May 15th, 2015

Good Night, and Good Luck

With this post, CardioExchange closes the book on six years of discussion and debate. It’s been interesting and illuminating, collegial even when contentious, and, above all, an ongoing conversation. And, though it’s been said already, it’s been an honor and a pleasure to engage in that conversation with you. Thank you for all you brought to the community, and we hope to connect with you again.

May 13th, 2015

Get a Grip: Global Study Finds Grip Strength Is a Simple and Powerful Predictor Of Death

A large global study finds that grip strength is a simple, powerful, and broadly applicable test that can help predict the risk of death and cardiovascular disease. The new findings from the Prospective Urban-Rural Epidemiology (PURE) study were based on data from nearly 140,000 adults in 17 countries. The study participants had their grip strength measured with a handgrip dynamometer and were followed for roughly 4 years.

The results, published in the Lancet, show that grip strength is an even stronger predictor of death than systolic blood pressure. After adjustment for other factors, every 5-kg decrease in grip strength was linked to a 16% increase in death overall, a 17% increase in both cardiovascular and non-cardiovascular mortality, a 7% increase in the risk of myocardial infarction, and a 9% increase in the risk of stroke. The findings were broadly consistent across different countries and economic levels.

An unexpected finding was that grip strength was a more powerful predictor of cardiovascular mortality than of incident cardiovascular disease. This, the authors write, “suggests that low grip strength is associated with increased susceptibility to cardiovascular death in people who do develop cardiovascular disease.” A similar pattern was observed for non-cardiovascular diseases, suggesting that “low muscle strength might not play a major causal part in the occurrence of cancer, falls, fractures, or the need for hospital admission for respiratory illnesses, but that, as with incident cardiovascular disease, low muscle strength predisposes to a fatal outcome if these non-cardiovascular diseases develop.”

In an accompanying comment, Avan Aihie Sayer and Thomas B L Kirkwood write that the results, taken with previous research, mean that “there can be no doubt that grip strength predicts future all-cause mortality.” “Grip strength,” they write, “might act as a biomarker of ageing across the life course,” while “loss of grip strength … might be a particularly good marker of underlying aging processes.”

The lead author of the study, Dr Darryl Leong, said that “grip strength could be an easy and inexpensive test to assess an individual’s risk of death and cardiovascular disease.” He cautioned, however, that “further research is needed to establish whether efforts to improve muscle strength are likely to reduce an individual’s risk of death and cardiovascular disease.”

May 12th, 2015

Diet Drug Study Crashes and Burns in the Wake of Leaked Results

The ill-fated Light trial, which was supposed to examine the cardiovascular outcomes of the weight loss drug Contrave, a combination of naltrexone and bupropion marketed by Orexigen and Takeda, came to a spectacular halt today. The action was probably inevitable given the extreme controversy generated earlier this year when it became known that Orexigen had widely disseminated results from an early interim analysis of the study.

The news about the trial was announced in a press release from the companies and a press release from the Cleveland Clinic, the home institution of Steve Nissen, the trial’s chairman.

Contrave was approved by the FDA in 2014 partly on the basis of a pre-specified interim analysis of Light, which ruled out a significant doubling of cardiovascular risk for people taking the drug. (It is worth noting that the idea for approving drugs based on early results of outcomes trials was originally proposed by Nissen and Thomas Fleming, who was the chair of the data and safety monitoring committee of the trial.) The interim analysis was performed after the 9,000-patient trial had achieved 25% of its primary endpoint events, major adverse cardiovascular events. This analysis contained only 94 events: 59 in the placebo group and 35 in the Contrave group. The results were supposed to be held in strict confidence, but Orexigen shared them with over 100 people both inside and outside the company. When the FDA found out about the initial leak, it said that a second cardiovascular outcomes trial would have to be performed.

Then in March of this year, the interim results became public knowledge when Orexigen used the data to support a patent application. This caused a firestorm of criticism and controversy. In an interview, Nissen said that the trial’s executive committee unanimously agreed that the release of the 25% data “made it impossible to complete the Light trial as originally intended.” The committee further agreed that data from the 50% interim analysis should be released, “with the view that this information was important in that patients are receiving the drug on the mistaken belief of cardiovascular benefit.”

