IMPROVE-IT Trial Paper Won’t Be Published Right Away In The New England Journal Of Medicine 1

The presentation of the eagerly awaited IMPROVE-IT trial, scheduled for Monday at the American Heart Association meeting, won’t be accompanied by a simultaneous publication in the New England Journal of Medicine. Although no one except for a small group of insiders knows for sure, this news may have important implications.

Click here to read the full post on Forbes.

 

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Newly Identified Mutations Act Like a Lifetime of Treatment with Ezetimibe Reply

A very large genetic study published in the New England Journal of Medicine offers compelling evidence in support of a central role for LDL cholesterol in coronary heart disease.

In a series of studies analyzing blood samples from nearly 100,000 people, Sekar Kathiresan and colleagues identified 15 rare mutations that block the activity of a single gene — called Niemann-Pick C1-Like 1 (NPC1L1). The mean LDL level was 12 mg/dL lower in mutation carriers than noncarriers. There were just 11 carriers of the mutations among 29,954 people with CHD versus 71 carriers among 83,140 people without known CHD (carrier frequency: 0.04% vs. 0.09%).  This worked out to a 53% reduction in CHD risk for mutation carriers.

Click here to read the full post on Forbes, including comments from James Stein, Sekar Kathiresan, and Harlan Krumholz.

What You Need To Know About IMPROVE-IT Reply

The IMPROVE-IT trial will be big news when its results are finally presented on November 17 during the annual meeting of the American Heart Association. The results of the trial–underway for nearly a decade– have been long and eagerly awaited by everyone interested in cardiovascular medicine.  The trial could impact the future sales of a key Merck drug, ezetimibe, though because it is nearing the end of its patent life the commercial significance is somewhat limited. However, IMPROVE-IT will also have very important implications beyond its specific effect on one drug franchise and could influence the fate of several new drugs now being investigated and may even alter the entire drug development and evaluation process.

Here’s some background information and links to useful resources.

Click here to read the full post on Forbes.

 

Genetic Study Suggests Possible Causal Role for LDL in Aortic Valve Disease Reply

Although LDL is an important risk factor for aortic valve disease, the precise role it plays has been uncertain. Lipid-lowering therapy in people with established aortic valve disease has not been shown to be beneficial. Now, however, a new genetic study published in JAMA suggests that LDL cholesterol may in fact cause an increase in aortic valve calcium and aortic valve stenosis. This may mean that LDL-lowering therapy could prove beneficial when given earlier in the disease process.

Click here to read the full post on Forbes.

 

Cholesterol Drugs Haunted By Ghosts Of Past, Present, And Future Reply

Cholesterol drugs, both new and old, are in the news again. There’s a lot going on now but the picture won’t really become clear until next month, when the results of a decade-old trial will finally be revealed. Briefly, here’s what’s happening:

  • Two new trials presented fresh evidence that PCSK9s, the much discussed new class of cholesterol drugs, have powerful LDL-lowering properties.
  • A new drug from Esperion, the phoenix of biotech companies, also showed promising results. The drug, ETC-1002, is a few years behind the PCSK9s in development but has some important theoretical advantages that may prove very important down the road.
  • At the annual meeting of the American Heart Association in November the results of the IMPROVE-IT trial will be presented. The results of this trial, as I have argued in the past, may have a broad if not decisive impact on the future of the PCSK9s and ETC-1002.

 …

Click here to read the full post on Forbes.

 

Early Hint At Cardiovascular Outcomes With Sanofi’s and Regeneron’s Rapidly Advancing Cholesterol Drug Reply

Amid a slew of new data demonstrating yet again that PCSK9 inhibitors lower LDL cholesterol– drastically and in a wide variety of different patient populations– data from one trial offers the first suggestion that the drugs may in fact improve cardiovascular outcomes. But the analysis, the authors cautioned, is a post-hoc analysis of a trial neither designed nor powered to study outcomes, so should be considered preliminary and speculative at best.

Four phase 3 trials with the Sanofi and Regeneron PCSK9 inhibitor alirocumab (pronounced “allee rock you mab” by Chris Cannon at a news conference) were presented today at the European Society of Cardiology meeting in Barcelona.

Click here to read the full post on Forbes.

 

IMPROVE-IT Trial Scheduled For Presentation In November Reply

Results of the eagerly-awaited and highly controversial IMPROVE-IT trial are finally going to be revealed. The American Heart Association has announced that the  trial will be presented by Chris Cannon on November 17 at 11:51 AM (central time) in Chicago at the group’s annual scientific sessions . IMPROVE-IT compared the effect on cardiovascular outcomes of the statin simvastatin with Vytorin (the combination of simvastatin and ezetimibe, manufactured by Merck) in more than 18,000 patients with acute coronary syndromes.

