What were the “non-fatal serious adverse events” that showed a statistically significant increase?

Did the study fail because of niacin or laropiprant?

We will need to decide whether to withdraw patients from niacin.

Update: Here’s a terrific comment posted below from cardiologist John Osborne:

Also don’t forget that this trial did not have a cut-off for HDL, so that patients could have any level of HDL and still get into this trial, not just patients with low HDL where presumptively the greatest benefit would be seen, according to the HDL-raising hypothesis. We will need to see how this sub-group responded, which was a pre-specified sub-group analysis. As far as the vague “excess of non-fatal serious adverse events”, it is no surprise given the known issues with the use of niacin, such as flushing (even occasionally to the point of causing vasodilation resulting in rare syncope), hyperuricemia, gout and gout flares, peptic ulcer disease, and hyperglycemia. If these non-fatal adverse events were higher int the niacin-laropriprant arm, I would not be at all surprised. If, however, we saw an excess of non-fatal strokes, as a tendency was seen in AIM-HIGH, that would be much more concerning. Obviously science and medical care cannot and should not be based on lay press reports and we need to see and digest all the data from this trial when it comes out. Stay by your radios (and Internet feeds), my friends!

Update #2: James Stein sent the following comment:

HPS did not THRIVE!  I am disappointed.  It suggests that in people on a statin with well controlled LDL and non-HDL cholesterol levels, adding niacin may not reduce CVD risk.  I still think niacin is a useful drug for those who can’t reach goals on statins or who can’t take them, and for selected patients with combined dyslipidemia.  However, this may be as much about laropiprant as it is about niacin. I am especially concerned about the increase in non-fatal serious adverse events in the group that received extended-release niacin/laropiprant. You may recall that the idea for using laropiprant was to improve the tolerability of niacin by blocking flushing. However a close look at the laropiprant data for its effectiveness as a flushing blocker showed that at the dose it was being used at, it was not significantly better than adult dose aspirin.

More worrisome, pre-clinical Merck research showed an off-target effect of laropiprant on platelet DP1 receptors. Bleeding times were not prolonged, so the meaning of this off-target effect is unclear, but this is evidence that the drug may affect more than just the DP1 receptor on dermal blood vessels.   We know DP1 receptors also are on neurons and lung tissue, among other places.  We in the lipid world need to be very humble about off target effects – even if we can’t explain them with our current knowledge base.

Click here to read the Merck press release…

Pradaxa To Be Contraindicated In Patients With Mechanical Heart Valves 1

Boehringer Ingelheim is starting to inform physicians about a new contraindication for its oral anticoagulant drug Pradaxa (dabigatran). The company has told investigators in trials utilizing dabigatran that it will shortly be sending a “Dear Doctor Letter,” also known as a Direct Healthcare Professional Communication (DHPC), to healthcare professionals. The letter will inform physicians that Pradaxa is now contraindicated in patients with mechanical heart valves. The change was based on a recent decision of the FDA, BI told its investigators.

The FDA action follows a similar decision by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency, which announced last week that it had recommended that Pradaxa be contraindicated in patients with prosthetic heart valves.

Both the FDA and the CHMP actions appear to be based on findings from the RE-ALIGN trial in patients with mechanical heart valves, which Boehringer Ingelheim announced last week had been stopped prematurely. (Click here for the CardioBrief story.As reported here in October, the company had previously terminated one arm of the study after an interim review of the data by the trial’s Data Safety Monitoring Board

One cardiologist who is a dabigatran investigator told CardioBrief that the label change

is consistent with the findings in Re-Align, although I wish it were presented and published in a peer reviewed journal. I do understand the urgency on behalf of the FDA to ensure that the use does not stray beyond its labeling for A-fib given both the prospective, randomized data from Re-Align and case reports of strokes on Pradaxa with mechanical valves. I don’t think this is the final word on Pradaxa (or other new generation anticoagulants), but if we are to use them, the doses will undoubtedly be different, and presumably higher, than the doses used for A-fib. The question is whether one can find a dose that prevents thromboembolic strokes with the new generation anticoagulants at an acceptable level of bleeding. It’s also worth noting that they did not recommend Pradaxa in patients with bioprosthetic valves, but didn’t absolutely contraindicate it. Yet.