The Cleveland Clinic press release includes important additional information about the trial from the 50% interim analysis. Most importantly, the new results failed to confirm the earlier finding of cardiovascular benefit. The new analysis contains a total of 192 endpoint major adverse cardiovascular events: 102 in the placebo group compared with 90 in the Contrave group (HR=0.88, CI 0.66 – 1.17). This result reflects a shift in the outcomes: the early benefit in the first quarter of the trial was reversed in the second quarter, in which there were 43 events in the placebo group and 55 events in the Contrave group.

With some bitterness, Nissen notes that Orexigen was “perfectly willing to allow” the positive data from the 25% analysis to be made public but not the data from the 50% analysis. After 6 weeks of negotiations, the companies announced the termination of the trial but did not include the data from the 50% analysis. “We felt it was important to get this information out to the public,” said Nissen. The trial leaders therefore issued their own press release.

Nissen said that no one could be certain whether the change in direction represented a regression to the mean or an emerging signal of a possible long-term adverse effect associated with long-term use of the drug.

“These results show neither benefit nor harm for patients taking the drug, but are consistent with the requirement by the FDA that the Light Trial demonstrate an absence of a doubling of cardiovascular risk for patients taking the drug,” said Nissen in the Cleveland Clinic press release. “The inconsistency of effects on cardiovascular outcomes between the first 25 percent and the second 25 percent of the Light Study clearly illustrates the risks inherent in pre-judgment of clinical trial results based upon an interim analysis and demonstrate why interim results should remain confidential during any ongoing trial.”

May 11th, 2015

Selections from Richard Lehman’s Literature Review: May 11th

CardioExchange is pleased to reprint this selection from Dr. Richard Lehman’s weekly journal review blog at Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.

NEJM 7 May 2015 Vol 372

Approaches to Catheter Ablation for Persistent Atrial Fibrillation (pg. 1812): Are the latest methods of pathway ablation for atrial fibrillation just fancy toys for boys? As a total ignoramus, I couldn’t possibly comment, but here is the conclusion of a trial comparing three techniques: “Among patients with persistent atrial fibrillation, we found no reduction in the rate of recurrent atrial fibrillation when either linear ablation or ablation of complex fractionated electrograms was performed in addition to pulmonary-vein isolation. (Funded by St. Jude Medical).”

JAMA Intern Med May 2015

Safety and Procedural Success of Left Atrial Appendage Exclusion With the Lariat Device (OL): A major breakthrough in stroke prevention for patients with atrial fibrillation is closure of the left atrial appendage, the place where clot forms before it shoots into the brain. The Lariat device has received US Food and Drug Administration (FDA) 510(k) clearance for soft-tissue approximation and is being widely used off-label for left atrial appendage (LAA) exclusion. But a study based on published reports comes up with some worrying findings: “In the FDA MAUDE database, there were 35 unique reports of adverse events with use of the Lariat device. Among these, we identified 5 adverse event reports that noted pericardial effusion and death and an additional 23 reported urgent cardiac surgery without mention of death.”

Ann Intern Med 5 May 2015 Vol 162

Low-Molecular-Weight Heparin for Women With Unexplained Recurrent Pregnancy Loss (pg. 601): I don’t know if anyone in the UK uses low-molecular-weight heparin for women with unexplained recurrent pregnancy loss, but a new trial from Germany and Austria shows that it makes no difference to outcomes when given up to 24 weeks into gestation.

The Obesity Paradox in Type 2 Diabetes Mellitus: Relationship of Body Mass Index to Prognosis (pg. 610): Just to remind you of the “obesity paradox” in type 2 diabetes, as observed in over 10,000 citizens of East Yorkshire with T2DM but no initial cardiovascular disease. Over 10 years, “overweight or obese patients (BMI >25 kg/m2) had a higher rate of cardiac events (such as the acute coronary syndrome and heart failure) than those of normal weight (BMI, 18.5 to 24.9 kg/m2). However, being overweight (BMI, 25 to 29.9 kg/m2) was associated with a lower mortality risk, whereas obese patients (BMI >30 kg/m2) had a mortality risk similar to that of normal-weight persons. Patients with low body weight had the worst prognosis.”