Both Vytorin and IMPROVE-IT have been the subject of considerable controversy.

Click here to read the full post on Forbes.

 

New Evidence Fuels Concerns About The Safety Of Niacin Reply

The string of failures– for HDL therapies in general and for niacin in particular– continues unabated.  The publication of the main results of the HPS2-THRIVE trial, along with new information from the AIM-HIGH trial, provide no evidence of a beneficial effect for niacin but do fuel concerns that it may cause serious adverse effects.

Click here to read the full post on Forbes.

 

 

After Long Wait, Updated US Cardiovascular Guidelines Now Emphasize Risk Instead Of Targets 1

Updated cardiovascular health guidelines were released today by  the American Heart Association (AHA) and the American College of Cardiology (ACC). The guidelines are designed to provide primary care physicians with evidence-based expert guidance on cholesterol, obesity, risk assessment, and healthy lifestyle.

The new guidelines reinforce many of the same messages from previous guidelines, but also represent a sharp change in philosophy. That change is most evident in the new lipid guidelines, in which the focus has shifted away from setting numerical targets for cholesterol levels in favor of treatment decisions based on individual risk status.

“This guideline represents a departure from previous guidelines because it doesn’t focus on specific target levels of low-density lipoprotein cholesterol, commonly known as LDL, or ‘bad cholesterol,’ although the definition of optimal LDL cholesterol has not changed,” said Neil J. Stone, chair of the lipid expert panel that wrote the new guideline. “Instead, it focuses on defining groups for whom LDL lowering is proven to be most beneficial.”

The long-awaited and often controversial guidelines are the successors to the extremely influential NHLBI guidelines, including the Adult Treatment Panel (ATP) series of guidelines that brought cholesterol to the consciousness of millions of people. Earlier this year the NHLBI announced that it would no longer issue guidelines but would, instead, provide support for guidelines produced by other organizations. Following the NHLBI announcement, the AHA and the ACC said that they would take over publication of the guidelines.

Statins Indicated for Four Broad Groups

Click here to read the full post on Forbes.

Guideline Maze

Original illustration by Max Husten

 

WSJ Article Fails To Raise Key Questions About Cardiovascular Risk In Children Reply

There’s probably no greater public health issue than the long-term  consequences of the childhood obesity epidemic. So the Wall Street Journal should be commended for digging into some of the important science behind this problem in a feature article in today’s paper. The author, Ron Winslow, is widely regarded as the best working journalist who regularly covers cardiovascular medicine. But I’m afraid the article fails to raise several key questions about the topic and therefore misses an opportunity to educate people about its complexities.

The article deals with the “growing concerns about the cardiovascular health of millions of children in the U.S. who are considered obese or overweight” and then focuses on one recent study published in Pediatrics that “suggests there is a simple way to assess a child’s arterial health with a calculation based on an often-overlooked component of cholesterol: triglycerides.” Winslow faithfully reports the main finding of the study, which is that the triglyceride to HDL ratio corresponds closely with arterial stiffness. A stiff vessel is a sign of “accelerated aging” and “likely raises the risk of dangerous outcomes relatively early in adult life,” writes Winslow.

Winslow notes that an NHLBI panel now recommends universal cholesterol screening for children between 9 and 11, but there is no mention that some experts disagree with this recommendation.  Further, these screening tests focus on the measurement of LDL cholesterol. Winslow doesn’t discuss whether  LDL would be equally effective as triglycerides and HDL at identifying children with stiff arteries. Winslow writes, reasonably, that high triglycerides and low HDL “are a hallmark reflection of the poor diets and sedentary lifestyles that researchers say are behind the wide prevalence of obesity among both children and adults,” but there’s a big gap between that association and concrete recommendations to measure HDL and triglycerides in children and, more importantly, to take actions based on these measurements.

Click here to read the full story on Forbes.

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HPS2-THRIVE: A ‘Disappointing But Clear’ Result Reply

The results of HPS2-THRIVE were “disappointing but clear,”  said Jane Armitage, who presented the results this morning at the ACC in San Francisco.

HPS2-THRIVE randomized 25,673 high-risk patients who could tolerate niacin to either placebo or extended-release niacin plus laropiprant (Tredaptive, Merck), an anti-flushing agent, in addition to background therapy. The primary endpoint was the time to first major vascular event, defined as the composite of non-fatal MI or coronary death, any stroke or any arterial revascularization.