Promising One Year Results For Renal Denervation In Resistant Hypertension Spark Hype Reply

Denervation of the renal sympathetic nerve may become an important new tool in the fight against resistant hypertension.  Previously, the main results of the Symplicity HTN-2 trial demonstrated that in selected patients renal denervation resulted in a large and highly significant reduction in systolic blood pressure (BP) at six months. Now, longer followup from the trial, published in Circulation, demonstrates that the benefits at 6 months extend to one year, and that control patients who crossed over to renal denervation also experienced large reductions in BP.

For 47 patients with resistant hypertension, the reduction in systolic BP at one year (−28.1 mm Hg) was similar to the reduction at 6 months (31.7 mm Hg). For 35 control patients  who crossed over to renal denervation after six months, mean systolic BP dropped from 190.0±19.6 before the procedure to 166.3±24.7 mm Hg. The authors reported one case of renal artery dissection in the crossover group, which was fixed with renal artery stenting, and one episode of hypotension, which was fixed with a medication adjustment.

The results, according to a clinical perspective accompanying the article, suggest that “radiofrequency ablation of renal nerves can significantly lower blood pressure in patients with systolic blood pressures >160 mm Hg with no loss of treatment effect through 1 year and thus may provide a safe and effective adjunctive therapy for treatment-resistant hypertensive patients.”

Comment: Excitement about renal denervation has been growing in recent years. At least some of the optimism may well be warranted. But, for now, the greatest danger is hype. Here’s the #4 item on the AHA’s list, released just this week, of the top advances of 2012:

“Disconnecting” the kidneys might be the key to treating high blood pressure

What does that mean, “the key to treating high blood pressure?” As an invasive procedure, renal denervation will never be more than a important therapeutic option after lifestyle and polypharmacy have failed. I applaud the AHA for highlighting this important new technology, but I think it should have used more cautious wording.

Get ready for much worse. Gullible or naive reporters and editors have already fallen into the trap. Here’s the headline and opening sentences of a story that appeared earlier today in TheStar.com:

Zapping kidneys with radio waves could cure high blood pressure, study finds

In what’s being described as a potential public health miracle, a new study shows that zapping the kidneys with radio waves can safely and dramatically lower blood pressure.

“It makes one dizzy to think about the next set of benefits that follow,” said Dr. Clyde Yancy, head of cardiology at Chicago’s Northwestern University.

This is almost a textbook example of how science and medicine stories should not be reported. It’s important to activate your BS detector whenever you see words like “cure” and “miracle” in a health story. Renal denervation is not a cure and it’s not a miracle. If things work out, it may represent a welcome and significant advance for some patients with resistant hypertension.

To be fair, the rest of the story contains some great quotes and perspective from Clyde Yancy. But by then the damage has been done. It’s impossible to be rational in the presence of cures and miracles. Of course, any reporter can slip at some point and buy into the hype. We’re not perfect. But it helps if the reporter has some prior knowledge and experience in the field. I’m assuming this reporter had little background in this field, since no experienced health reporter would describe renal denervation as “bathing the kidneys in radio waves.” It’s hard enough for physicians and grizzled journalists to figure this kind of stuff out. This is no spot for learning on the job.

But let’s not blame the reporter. He was probably just doing his job as best he could, on a deadline and with few resources. He should be congratulated for getting a good interview with Clyde Yancy. The larger problem here is the way most media treat health, medicine and science stories. Breakthroughs and cures aren’t everyday events, except in the filler pages of tabloids, and on news broadcasts and websites, where scientific inflation is an everyday occurrence. In this context, scientific reporting becomes, essentially, worthless. If everything is a breakthrough then nothing is a breakthrough.
Click here to read the Medtronic press release…

Amgen Pleads Guilty To Misbranding Anemia Drug Aranesp Reply

Biotechnology giant Amgen today pleaded guilty in federal court to a misdemeanor charge of misbranding Aranesp (darbepoetin alfa), its highly successful anemia drug. The government accused Amgen of marketing Aranesp for indications not approved by the FDA and other illegal marketing practices.

The judge deferred a decision on the plea until Wednesday. When the final settlement is announced further details about pending civil suits against Amgen will be unveiled. The acting US Attorney said that the terms of the agreements will include multiple measures to insure that Amgen complies with regulations. The measures will mean that Amgen “won’t view this as the cost of doing business,” he said in a press conference.

The agreement includes $150 million for criminal fines and penalties and an additional $612 million civil settlement. In 2011 Amgen reported $2.3 billion in sales for Aranesp.

