Reasons to Abandon Low-Density Lipoprotein Cholesterol Targets

Interviewed by Steven Greer, MD

Harlan Krumholz, MD, cardiologist from Yale, discusses his open letter in the journal Circulation recommending that LDL be scrapped as a treatment target for statins.

Exclusive: Why did Dr. Nissen resort to secret tapes?

February 23, 2010- By Steven E. Greer, MD

Many in the cardiology community are a bit confused as to why Dr. Steven Nissen Read more »

The FDA discusses Brilinta

February 4, 2014- The WSJ is reporting today on a Johns Hopkins doctor who filed a federal court complaint, using the Federal False Claims Act. The WSJ reports, “In July 2011, the Food and Drug Administration approved AstraZeneca PLC’s anticlotting drug Brilinta for patients with certain severe coronary conditions. A study had shown the pill saved lives and reduced heart attacks—a real eye-opener in medicine.

But behind the scenes, a drama is unfolding over whether the drug should have been approved. In a sealed complaint filed in U.S. district court in the District of Columbia, Victor Serebruany, an adjunct medical professor at Johns Hopkins Hospital who specializes in such drugs, contends the study numbers may have been manipulated.

Dr. Serebruany has told federal investigators that the number of deaths in the study’s control group—those taking a competing drug—was unusually high compared with earlier trials. He also has questioned the tabulation of heart attacks in the study, alleging it was skewed in Brilinta’s favor, according to people familiar with the matter and documents reviewed by The Wall Street Journal. The study measured cardiovascular deaths, heart attacks and strokes.

Dr. Serebruany filed his complaint under the federal False Claims Act. Under that law, the U.S. government has the option of joining the lawsuit to recover money.”

July 20, 2011-In a somewhat surprising move, the FDA approved AstraZeneca’s anticoagulation drug branded as Brilinta (ticagrelor). This drug had the PDUFA date delayed as the FDA wrangled with the messy clinical data that failed to show any benefit in the North American cohorts. It had become a case study in the bigger problem of Big Pharma relying on CRO’s to conduct their clinical trials.  Steven Greer, MD spoke with Janet Woodcock, Director of the FDA’s CDER, about the label. In addition, Pradaxa and Xarelto, two other new anticoagulation drugs, were discussed.

Gordon Guyatt, MD: Update on the problem of clinical trials being stopped early to inflate efficacy of drugs

Gordon Guyatt, MD, epidemiologist, internist, and biostatistician at McMaster University updates us on the progress being made against the problem of clinical trials being stopped early to inflate efficacy of drugs. Since our first coverage of the topic two years ago, the FDA, the Cochrane group, and other agencies have implemented changes in policy.  Dr. Guyatt discusses the Crestor JUPITER trial as an example of a trial that was stopped early and inflated efficacy.

Cardiology genomic, stem cell, and interventional research at U. Miami

The Healthcare Channel hosted, in conjunction with Mark Schoenebaum of ISI, a tour of the University of Miami medical center campus. A panel of world leaders in cardiology gave an overview of the latest in stem cell regeneration of myocardial infarction, genomics, and interventional procedures.

In Part 1, Dean Goldschmidt introduces the faculty.

In Part 2, Dr. O’Neill leads of the discussion with an overview of research at Miami.

William Neal, MD: Should obese children be screened for elevated cholesterol?

A retrospective study in the journal pediatrics made national attention when it recommend that all children be screened for elevated cholesterol and indicated than many children should be treated with statins. The research came from a non-drug-funded institute at West Virginia University. The PI of the study, William Neal, MD, Chief of Pediatric Cardiology, discusses the paper.

Daily aspirin for prevention of death from MI unwarranted in most people

Interviewed by Steven Greer, MD

For decades, doctors have recommended daily aspiring to prevent death from myocardial infarction to patients with certain risk factors other than previous MI (i.e. primary prevention). However, numerous randomized trials have been adding to the mounting evidence that the serious bleeding risks from aspirin outweigh the benefits. Dr. Kausik Ray from St. George’s University of London was an author of the latest meta-analysis of these trials, and discusses the findings.

(In full screen 1080i HD)

After 18 months of real world experience, why the new blood thinners are not displacing warfarin.

April 26, 2012 By Steven Greer, MD

Millions of patients have atrial fibrillation that can lead to blood pooling and clot formation, which then can migrate to the brain and cause ischemic strokes. For many decades, warfarin has been the only option available to anticoagulate these patients at risk of stroke. However, warfarin (also used as a rat poison) is infamous for being tricky to properly dose and requires frequent blood draws and testing to prevent hemorrhagic stroke or ischemic stroke.

To address this unmet clinical need, and large potential market, the pharmaceutical industry, cardiology community, and certain academic research organizations, such as Harvard’s TIMI and Duke’s DCRI, have helped introduce to the market new oral drugs that promise to replace warfarin.

Pradaxa (dabigatran, made by Boehringer-Ingelheim) and Xarelto (rivaroxaban, co-marketed by Johnson&Johnson, developed and manufactured by Bayer) are currently approved in The U.S. to prevent ischemic stroke and systemic embolism in non-valvular A-fib. Brilinta (ticagrelor, made by AstraZeneca) and Effient (Prasugrel, made by Daichi Sankyo and marketed by Eli Lilly) are on the U.S. market, but are not approved for A-fib stroke prevention. Eliquis (apixaban, being developed by Pfizer and Bristol-Meyers Squibb) is not approved for any indication and is currently under regulatory review.