Major vascular events occurred in 13.2% of the niacin arm and 13.7% of the placebo arm (p=0.29), despite causing average reductions in LDL of 10 mg.dL and triglycerides of 33 mg/dL, in addition to a 6 mg/dL increase in HDL. Armitrage reported that based on data from previous trials and observational studies, “it was anticipated such lipid differences might translate into a 10-15% reduction in vascular events.”

HPS2-THRIVE study chairman, Rory Collins, responded to a question in the press conference: “To the question is niacin dead? Well, it’s not healthy!”

Click here to read the full story on Forbes.

 

Amid Rising Tide Of Diabetes More Patients Reach Treatment Goals Reply

There’s a glimmer of good news amidst all the recent bad news about diabetes. Although the prevalence of diabetes has doubled over the last generation, more people today  are reaching their treatment goals than in the past. New data from the National Health and Nutrition Examination Surveys (NHANES), published online today in Diabetes Care, show that efforts to control hemoglobin A1C, blood pressure, and LDL cholesterol in patients diagnosed with diabetes have achieved some success, but they also demonstrate that there’s enormous room for improvement.

Click here to read the full post on Forbes.

العربية: جهاز قياس غلوكوز الدم. Česky: Glukome...

Should Niacin Still Be Prescribed? William Boden Versus Harlan Krumholz 1

In the wake of HPS2-THRIVE many have argued that there is no longer any reason to prescribe niacin. William Boden, the lead investigator of AIM-HIGH and COURAGE, thinks there were enough flaws in the design of the niacin trials to justify the cautious use of niacin in certain circumstances. Says Boden:

“There is evidence of clinical outcome improvement (i.e., CHD death/MI reduction) from VA-HIT for gemfibrozil; there is similar clinical outcome improvement for niacin from the Coronary Drug Project. Numerous studies show niacin’s benefit on surrogate outcome measures (i.e., quantitative coronary angiography, IVUS, cIMT, etc.). What more evidence do you need?”

” I have not given up on niacin.”

Harlan Krumholz  disagrees:

“We have to face the facts about the trials. They have failed to be supportive, and despite concerns about their flaws, they were developed by some of the best minds in our profession (including yours) and had millions of dollars devoted to them. I just feel that we cannot justify millions of people being prescribed a drug that has failed in two recent, large, prominent trials, which actually had signals of harm…”

Read the entire fascinating discussion over on CardioExchange.

Boden

William Boden

Harlan Krumholz

Harlan Krumholz

Large Metaanalysis Finds Statins Effective in Low Risk Patients Reply

A very large metaanalysis provides strong evidence that the relative reduction in risk of statins is at least as great in low-risk patients as in high-risk patients. The finding, write the authors, provides evidence that expansion of guidelines to lower risk populations should be considered.

In their paper in the Lancet, the  the Cholesterol Treatment Trialists’ (CTT) Collaborators analyzed data from 134,537 patients in trials comparing statins to control therapy and 39,612 patients in trials comparing low and high dose statins. They examined the impact of statin therapy according to the baseline 5-year risk of a major vascular event on control therapy.  Statin therapy caused a consistent reduction in the relative risk of major vascular events and all-cause mortality independent of other factors, including age, sex, baseline LDL cholesterol, or established CV disease.

Here is the rate ratio for major vascular events across five levels of risk at baseline (note that 1 mmol of LDL cholesterol is equivalent to about 39 mg/dl of LDL):

        5 Year Risk         Rate ratio per 1.0 mmol/L of LDL reduction

  • <5%                          0·62 [99% CI 0·47–0·81]
  • ≥5% to <10%          0·69 [99% CI 0·60–0·79]
  • ≥10% to <20%       0·79 [99% CI 0·74–0·85]
  • ≥20% to <30%       0·81 [99% CI 0·77–0·86]
  •  ≥30%                       0·79 [99% CI 0·74–0·84]

The metaanalysis found no evidence for harm associated with statin therapy, including cancer or other non-vascular mortality.

The authors noted that people in the lowest two categories of risk in the study, who are expected to have a 5 year event rate lower than 10%, are not recommended for statin therapy in current guidelines. As generic statins are highly cost-effective, the result “suggests that these guidelines might need to be reconsidered.”

In an accompanying comment, Shah Ebrahim and Juan Casas ask whether everyone over the age of 50 should take statins. They calculate that, in the UK, adoption of a threshold of 10% would result in 83% of men over 50 years of age and 56% of women over the age of 60 as needing statins.
Click here to read the Lancet press release…