May 11th, 2015

Prominent Harvard Cardiologist Moves to Google X to Head Large Study

Here’s a clear sign of the ascending role of digital/precision/personalized medicine: a prominent cardiologist has left a top academic and clinical position in Boston to run a large, innovative study in Silicon Valley. Jessica Mega was widely perceived as a rising star at Harvard Medical School and the Brigham and Women’s Hospital. She has now joined Google X, Google’s research arm, where she will head up the much publicized Baseline Study.

“I’m jealous,” said one academic cardiologist at a top hospital, upon hearing the news.

Baseline is one of the ambitious projects undertaken by the life sciences division of Google X. First announced last year, the Baseline Study is designed “to understand what it means to be healthy, down to the molecular and cellular level,” according to a Google press statement. In its first small pilot phase the study is collecting genetic and molecular information on 175 people. The researchers aim to employ “powerful software algorithms and large amounts of computing power to query enormous and complex data sets to find connections that no one has been able to probe before.” Google X has teamed with researchers at Stanford and Duke to design and conduct the larger study which will enroll thousands of patients and involve an unprecedented quantity of data.

Mega gained considerable attention as a senior investigator with the TIMI Study Group, where she played a leading role in several important clinical trials, including ATLAS ACS-TIMI 46 and ATLAS ACS 2-TIMI 51 with rivaroxaban (Xarelto, Johnson & Johnson). She  was the principal investigator of the ELEVATE-TIMI 56 trial, which studied escalating doses of clopidogrel based on CYP2C19 genotype.

Google X says that the study “is intended as a contribution to science; it’s not intended to generate a new product at Google,” though it may “unlock lots of ideas for future projects, not just at Google but across the health and technology industries.” Google says the results of the study will be made available to qualified researchers for their own use.

Bob Harrington, chairman of Stanford’s Department of Medicine, said that he was “thrilled by Google’s recruitment of Jessica to join the team working with our group and Duke. She was an inspired choice: smart, insightful, experienced, great communicator etc. She understands the science and the operations of clinical research given her TIMI background. In addition to her role at Google, we hope to get her engaged in other clinical and research activities on the Stanford campus in our department. Finally, we are pleased to welcome her back home to the Farm as she is a Stanford grad!”

Robert Califf, who played a key role in bringing the trial to Duke, is now the Deputy Commissioner for Medical Products and Tobacco at the FDA. “Dr. Mega has all the skills and temperament to lead this effort for Google, which will break new ground for precision medicine and complement the Precision Medicine Initiative. Her scientific knowledge, experience in clinical trials, and positive personality are a great fit,” said Califf.

May 7th, 2015

Big Data, Big Problems

As we are wrapping up CardioExchange, I wanted to ask our community members to think about a pressing issue facing us as health care providers, and health care consumers, over the next few years. When CardioExchange was founded six years ago, online communities were the “next big thing.” Today, wearable devices — commonly referred to as wearables — and biosensors hold that title. However, there is a complexity with wearables, particularly around ownership of data, that I feel has not been adequately addressed.

Wearables include devices such as fitness tracking bands and smart watches, which collect and analyze large amounts of physiological data from their users. These data may include heart rates, temperature, activity levels, and sleep patterns, among other measurements. In the future, measurements may expand to blood-sugar levels, blood-alcohol levels, and acid/base disturbances. Futurists propose even genetic and genomic analysis through wearables, although that is admittedly some way off.

In an era when we are redefining ownership of and access to data, it is important to define data ownership as it pertains to wearables. Currently, the data are collected by data brokers who can provide it to companies who pay for the information. The terms of service of wearables are complex and essentially non-negotiable, in particular at the time of the purchase of the device or download of the app. The device cannot be used without agreeing to the terms and conditions (“I agree”). As we have asked for more transparency from our pharmaceutical companies, our researchers, and our health care systems, it is time to ask for more transparency from the tech companies that have entered into the wearable market, collecting what in broad terms can be considered as health care data.

In terms of the data generated by wearables, who ultimately owns this information and who has the right to decide what is done with the information collected? Is it the consumer who paid for the device and wore it on their first 5k? Is it the company who invested time and capital into creating the device? Is it a third party that decides that they need the data to do market analysis? Or, finally, is it a researcher who gets a grant to analyze the Big Data created by these novel measuring devices?