After more than a year of real-world experience with Pradaxa (approved in October of 2010), and just a few months after the approval of Xarelto to prevent stroke in the A-fib setting, the drugs are not being widely adopted. Total Pradaxa prescriptions in January, 2012, were 76,000, or just 3% of the 2.6 Million warfarin prescriptions.

Why is warfarin still the dominant drug? The bad economy, high unemployment, and fewer people with health insurance, has made costly drugs an unacceptable option for many patients. Pradaxa costs more than $3,000 per year, compared to less than $100 per year for generic warfarin. But safety issues of excessive bleeding are equally concerning.

Patients often need to have their anticoagulation reversed if they are overdosed or need emergency procedures. Warfarin can be reversed with Vitamin K. However, neither Pradaxa nor Xarelto have convenient antidotes and hemodialysis might be required, especially in the setting of life-threatening bleeding.

How can doctors prescribe Pradaxa and Xarelto safely, and which patients should receive the new drugs with uncertain safety profiles? Most cardiologists agree that the patients with small body mass and/or extremes in ages pose too great a risk to try the new drugs. These drugs should be avoided in patients with poor renal function (creatinine clearance less than 15-30 ml/min). Patients taking aspirin and Plavix (clopidogrel) should also be cautioned about increased bleeding risk while also taking Pradaxa or Xarelto.

Regarding the GI bleeding adverse events, many doctors mistakenly believe that upper GI remedies of proton pump inhibitors or other antacids can reduce the risk. In fact, the risk of bleeding is primarily in the lower GI tract where PPIs, etc, have no effect.

Most patients with A-fib undergo attempts to electrically shock (cardiovert) them to normal rhythm. The data are lacking as to how best to use Pradaxa or Xarelto in these patients. Should they be switched to warfarin with the potential increased risk of hemorrhagic stroke that ensues?

With the higher cost, lack of superior efficacy, and increased safety concerns of the new drugs, what type of patient should be attempted therapy with Pradaxa or Xarelto? Patients who are poorly controlled on warfarin; some patients who develop rare but life-threatening side effect of skin necrosis on warfarin; others who are unable or unwilling to go through the blood tests and monitoring required for warfarin might be considered appropriate candidates.

Compounding the real adverse events is the Weber effect. New drugs have a higher reporting rate of adverse events than old familiar drugs, such as warfarin.

As a result of the headwinds against adoption of Pradaxa, Xarelto, and possibly Eliquis, many doctors who study the anticoagulation clinical data for a living are skeptical that the new drugs will make significant gains in market share over warfarin for the next five years.

Nortin Hadler, MD: lack of evidence for widespread statin use

Produced and interviewed by Steven Greer, MD

Nortin Hadler, MD, Professor of medicine and microbiology/immunology at The University of North Carolina School of Medicine, discusses the weakness in the body of literature to support the widespread usage of statins to lower cholesterol.

Limitations of The Lancet papers espousing the cancer risk reduction of daily aspirin

March 21, 2012 By Dr. Kausik Ray from St. George’s University in London

Here are my thoughts on The recent Lancet papers that uses meta-analysis to study whether daily aspiring reduces the risk of cancers. I think the editorial was very good and I concur with the conclusions. There were methodological limitations:

1) The meta analyses conducted included data on about 36 000 people and about 360,000 person years of follow-up (FU). However, they excluded the two largest trials which had cancer incidence as a prespecified endpoint (the Women’s Health study and the Physicians Health study). We included those in our paper and had data on 102,000 people and 700,000 person years of FU.

2) That being said, the present data provide mechanistic insights into the potential role of aspirin. The fact that benefit on cancer incidence with low dose appears after 3 years fits with what we understand about cancer neogensis and the fact that in the second paper there were favorable effects on cancer metastases provide supportive data for a potential role for aspirin.

3) The data do not tell us much about who to treat or the risk benefits, as you need to treat about 189 people for 10 years or 1890 people for 1 year to prevent 1 new cancer. In contrast for every 219 people treated for 5 years there’s one extra major non cerebral bleed, or 1095 people/year. So the risk benefit, on average, is 2 extra bleeds per incident cancer prevented. Remember these do not capture intracerebral bleeds, retinal bleeds hospital admissions etc as cancer incidence is collected in cancer registry and is more reliable than collecting bleeding data after trial follow up has finished. The data that bleeding declines and aspirin is protective against bleeds >5 years is biologically implausible. The implication is if you treat whole populations and more bleed especially early they come off drug so the NNT (i.e. those who stay on drug) to prevent one event will become even higher.

4) The studies published add considerably to our understanding, but guidelines should not change on the basis of these for general populations. We need the results of ongoing studies which accurately record cancer incidence and document non-trivial bleeds over extended follow up to determine net benefit. Beyond that we need at an individual level to determine who is at high absolute risk of bleeding and who is at high absolute risk of cancer to determine on a personalized level whether the treatment is suitable. (e.g. those with a high bleeding risk score versus a low risk score for cancer would not be individuals the medical community should perhaps offer this treatment to.)

Ongoing trials will help clarify matters, and what the present study adds is the possibility that in a few years time, if we correctly identify risk versus benefit, we might use aspirin for the primary prevention of cancer rather than vascular disease.

The following is or previous interview with Dr. Ray on the bleeding risks of aspirin.