Aranesp is approved to treat anemia in chemotherapy patients and in anemia patients with chronic kidney disease. The label now includes a black box warning that it can increase the risk of death, MI, stroke, venous thromboembolism, thrombosis of vascular access, and tumor progression or recurrence.

Although it had been the subject of earlier questions, serious criticism emerged with the publication in 2009 of the TREAT trial, which found no clinical benefit for the drug in patients with chronic kidney disease. Results of TREAT prompted a dramatic FDA advisory committee meeting in 2010 followed by a major label revision in 2011.

Click here for a PDF of the US Attorney’s Explanation of the Charges.

JACC Issues Notice of Concern Over Three Poldermans Papers 2

The editors of the Journal of the American College of Cardiology have issued a “Notice of Concern” over three JACC articles in which Don Poldermans, the disgraced Dutch researcher, served as the first or the last author. The editors relied on the report of the investigation committee at Erasmus Medical Center published in October. In each case the editors have accepted the committee’s finding that although the studies contain numerous examples of scientific “irregularities,” the evidence does not warrant full retractions for the papers.
jaccFor the first paper, the committee cited numerous irregularities, including  inconsistencies between source documentation and the Case Report Forms and “an unreliable working procedure for collection of scientific data.” But the committee also found no “evidence for any manipulation of the research results by the researchers in the sense of deliberate steering of results into a particular direction” or that “the research conclusions as published in the above mentioned article are wrong.” “It is impossible,” the editors write, for them “to determine the effect of this breach of scientific integrity upon the overall conclusions of the manuscript.”
For the second study, the committee expressed “doubt about the validity of the causes of death recorded in the data base.” The lack of  source documentation is “unfortunate” but the editors, like the committee, “could not determine how these facts influenced the conclusions of the manuscript.”
For the third study, the committee found negligence relating to informed consent, preservation of case report forms, and data collection. Although the committee was “unable to vouch for  the reliability of the findings” the editors, once again, “could not determine with certainty that the findings of the study were erroneous.”
Here is the conclusion of the editors’ notice of concern:

Since it is not possible for the Editors of JACC to determine with certainty that the findings in the above articles were erroneous, we have elected not to retract these manuscripts. However, given the uncertainty regarding the accuracy of the data, and the inability to validate the collection of data, readers should be cautioned in the application of the findings of these manuscripts to clinical practice.

Hat tip: Marilyn Mann

New Guidelines Define State-of-the-Art STEMI Care Reply

New guidelines published online today in Circulation and the Journal of the American College of Cardiology provide an efficient overview of the best treatments for STEMI patients. (Click here to download the PDFs of the full version (64 pages) or the executive summary  (27 pages) of the 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction.)

“We’re looking to a future where more patients survive with less heart damage and function well for years thereafter,” said Patrick O’Gara, the chair of the guidelines writing committee, in a press release. “We hope the guidelines will clarify best practices for healthcare providers across the continuum of care of STEMI patients.”

The new document strongly supports the establishment and maintenance of regional systems to treat STEMI, which should include assessment and continuous quality improvement programs.

Primary PCI remains the preferred method of reperfusion when it can be performed by experienced operators in a timely fashion. For people who can’t receive primary PCI within 120 minutes of arrival, fibrinolytic therapy should be given within 12 hours of the the onset of symptoms.

The first medical contact (FMC)-to-device time should be 90 minutes at PCI-capable hospitals. Patients who arrive at non PCI-capable hospitals should be transported to a PCI-capable hospital within 30 minutes and should be treated with a FMC-to-device system goal of 120 minutes of less.

Drug-eluting stents should not be used in patients who can’t or won’t comply with long-term dual antiplatelet therapy (DAPT). After receiving a stent patients should receive DAPT with aspirin and either clopidogrel, prasugrel, or ticagrelor.

Click here to read the AHA press release…

American Heart Association Lists Top 10 Research Advances Reply

The AHA has published its annual list of the top 10 advances in heart disease and stroke research. It’s probably worth remarking that not a single item on the list is related to drug therapy. I haven’t gone back and checked past lists, but I would bet this hasn’t happened before.

