Big Sugar Tips The Balance Of The Research Scale Reply

It might seem obvious: people who drink sugar-sweetened beverages are more likely to gain weight or to be obese. Most research supports this intuitive finding. The big exception: when researchers receive support from the sugar and beverage industries they are much less likely to make the connection.

Researchers in Germany and Spain conducted a systematic review of systematic reviews (yep) examining the association between sugar-sweetened beverages and weight gain and obesity.

Click here to read the full post on Forbes.

Sugar Sweetened Beverages

 

About these ads

TACT Principal Investigator Reflects On A Long And Contentious Journey Reply

In a fascinating and important blog post, Gervasio Lamas offers a deeply personal perspective on the long and contentious journey of the Trial to Assess Chelation Therapy (TACT), for which he was the principal investigator.

gervasio-lamasHere are a few quotes from his post, but I can’t urge you strongly enough to read the entire post over on CardioExchange. (Click here for my brief summary of TACT.)

Changing minds is difficult. Unexpected results meet resistance. Out of the mainstream research is subject to heavy criticism. I guess I knew all these truisms when we embarked on the Trial to Assess Chelation Therapy (TACT). Still, I thought we were answering an important clinical question.

To say that this trial was controversial is an understatement. I had previously worked peacefully in other clinical trials, worrying about enrollment, about the DSMB, and about interpretation of data. Not so, here. In retrospect, I had always thought that the adversaries to this study would be the chelation practitioners. After all, they were using an unproven therapy. Why would they want us to show it did not work?

The opposite was true. The chelation practitioners and their main professional organization, the American College for Advancement in Medicine, helped us at every turn. They felt they were doing good, and that bringing chelation to the crucible of a clinical trial would lead to many more patients being helped.

In fact, the principal obstructionists were groups of self-appointed anti-chelation “experts”, who had never administered chelation, had never designed or run clinical trials, but who knew how to make noise and recruit media to their dubious cause – that scientific thought should not be brought to bear on the question of whether chelation was safe and effective.

The gist of the objections to the trial, once legitimate methodological concerns were addressed, was an outcry that, because cardiologists believed that EDTA was quackery, the study had to be negative. Therefore we had done something wrong. Just imagine if this had been stem cells or a new anti-platelet: Kudos all the way, right? Humble chelation got heckles and hecklers. I told my dean at Columbia that people were very upset because they did not like the results. He said “That’s why you do research.”

So now what? Do we recommend chelation? This is where the cautious scientist has to take control. We reported a subgroup, and we have been fooled by subgroups before, so more research has to take place before all of us can jump on this bandwagon.

 

More Reasons Why Health Hype Stories Are Bad Reply

In response to my post yesterday about why health stories should nearly always be received with caution, I received the following comment from a distinguished cardiovascular researcher:

One lost point is the role of the investigators and media in hyping their research. Hazen (principal investigator of the first study) is a bright and thoughtful guy, but through the Cleveland Clinic PR department, his nice hypothesis-generating research got turned into the missing link between red meat and heart disease, which obviously is a huge leap. The paper itself is much more measured than the press release and subsequent coverage. Same for the carnitine meta-analysis It is a meta-analysis of small studies published in a 3rd tier medical journal. I haven’t read the original article, but I bet it is pretty measured in its discussion and conclusion. But then comes the press release and the media, and boom, we have a cure for heart disease that conflicts with a cause for heart disease. Both studies are hypothesis-generating and non-conclusive. They are important additions to our medical knowledge base, but offer nothing for the public right now.

So here I blame the PR departments, but the investigators go along with this, so they get some of the blame, as well as the media who hype it. By the way, from the standpoint of the investigators, the institutions, and the journals they published in, this media frenzy was considered a huge success. For the rest of the medical community and the patients, it was a nuisance, a distraction, led to confusion, and then phone calls to doctors.

Hype shot glass

I’d like to offer one additional caveat about the L-carnitine metaanalysis. This is a perfect example of a topic that might be seriously distorted by publication bias. In other words, a potentially important finding– in this case, a result showing that carnitine is beneficial after a heart attack– is much more likely to be published than a negative finding. This doesn’t mean that the metaanalysis is necessarily wrong, but it does provide yet another reason why we should always be careful when looking at studies like these.