May 7th, 2015

Selections from Richard Lehman’s Literature Review: May 7th

CardioExchange is pleased to reprint this selection from Dr. Richard Lehman’s weekly journal review blog at Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.

JAMA 28 April 2015 Vol 313

Effect of a Retrievable Inferior Vena Cava Filter Plus Anticoagulation vs Anticoagulation Alone on Risk of Recurrent Pulmonary Embolism (pg. 1627): About 30 years ago, one of my patients returned from the US with a filter in his inferior vena cava, having had a very expensive pulmonary embolus in the land of the free. This procedure has never caught on in the NHS, and a good thing too. But it persists across the Atlantic, despite many trials proving its lack of effect. The latest shows that “Among hospitalized patients with severe acute pulmonary embolism, the use of a retrievable inferior vena cava filter plus anticoagulation compared with anticoagulation alone did not reduce the risk of symptomatic recurrent pulmonary embolism at 3 months.”

Ann Intern Med 21 April 2015 Vol 162

Cost-Effectiveness and Population Impact of Statins for Primary Prevention in Adults Aged 75 Years or Older in the United States (pg. 533):  Last year I had several tries at writing a short critique of the National Institute for Health and Care Excellence guideline on statins, but in the end I had such a severe hemiplegic migraine that I decided that I might die in the attempt. Fortunately, others have risen to the challenge, and I hope that continuing debate about this issue will mark a turning point in our conceptualisation of population risk and how to make decisions with individuals. One of the most extraordinary recommendations was to offer all people over the age of 85 a statin because of their 10+% risk of a cardiovascular event. In this paper, an attempt is made to predict the cost effectiveness of statin treatment of all American adults aged 75 to 94 years using Markov modelling. Do access it if you are interested, but to me it just proves how inadequate the data are to support such modelling, even if it was legitimate to apply it . . . But don’t get me started. I can feel a migraine coming on.

The BMJ 2 May 2015 Vol 350

Risk of GI Bleeding Associated with Oral Anticoagulants: Stents, mabs, and NOACs. They’ve dominated the journals these last 17 years, and I hope you haven’t grown as weary trying to follow them as I have trying to write about them. NOACs are novel oral anticoagulants. Throughout the 2000s, they started pouring from the drug companies. These exciting drugs promised an end to the need for warfarin and blood testing. One week it would be apixaban for atrial fibrillation. The next week it might be dabigatran for VTE. As they proliferated, and one began to multiply all the drugs by all the indications by all the comparisons, it seemed that the line might stretch to th’ crack of doom. One began to lose the will to read, if not to live. This week’s BMJ attempts a reality check in the form of two American papers comparing dabigatran v rivaroxaban v warfarin for all indications in relation to the risk of gastrointestinal bleeding. They are much of a muchness, within wide confidence intervals.

May 7th, 2015

Advocates Say Precision Medicine Could Lead to Enormous Benefits

Personalized and precision medicine (PPM) could deliver hundreds of billions of dollars worth of improved health in the next 50 years in the United States, writes Victor Dzau, the new president of the Institute of Medicine, and coauthors in a Viewpoint published in the Lancet.

The authors used a health simulation model to estimate the effect of improved screening and risk prediction to treat people at high risk for six conditions: cancer, diabetes, heart disease, high blood pressure, lung disease, and stroke. They then calculated the resulting gains in life expectancy and quality-adjusted life expectancy.

They calculated that reducing heart disease by 50% “would generate a staggering $607 billion in improved health over 50 years.” More modest reductions of less prevalent diseases would produce smaller but still quite impressive benefits: even a 10% reduction in diabetes and cancer would generate $96 billion and $70 billion, respectively, they write.

The authors express concern that because the “real benefits of PPM innovations accrue over” a long time “as individuals live longer, healthier lives,” private payers in the U.S. may not be inclined to cover the PPM interventions. Single-payer systems in Europe and elsewhere may be more far-sighted, they speculate.