Here’s the list:

  1. Extended CPR saves lives
  2. Converting “non beating” heart cells into “beating” heart cells
  3. Biopsied heart cells improved heart function and reduced scars
  4. “Disconnecting” the kidneys might be the key to treating high blood pressure
  5. Progress for children in transplant bridging and Kawasaki Disease
  6. Why children and adolescents should “just say no” to sugary drinks
  7. Global impact: ECHO screening for rheumatic heart disease
  8. Devices for stroke
  9. Ideal cardiovascular health practices lead to longer life, lower risk
  10. Bypass surgery vs. drug-coated stents for diabetes patients

Click here to read the full AHA press release. with full explanations and citations…

CHMP Recommends Against Approval For Mipomersen In Europe Reply

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency today recommended that mipomersen (Kynamro, Isis and Genzyme) not be approved for use in Europe. The novel antisense oligonucleotide works by inhibiting the synthesis of apo-B and is under development in the United States and Europe for the treatment of familial hypercholesterolemia.

CHMP agreed that mipomersen effectively lowered LDL cholesterol in people with homozygous and severe heterozygous familial hypercholesterolemia. The negative recommendation was based on the committee’s concerns about the safety of mipomersen. Here is the CHMP discussion of the safety issue:

However, the CHMP was concerned about the medicine’s safety. The Committee noted that a high proportion of patients stopped taking the medicine within two years, even in the restricted group of patients with homozygous familial hypercholesterolemia, mainly due to side effects such as flu-like symptoms, injections site reactions and liver toxicity. This was considered important because Kynamro is intended for long-term treatment in order to maintain the cholesterol-lowering effect. The CHMP was also concerned by liver test results in patients taking Kynamro showing a build-up of fat in the liver and increased enzyme levels, and was not convinced that the company had proposed sufficient measures to prevent the risk of irreversible liver damage. Moreover, the Committee was concerned that a greater proportion of patients taking Kynamro experienced serious cardiovascular events (problems with the heart and blood vessels) than patients taking placebo. This prevented the CHMP from concluding that Kynamro’s intended cardiovascular benefit, in terms of reducing cholesterol levels, outweighed its cardiovascular risk.

In October the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee gave a weak endorsement to mipomersen, voting 9-6 in favor of an approval recommendation. Comments during the panel meeting, however, clearly indicated that committee members were concerned about both the efficacy and safety of the drug.

Another new drug under development for lowering cholesterol in FH patients is lomitapide (Aegerion). The same FDA panel in October gave lomitapide a slightly stronger approval recommendation.

The CEO of Genzyme expressed disappointment with CHMP’s recommendation. “Patients with HoFH carry extreme, ongoing cardiovascular risk with significantly elevated LDL-C levels despite use of currently available therapies. This is a rare disease patient population, with a life-threatening condition, in need of new therapies. We will work closely with the CHMP during the re-examination process to address the Committee’s concerns, with the goal of making this important medication available to HoFH patients in Europe.”
Click here to read the Genzyme press release…

Hypertension And Smoking Top List Of Global Risk Factors 1

Screen Shot 2012-12-13 at 2.57.27 PMWorldwide, hypertension and tobacco smoking are the single largest causes of death and disability, according to findings from the Global Burden of Disease Study 2010 (GBD 2010), the largest ever assessment and analysis of global health and disease. In an unprecedented move, the Lancet devoted an entire issue to the study, including seven separate articles and eight comments.

GBD 2010 was led by the Institute for Health Metrics and Evaluation (IHME) at the University of Washington. In a press release, IHME director Chris Murray said, “For decision-makers, health-sector leaders, researchers, and informed citizens, the global burden of disease approach provides an opportunity to see the big picture, to compare diseases, injuries, and risk factors, and to understand in a given place, time, and age-sex group, what are the most important contributors to health loss.”

Despite significant reductions in the rate of ischemic heart disease and stroke since 1990, overall these retained their position as the #1 and #2 worldwide causes of death. Among men 15-49 years of age, CV disease was the single largest cause of death, accounting for 12.8% of all deaths. For women of the same age CV disease was the third largest cause of death, following HIV/AIDS and other non-communicable diseases, accounting for 10.7% of all deaths.

Ischemic heart disease in 2010 now ranks as the largest single cause of global years of life lost. In 1990 it had ranked fourth, behind lower respiratory infections, diarrhea, and preterm birth complications. Stroke moved from fifth place to third place.

High blood pressure emerged as the single most important risk factor for death and disability, followed by tobacco smoking. In 1990 the top two risk factors were childhood underweight (#8 in 2010) and household pollution (#4 in 2010).