 

 

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…

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…

L.A. Confidential: Preview Of AHA Scientific Sessions 2012 Reply

The American Heart Association scientific sessions, which start next weekend in Los Angeles, will be bigger than ever, with 853 separate sessions– 111 more than last year– and 27 late-breaking clinical trials– 6 more than last year. Elliott Antman, chair of the scientific sessions program committee, provided a preview of some of the highlights of this year’s late-breakers.

Two of the most interesting trials will be presented at the first late-breaking session on Sunday afternoon. Perhaps the most eagerly anticipated trial of the entire meeting is the NIH’s FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial, which will be presented by Valentin Fuster. The trial will evaluate the relative worth of CABG and PCI in patients with diabetes.

Immediately preceding FREEDOM on the program is another NIH-sponsored trial, TACT (The Trial to Assess Chelation Therapy), testing the potential value of chelation therapy, a controversial alternative therapy. “We ought to take our hat off to the NIH for doing this trial, since industry was never going to fund this trial,” said Antman. Although most physicians have a skeptical view of chelation therapy, patients often express interest in it. TACT will finally provide real data about this approach.

Directly following the first session, the second late-breaking session will focus on economic and quality-of-life studies, including a quality of life TACT substudy and a cost-effectiveness FREEDOM substudy.

On Monday, two Italian trials will look at the role of omega-3 fatty acids for recurrent atrial fibrillation (FORWARD) and for the prevention of post-operative AF (OPERA). The Physicians Health Study II will examine the effect of multivitamins for cardiovascular endpoints. The UMPIRE study will test the feasibility of giving the polypill in 2,000 patients for a period of 15 months.

The second late-breaker session on Monday will present the results of three phase 2 trials of PCSK9 inhibitors. The session will include a panel discussion and an overview of this fast-moving and much-anticipated new therapeutic area. Also at this session will be the results of the  dal-OUTCOMES phase 3 trial of the CETP inhibitor dalceptrapib. Although the drug is no longer in clinical development, many observers are eager to see if the results will have implications for other CETP inhibitors.

A Tuesday morning session will be entirely devoted to stem cell regeneration trials. Antman said this was a “promising avenue of investigation” but acknowledged that we still don’t know if this whole approach might fail.

Later on Tuesday, Arthur Moss will present the results of the MADIT Randomized Trial to Reduce Inappropriate Therapy, comparing customized programming to standard programming for the reduction of ICD-induced inappropriate shocks. At the same session the results of RELAX-AHF will be presented, testing the novel agent relaxin in acute heart failure. Finally, the CARRESS-HF  study will offer insight into the role of ultrafiltration in patients with acute decompensated heart failure and worsening renal function.

Research And Denial At St Jude Medical 2

Research and development is the cornerstone of medical progress, but sometimes R&D turns into its evil twin brother, research and denial.

Yesterday I reported on the the RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) trial presented at the TCT meeting in Miami. The trial missed its primary endpoint, and although there were definite hints of possible benefit in the trial, most outside observers seemed to agree that the trial did not establish a firm basis for the routine clinical use of PFO closure devices in stroke. FDA approval of the device based on RESPECT seems unlikely.

This wasn’t the first we’d heard of RESPECT. Last summer, as I reported here, during an earnings call, St. Jude CEO Dan Starks gave a preview of the RESPECT results: “we are optimistic that these will be favorable results,” he said. Then, yesterday, the company doubled down on its position and issued a press release stating that the trial “provides clinical evidence of risk reduction” and offers “compelling evidence” for use of the St. Jude device “over conventional medical management alone.” A St Jude spokesman told me that the company “absolutely intends to move forward with our regulatory process and will file our PMA submission” in the fourth quarter of 2012.

Deepak Bhatt, an influential interventional cardiologist at Harvard’s Brigham and Women’s hospital, offered a very reasonable assessment of the trial in an interview with Bloomberg News: “We need a definitive trial of this approach if it’s going to be broadly used for PFO closure. Anecdotally, there are patients who seem to benefit. It’s unfortunate that none of the trials have been able to absolutely nail that down.”

The stock market provided further evidence that St. Jude’s view of the trial was not the prevailing view. Despite what the company called “compelling evidence,” St. Jude’s stock price dropped 3.6% when the news of RESPECT was released.