Sanjay Kaul provided the following response to the paper:

The projections from the modeling exercise are predicated on two key assumptions for which there is little or no evidentiary support. First, the claim that genetic testing can lead to identification of individuals at extraordinary risk of developing CV disease in whom ‘aggressive preventive and interventional strategies have a much greater likelihood of success’ rests on a shaky foundation. Take the example of 9p21, the best studied genetic variant for CHD. It is associated with approximately 40% increased risk, a relatively small effect size which is clearly not commensurate with ‘an extraordinary risk of developing CV disease’. Given the feeble prognostic utility, it should not come as a surprise that there is precious little evidence to show that genetic variants, either singly or in combination, offer incremental improvement in risk discrimination or net reclassification compared to conventional risk models. Second, empirical support for the notion that genetic knowledge of increased susceptibility to CV disease will motivate individuals to modify their lifestyle and improve health is currently lacking. Thus, the predictive utility of genetic tests in therapeutically modifying CV risk remains an unanswered question. The recent announcement of the Precision Medicine Initiative by President Obama has created quite a buzz within the medical and research community. However, the transition of Precision Medicine from a buzzword to clinical reality should be driven by tangible evidence of benefit, rather than some rosy predictions of value derived from a modeling exercise.”


May 4th, 2015

Increased Mortality Risk Found With Digoxin

For more than 200 years physicians have been trying to figure out how and when to use digoxin. Although it has a narrow therapeutic window and potentially dangerous interactions with other drugs, it is endorsed by current guidelines and widely given to patients with heart failure (HF) and atrial fibrillation (AF). However, there have been no randomized trials in AF and only one trial, the famous DIG trial, in HF. In that trial digoxin had no impact on mortality but was found to help reduce the rate of hospitalization for HF.

Now researchers led by Stefan Hohnloser have performed a meta-analysis of 19 studies of digoxin, including more than 235,000 AF patients and 91,000 HF patients. With the exception of the randomized, placebo-controlled DIG study, all the studies were observational.

Overall, there was a 21% increase in the relative risk of death in people taking digoxin (HR 1.21, CI 1.07 – 1.38, p= 0.01). Separately, the increased risk was 29% in the AF population and 14% in the HF population. There were three studies that included both AF and HF patients. In these trials there was a 28% increase in mortality in the AF group but no significant effect in the HF group.

The authors write that their finding “calls for randomized trials of dose-adjusted digoxin therapy at least in CHF patients. Until such proper randomized controlled trials are being completed, digoxin should be used with great caution (including monitoring plasma levels), particularly when administered for rate control in AF.”

In a press release from the European Society of Cardiology, Hohnloser said that his “personal feeling is that the time of digoxin – particularly as a heart rate-controlling drug in AF – is over. But this needs to be tested in appropriately designed studies.”

May 1st, 2015

A Message from the Editor-in-Chief

Dear Colleagues,

I would like to take this opportunity to thank all who have made CardioExchange such an outstanding venue for honest interchange on cardiology issues over the past 6 years.

CardioExchange is just a great community, and I will miss the opportunity for this extended family to get together in this venue. We didn’t always agree. We had a few who expressed some opinions persistently (even the Editor) – and yet, it seemed to work. It was a good place to go to express an opinion, ask a question, or learn from others. We designed it to be simple – nothing fancy – just a place for good content and brief conversations.

This community began as a trial by the Massachusetts Medical Society. We never knew if it would last a few months… and here we are six years later. We have had a spectacular team. In the beginning we had Anju Nohria, Susan Cheng, and Matt O’Rourke – more recently John Ryan, Kristin Odmark, and others too numerous to mention. And just about from the outset we have been fortunate to have one of the leading independent journalists in our field, Larry Husten. My deep gratitude goes out to them all for their contributions over the years. They are my friends, and I was fortunate to have them as my teammates on this effort.

MMS will continue to try new ways to engage the community. You will hear more about that.

The platforms for our interactions will continue to evolve. Truly independent platforms where our diversity of voices can be heard – and not only tolerated but encouraged – will remain important. We need to be able to cut through hype, promotion, and marketing – and be able to debate what is known and what is uncertain in medicine. We need a place to discuss what is important for patient care. We need to see if we can struggle together to find the truth. And we need to know that we will not always see things the same way, and that may just reveal that there is more than one way to interpret the same objective information.

The spirit of CardioExchange was to question respectfully, to share generously, and always to be willing to consider other points of view. I hope that we will continue to find places to do that down the road.

Thanks for joining us on this journey.