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

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

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

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

Here’s the data from the meta-analysis:

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

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

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

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

State Of The Heart: AHA Publishes Year-End Statistical Update Reply

Although deaths from cardiovascular disease have been declining for many years, continued progress is threatened by disturbing trends in US lifestyles. That’s the clear message from the American Heart Association’s year-end report, “Heart Disease and Stroke Statistical Update 2013,” published in Circulation.

“Americans need to move a lot more, eat healthier and less, and manage risk factors as soon as they develop,” said Dr. Alan S. Go, the chairman of the report’s writing committee, in an AHA press release. “If not, we’ll quickly lose the momentum we’ve gained in reducing heart attack and stroke rates and improving survival over the last few decades.”

Here are some of the key statistics contained in the hefty report:

“The Epidemic of Poor Health Behaviors”

  • Among adults, 21.2% of men and 17.5% of women continued to smoke cigarettes. 18.1% of high school students are smokers.
  • Among high school students, 17.7% of girls and 10.0% of boys reported they had less than one hour of moderate-to-vigorous exercise.
  • Thirty-three percent of adults reported engaging in no aerobic leisure-time physical activity.
  • From 1971 to 2004, calorie intake increased from 1542 to 1886 kcal/d (22%) in women and from 2,450 to 2,693 kcal/d (10%) in men. Most of the change is due to an increased consumtpion of starches, refined grains, and sugars.
  • 68.2% of adults are overweight or obese. 34.6% are obese.
  • 31.8% of children 2-19 years of age are overweight or obese. 16.9% are obese.

“Prevalence and Control of Health Factors and Risks Remains an Issue for Many Americans”

  • 13.8% of US adults have serum serum cholesterol levels ≥240 mg/dL.
  • 33.0% of US adults have hypertension. About 82% are aware of their condition, 75% receive antihypertensive therapy, but only a little more than half (53%) have achieved target blood pressure levels.
  • 8.3% of US adults have been diagnosed with diabetes. 38.2% have abnormal fasting glucose levels (prediabetes).

CV Disease and Mortality

  • Although the percentage of deaths attributable to CV disease has been declining for decades, in 2009 CV disease  was responsible for nearly one-third (32.3%) of all deaths in the US.
  • About 635,000 people have a first MI or CHD death each year. About 280,000 have a second MI.
  • About 795,000 people have a new or recurrent stroke each year.
  • The 2009 total direct and indirect estimated cost of CVD and stroke:  $312.6 billion.
  • The 2008 total direct and indirect estimated cost of all cancer and benign neoplasms: $228 billion

Click here to read the AHA press release:

Boehringer Ends Phase 2 Trial Of Dabigatran In Mechanical Valve Patients 2

Boehringer Ingelheim today announced that it had discontinued a phase 2 trial of its anticoagulant drug dabigatran (Pradaxa) in patients with mechanical heart valves. As reported here in October, the company had previously terminated one arm of the study after an interim review of the data by the trial’s Data Safety Monitoring Board

The RE-ALIGN trial was an open-label, 12-week randomized comparison of warfarin and dabigatran in 400 patients who received a mechanical valve. The first arm randomized patients during their initial hospital stay. The second arm randomized patients more than 3 months after their surgery.

Despite the recent advent of novel oral anticoagulants, the much-maligned warfarin remains the only current option available for patients who have received a mechanical valve. Now the first trial to explore this indication for one of the newer oral anticoagulants has been stopped.

In October Boehringer told members of its speakers bureau that the post-surgery arm of the trial had been terminated due to “lower than projected plasma levels of dabigatran in this population, and an imbalance in reports of thromboembolic events (primarily strokes).” At that time the company said the second arm of the trial would continue.

Dabigatran has been approved in Europe, but not in the United States, for venous thromboemoblism (VTE) prevention after knee and hip replacement surgery. Rivaroxaban (Xarelto) has been approved for both VTE prevention in the United States and Europe. To date there have been no head-to-head comparisons of the newer anticoagulants.