In contrast to St. Jude, Gore, which is conducting REDUCE, a separate study of its own device for PFO closure, said that the RESPECT data “suggest [my emphasis] closure therapy for PFO may be beneficial, but further research is required.” Gore reaffirmed its intent to complete the REDUCE trial and pursue the indication for PFO closure. Of course, by the time REDUCE is completed there’s no guarantee that Gore won’t enter its own reality distortion field. Commercial pressures can be a heavy burden on the objective assessment of reality. But for now Gore’s perspective is sensible.

Closing the Hole in Medical Progress

The mutation of research and development into research and denial has worse consequences than a drop in stock price. It can paralyze medical progress. For more than a decade the value of PFO closure in stroke has been an unanswered question. Trial enrollment has been notoriously slow and difficult. The main reason is that many interventional cardiologists don’t want to randomize their patients because they strongly believe, despite the lack of evidence, in the value of PFO closure. So expensive procedures continue to be performed, despite a lack of evidence, and despite the likelihood that good evidence will ever emerge. It’s a frustrating siutation.

Earlier this year, in an editorial in the New England Journal of Medicine, S. Claiborne Johnston wrote about the harmful effect that off-label use of PFO closure devices has on research. He recommended that reimbursement for PFO closure be limited to patients participating in a clinical trial. Seems like a good idea to me.

During the 9 years it took for the results of this trial [CLOSURE 1] to be reported, approximately 80,000 patients have had a patent foramen ovale closed with the use of a device at an average cost of $10,000 per procedure. Even if only half these patients were treated by this method for the purpose of preventing stroke, it would suggest that during that period of time $400 million was spent on a procedure that had no apparent benefit, to say nothing of the potential clinical risks involved. By limiting the use of device closure to within the remaining clinical trials, such an expense could be curtailed and completion of these trials might be accelerated. In this setting, a strategy of withholding reimbursement for unproven device therapy unless such treatment is part of a randomized trial seems justified.

 

Danish Study Gives A Boost To Hormone Replacement Therapy Timing Hypothesis Reply

Hormone replacement therapy (HRT) suffered a sharp blow a decade ago when the Women’s Health Initiative failed to show any cardiovascular benefit in women taking HRT. Despite the setback, many researchers theorized that HRT might still be beneficial in women who start HRT close to menopause. Now a new study from Denmark published in BMJ lends strong support to the “timing hypothesis.”

Louise Lind Schierbeck and colleagues analyzed data from 1006 recently postmenopausal or perimenopausal women who were randomized to HRT or no treatment.

After 10 years, there were 16 primary endpoint events (the composite of death, admission to the hospital for heart failure, or MI) in the HRT group compared with 33 in the control group (hazard ratio 0.48, CI 0.26-0.87, p=0.015).

  • Mortality: 15 versus 26, HR 0.57, 0.30-1.08, p=0.084
  • HF: 1 versus 7, HR 0.14, 0.02-1.16, p=0.07
  • MI: 1 versus 40.25, HR 0.03-2.21, p=0.21.

There were no significant differences in the overall rate of cancer or of breast cancer. Women who were under 50 years of age at the start of the trial appeared to enjoy the greatest benefit from HRT.

The authors concluded:

Our findings suggest that initiation of hormone replacement therapy in women early after menopause significantly reduces the risk of the combined endpoint of mortality, myocardial infarction, or heart failure. Importantly, early initiation and prolonged hormone replacement therapy did not result in an increased risk of breast cancer or stroke.

Andrew Kaunitz told Physician’s First Watch that, when “taken together with findings from a subanalysis of younger women from the WHI, these data should reassure clinicians and women that use of hormone therapy in recently menopausal women is safe.”
Click here to read the BMJ press release…

Many CHF Patients Not Receiving– Or Getting Benefits From– High Dose ACE Inhibitors And ARBs Reply

Although current guidelines recommend that ACE inhibitors and angiotensin-receptor blockers (ARBs) be used in high doses in patients with congestive heart failure, many CHF patients currently receive lower than recommended doses of these drugs. In a research letter published online in Archives of Internal Medicine, investigators in Montreal analyzed data from 43,405 patients with a first hospital admission for CHF in Quebec, 73% of whom received an ACE inhibitor and 27% an ARB.

Patients were classified as receiving low-, medium- or high-dose drugs. 29% received a low-dose. The groups were not evenly matched: patients in the high dose group were more likely to have hypertension and diabetes, while patients in the low dose group were more likely to have renal disease.