According to a recent study in Circulation: Cardiovascular Quality and Outcomes dabigatran now has about 19% of the oral anticoagulant market, mostly for the approved treatment of AF “but increasingly for off-label indications” as well. A recent letter in the Journal of the American College of Cardiology provided information about the off-label use of dabigatran in two mechanical valve patients. Both patients developed thrombosis after switching to dabigatran from warfarin. The authors noted that “while there is a wealth of data and clinical experience on dosing and therapeutic response to warfarin in this context, these data are unavailable for dabigatran.” Although newer anticoagulants “hold tremendous promise for mechanical valve anticoagulation… there is a need for dose-finding studies and clinical trials to demonstrate safety and efficacy in this setting.”
Click here to read the press release from Boehringer…

No Surprise: Smoking and Sudden Cardiac Death Closely Tied 3

Although cigarette smoking has long been linked to cardiovascular (CV) disease and sudden cardiac death (SCD),  the precise contribution of smoking, and the effect of smoking discontinuation, on SCD has not been clear. Now a new report from the Nurses’ Health Study published in Circulation: Arrhythmia & Electrophysiology provides new clarity about the relationship between smoking and SCD.

“Cigarette smoking is a known risk factor for sudden cardiac death, but until now, we didn’t know how the quantity and duration of smoking affected the risk among apparently healthy women, nor did we have long-term follow-up,” said lead investigator Roopinder Sandhu, in an AHA press release.

Dr. Sandhu and colleagues analyzed data from more than 100,000 women without known CV disease or cancer.  During 30 years of followup there were 351 incident SCDs. Compared to women who never smoked, the risk of SCD was significantly elevated in current smokers (relative risk 2.44) and former smokers (RR 1.40).

The number of cigarettes smoked each day was correlated with the increase in SCD risk, but even women who smoked only 1-14 cigarettes per day had a significant 1.84-fold increase in risk. Women who smoked more than 25 cigarettes a day had a 3.3-fold increase in risk. Smoking duration was also significant, resulting in an 8% increase in SCD risk for every 5 years of smoking.

Women who quit smoking reduced their SCD risk. After 15 years the reduction in risk achieved statistical significance, and by 20 years the risk was similar to women who had never smoked.

In an exploratory analysis, women smokers with coronary heart disease (CHD) had a much higher incidence of SCD than women without CHD. Women with CHD who quit smoking did not enjoy the same immediate reduction in SCD risk as observed in women without CHD.

“Sudden cardiac death is often the first sign of heart disease among women, so lifestyle changes that reduce that risk are particularly important,” said Dr. Sandhu. “Our study shows that cigarette smoking is an important modifiable risk factor for sudden cardiac death among all women. Quitting smoking before heart disease develops is critical.”
Click here to read the AHA press release…

Prolonged Anticoagulation With Apixaban Found Beneficial In Venous Thromboembolism Reply

A new study suggests that extending anticoagulant therapy for an additional year may be beneficial after patients with venous thromboembolism complete their initial course of therapy. The results of AMPLIFY-EXT (Apixaban after the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy-Extended Treatment) were presented at the annual meeting of the American Society of Hematology meeting in Atlanta and published simultaneously in the New England Journal of  Medicine.

After completing a standard anticoagulation regimen for 6-12 months, 2,486 VTE patients were randomized to either placebo or apixaban (2.5 or 5 mg twice daily) for an additional 12 months. At both doses, apixaban treatment was associated with a large reduction in clinical events and no increase in major bleeding events.

The primary endpoint, the composite of death or symptomatic recurrent VTE, was significantly reduced in the apixaban groups, from  11.6% in the placebo group to 3.8% in the low-dose apixaban and 4.2% in the high-dose apixaban groups (p<0.001 for both comparisons).

There were very few major bleeding events: 4 (0.5%) in the placebo group, 2 (0.2%) in the low dose apixaban group and 1 ((0.1%) in the high dose apixaban group. Clinically relevant non-major bleeds occurred in 2.3% of the placebo group, 3% of the low dose apixaban group, and 4.2% of the high dose apixaban group.

The investigators concluded that the results of the study “provide a rationale for continuing anticoagulation therapy” in VTE patients for whom there is uncertainty about the worth of continued anticoagulant therapy. They calculated that 14 patients would need to be treated to prevent one VTE case.

Should Body Weight Influence Choice of Antihypertensive Therapy? 1

The hypertension field has been troubled by repeated observations that normal weight patients have more cardiovascular (CV) events than obese patients. Now a new analysis of a large hypertension trial confirms this finding but also suggests that it may be explained by either an adverse effect of diuretics or a protective effect of calcium-channel blockers in non-obese hypertensives.

Michael Weber and colleagues analyzed data from more than 11,000 patients randomized in the ACCOMPLISH trial to shed light on this problem. In 2008 the main results of the trial showed that the combination of benazepril and amlodipine (calcium channel blocker group, CCB) was superior to the combination of benazepril and hydrochlorothiazide (diuretic group) in reducing CV events in high risk hypertensive patients.

The new analysis, published online in the Lancet, confirmed earlier observations and found significant differences in outcome based on weight. However, the differences in outcome occurred mostly in the diuretic group. In the diuretic group, the rate for the primary endpoint was significantly different between the groups (30.7 events per 1,000 patient-years in normal weight patients, 21.9 in overweight patients, and 18.2 in obese patients, p=0.0034). In the CCB group the rates were not significantly different (18.2, 16.9, and 16.5).

To explain their finding the investigators proposed that “hypertension in obese and lean patients is probably mediated by different forms of underlying pathophysiology.” Obese patients, who are more likely to have increased plasma volume and cardiac output, will be responsive to diuretics, while lean patients are more likely to have involvement of the sympathetic and renin-angiotensin systems. They concluded that “diuretic-based regimens seem to be a reasonable choice in obese patients in whom excess volume provides a rationale for this type of treatment, but thiazides are clearly less protective against cardiovascular events in patients who are lean. An alternative therapeutic regimen that includes a calcium channel blocker such as amlodipine, which works equally well across all BMI categories, provides an advantage with respect to clinical outcomes in patients who are not obese.”

In an accompanying comment, Franz Messerli and Sripal Bangalore write that the effectiveness of hydrochlorothiazide in obese people in ACCOMPLISH “has little if anything to do with obesity per se, but simply reflects the fact that among obese patients there was a preponderance of individuals at risk for heart failure who were prone to respond well to diuretic treatment.” They argue that “amlodipine-based treatment should be used irrespective of body size” for the indication of hypertension. Diuretics, on the other hand, should be used for the prevention of left-ventricular dysfunction.
Click here to read the press release from the Lancet…

Study Suggests Aspirin Resistance May Not Be Real 1

Is it resistance or pseudoresistance? According to a new study published in Circulation, aspirin resistance may be a myth, an artifact of the enteric coating of most aspirin tablets. The coating, which is designed to prevent gastrointestinal side effects caused by aspirin, may delay or conceal the effects of the drug, the study suggests, but the antiplatelet effects of the drug will eventually emerge. According to the authors, the study raises new questions about the value of point-of-care tests designed to detect aspirin resistance.

Before and after  receiving a single 325 mg dose or either immediate or enteric coated aspirin, 400 healthy volunteers underwent testing to assess the effect of COX-1 on platelets, which is widely considered to be the basis for the cardiovascular effects of aspirin. In this first phase of the study there were no instances of apparent aspirin resistance in the group of 40 subjects who received plain aspirin. By contrast, 108 out of the 360 subjects who received coated aspirin qualified as non-responders when tested at either 4 hours or at 8 hours.

In the second phase of the study the non-responders underwent repeat testing, at which point the number of nonresponders decreased to 42. In the third phase of the study, no patients were found to be aspirin resistant after either a week of aspirin therapy or when aspirin was added ex vivo.

The study authors, led by Garret FitzGerald, said that their study “failed to find a single person who satisfied” the criteria for aspirin resistance. The results, they said, suggest that people who appear to be aspirin resistant instead exhibit “pseudoresistance, due to delayed and reduced drug absorption” due to the drug coating. “These observations question the value of seeking to diagnose aspirin resistance with single point-of-care diagnostic approaches and support the finding of inconsistent platelet inhibition following enteric coated preparations of aspirin.”

In a comment given to the New York Times, Eric Topol disagreed with the study conclusions and pointed out that the study only used healthy volunteers, who are “very different” from people “who actually have heart disease or other chronic illnesses who are taking various medications.”

Sanjay Kaul sent the following comment:

In this elegantly designed study, the authors demonstrate that the prevalence of true aspirin resistance in a healthy cohort is rare and that the variability in aspirin responsiveness is mostly accounted for by variability in bioavailability (drug exposure) of enteric-coated aspirin. One should, however, exercise caution in not extrapolating from this study in healthy volunteers to patients with heart disease or chronic illnesses which might affect how aspirin works in the body. The concept of aspirin resistance rests on a shaky foundation. It is an unclear entity with unclear diagnosis, unclear mechanism, and unclear clinical relevance. It’s prevalence has been overblown, driven to a large extent by marketing considerations, i.e., development of tests to assess aspirin responsiveness, and availability of expensive alternatives to aspirin such as clopidogrel. Most guidelines appropriately do not endorse testing for aspirin resistance.