After adjusting for other factors, the risk of dying or being readmitted to the hospital was significantly reduced in the high dose group. Here are the hazard ratios for ACE inhibitors and ARBs (medium dose serves as the reference):
Click to continue reading…

Good Science/Bad Science: Contrasting Papers On Dietary Compositon In JAMA And BMJ 3

Two studies published on Tuesday on dietary composition offer a striking contrast. One tackles the interesting question of whether different diets producing the same amount of weight loss might have different effects on energy expenditure. The investigators performed a rigorous, carefully designed experiment that advances our knowledge about diets and metabolism. The second tackled an even more important question– the long term cardiovascular (CV) impact of different diets. In this instance, however, the investigators relied on weak observational data and reached conclusions that went way beyond anything observational data can provide. One study represents good science. The other does not.

In the first study, published in JAMA, Cara Ebbeling and colleagues carefully studied 21 overweight and obese young adults. After first reaching a 10-15% weight loss during the run-in period of the study, the 21 subjects then received 3 different diets, in random order, for 4 weeks each: a high carbohydrate, low fat diet; a low-glycemic index diet with moderate percentages of carbohydrates and fats; and a very low carbohydrate diet with a high proportion of fat.

Although the subjects received the same amount of calories with each diet, there were significant differences between the groups in the amount of energy burned with the different diets. (This may be an important question, because weight loss requires energy expenditure to be greater than energy intake. If, everything else being equal, diets differ in their effect on energy expenditure, this may lead to superior weight loss strategies.) When compared to baseline, total and resting energy expenditure decreased the most with the high carbohydrate diet and the least with the very low carbohydrate diet. Further, the investigators also found that the low fat diet resulted in an increase in serum leptin levels (which could predict future weight gain) and other factors associated with metabolic syndrome. These same factors decreased with the very low-carbohydrate diet, but were perhaps offset by an incase in CRP levels– a marker of inflammation– with the very low carbohydrate diet.
Click to continue reading…

You Know Nothing, Dr. Snow: Why Medicine Can’t Be More Like Facebook 3

Medicine can never be like Facebook, despite what Matt Herper argues over at Forbes. Perhaps he was just trolling for hits on a day when everyone is thinking about the Facebook IPO, but Herper proposed, with apparently seriousness, that medicine needs to model itself on the tech world in order to match the kind of progress– and profits– of a Facebook. But the medical news this week provided ample evidence why this will never happen. Biology is much more complex and resistant than the digital world.

For a medical journalist like myself this was a frustrating week. There were a whole bunch of large, major studies on important subjects published in top journals. But the take-away message from these studies, both individually and combined, is that achieving any kind of real progress in medicine is incredibly hard.

Let’s take a quick look at these studies:

1. Coffee in the New England Journal of Medicine: Despite some of the breathless news reports, some of which erroneously claimed that the study proved that drinking coffee can extend your life, this large study added little or nothing new to our knowledge about coffee. Even the editor of the journal, Jeff Drazen, acknowledged the limitations of this sort of study. The simple truth is this: although coffee is ubiquitous and has been the subject of hundreds of different studies of all different types and designs, we will almost certainly never learn to any degree of certainty whether coffee is good or bad for us. An enormous, decades-long randomized controlled clinical trial, which is the only possible way to ascertain the truth about coffee with any degree of certainty, would be nearly impossible to perform, for multiple reasons.

I don’t want to overstate my pessimism here. I think there is a much more limited lesson that can be derived from this NEJM study and the rest of the coffee literature. From the totality of the evidence it seems highly unlikely that coffee has any large effect, either positive or negative, on important outcomes like mortality or cancer. But we’ll never know for sure about small effects, and we will certainly never know if there are small populations or individuals who are particularly likely to derive benefit or harm from coffee.

2. HDL Cholesterol in the Lancet. In some respects the HDL cholesterol story is exactly the opposite of the coffee story. Unlike coffee, the epidemiology of HDL is clear-cut, and therefore the reverse association of HDL with cardiovascular disease is among the best established facts in all of medicine. But association is not causation, and despite more than a generation of intense research we still don’t know how– or even if– HDL works. In fact, as its name implies, high density lipoprotein is not so much a biological entity as an artificial construct of something that we can measure easily.
Click to continue reading…