Scientific Statement Examines Role Of Social Media In Fighting Childhood Obesity 1

Social media may become an important weapon in the battle against childhood obesity, according to a new American Heart Association scientific statement published in Circulation. However, the statement acknowledges that the evidence so far from published social-media intervention studies has been “mixed” and that social media is also associated with troublesome drawbacks.

The statement delivers an overview of recent research in the role of social networks in health and obesity, and it reviews intervention strategies that employ various forms of social media. Because children are increasingly drawn to it, social media represents “natural points for intervention,” but the statement cautions that “identifying and measuring outcomes would be difficult.”

“Teenagers are texting and using Facebook and other social media as their primary communication with their peers, and we need to find out what factors can be incorporated into social media that will increase the effectiveness of these interventions to initiate and maintain weight loss in kids and adolescents,” said Jennifer S. Li, the chair of the writing group, in an AHA press release.

As an example of the delicate balance required in this area, the statement notes that children prefer texting over traditional paper diaries, but it also warns that social media plays a role in cyber bullying, privacy issues, sexting, and internet addiction. “Doctors need to understand digital technology better so that they can offer guidance to patients and their families on avoiding such issues, and will be aware of any such problems that occur,” said Li.

“The studies we looked at suggest that more parental involvement and more interaction with counselors and peers was associated with greater success rates for overweight children and teens who participated in an online intervention,” said Li. But the statement also acknowledges that the results of the few randomized trials of internet-based obesity interventions have been “mixed.”
Click here to read the AHA press release…

Exercise And The Limitations Of Observational Studies 8

Last week I wrote twice about exercise. Strictly speaking, both stories were complete lies.

The first story was about a study published in the Lancet which analyzed data from more than 10,000 patients at 2 VA Medical Centers and found that patients with high fitness levels were less likely to die than patients with low fitness levels. The pattern held true whether patients were taking statins or not taking statins. The researchers concluded:

“Statin treatment and increased fitness are independently associated with low mortality among dyslipidaemic individuals. The combination of statin treatment and increased fitness resulted in substantially lower mortality risk than either alone, reinforcing the importance of physical activity for individuals with dyslipidaemia.”

Look carefully at that. The association of fitness and low mortality leads to the recommendation about “the importance of physical activity.” An accompanying editorial went further, recommending that “prescription of physical activity should be placed on a par with drug prescription.” Widespread media coverage of the study followed suit, with nearly all reports emphasizing the positive effects of exercise.

So what’s wrong here? It almost seems churlish to insist on the point, but of course the study (like all other observational studies) didn’t– couldn’t– actually say anything about the real effect of exercise on health. It seems reasonable to assume that more exercise leads to increased fitness leads to improved health. That’s what we all probably think and believe. It’s common wisdom. But it’s not entirely unreasonable to suppose that healthy people are much more likely to exercise, in effect reversing the cause and effect. And of course there may be other confounding factors that cloud the simple equation of exercise and health.

There’s more: even if you could prove that more exercise leads to better health that wouldn’t lead to an automatic conclusion that doctors should recommend exercise as much as drugs. First you would need to prove that an exercise prescription is just as effective as a drug prescription. It’s hard enough to get people to take inexpensive, life-saving drugs once a day. Is there any reason to think we can get any kind of effective level of compliance with an exercise prescription?

The other exercise story from last week had a much different conclusion. Editorialists in Heart concluded that although most exercise is good for you, too much exercise can actually be harmful. They may well be right, but there’s never been– and there almost certainly never will be– a good, properly designed randomized trial that could prove this theory. It’s entirely possible (in fact, almost certain) that people attracted to extreme endurance sports are different in many ways from the rest of us, and it’s quite plausible that some of those differences may have significant effects on health. Confounded again.

The last thing I want to do is trash exercise. I’m a big supporter of it. But these standards shouldn’t be compromised. So what is the proper way to report this kind of study? Here’s a brief, completely responsible version of the story (written by Kelly Young for Physician’s First Watch):
Click to continue reading…