June 13th, 2014
FDA Advisory Panel Supports Novel Drug-Coated Balloon
Larry Husten, PHD
The FDA’s Circulatory System Devices advisory panel voted unanimously on Thursday to support approval of CR Bard’s Lutonix Drug-Coated Balloon (DCB). It would be used to enlarge arteries in a subset of patients who have peripheral arterial disease — including obstructive de novo or nonstented restenotic lesions (≤ 15 cm in length) in native femoropopliteal arteries with reference vessel diameters of 4 mm to 6 mm.
The PreMarket Approval (PMA) application is based on the pivotal Levant 2 trial in which patients were randomized to the DCB or standard percutaneous transluminal angioplasty. The trial was successful in demonstrating both the safety and efficacy of the DCB. At one year the primary efficacy endpoint — freedom from target lesion restenosis and target lesion revascularization — was significantly higher with the DCB (65.2% versus 52.6%).
However, the advisory panel spent much of the day trying to interpret the complexities of the trial. There were a large number of protocol violations in the control arm, so that the results were no longer significant in the per protocol analysis. In addition, the DCB did not benefit women in the trial and the DCB was more effective in sites outside the U.S. than in the U.S. sites.
“We really had a hard time,” said panel member Rick Lange. “It looked like in the non-U.S. sites there was a clear advantage, but in the U.S. sites it was marginal, while in females it didn’t look like it was good.” Panel members had to decide whether to lump the data or split it. “We decided to lump it together,” said Lange.
The unanimous vote, said Lange, was a reflection of the committee’s view that the device was both safe and at least as effective as PTA. “It’s a little easier than a stent since you’re not leaving anything inside,” he said.
The panel urged the FDA to require the sponsor to provide long-term data for the DCB, including a post-approval study and continued followup of current patients. They said the outcomes study should be large enough to study men versus women and U.S. versus non-U.S..
If it is approved, Lutonix would become the first DCB available in the U.S. A second DCB from Medtronic is thought to be about six months behind Lutonix in the approval process.
June 13th, 2014
CoreValve Gains New Indication for High-Risk Patients
Larry Husten, PHD
Medtronic’s CoreValve system today gained a second indication from the FDA for use in patients with severe aortic stenosis who are at high risk for surgery. The transcatheter aortic valve replacement (TAVR) system was initially approved earlier this year for use in patients who were too ill or frail for traditional open heart surgery.
The new approval is based on results from the U.S. CoreValve High-Risk Study published in the New England Journal of Medicine. In the trial, 795 patients with severe aortic stenosis who who were at high risk for surgery were randomized to surgical aortic valve replacement (SAVR) or CoreValve. At 1 year the rate of death was 14.2% in the TAVR group versus 19.1% in the SAVR group, a difference that was highly significant for noninferiority (P<0.001) and even reached significance for superiority (P=0.04).
Medtronic said that the FDA had approved the entire CoreValve platform (23 mm, 26 mm, 29 mm and 31 mm size valves) — all of which are delivered through the smallest commercially available TAVR delivery system.
“This rigorous trial has defined a new standard for transcatheter valve performance, with superiority results that give physicians even more confidence in making TAVR treatment decisions,” said David Adams, co-principal investigator of the trial, in a Medtronic press release. “With this approval, we can treat more patients due to the broad range of CoreValve sizes, and we have an option compared to surgery that provides a greater chance for a longer life while minimizing the risk of stroke.”
After a somewhat slow start the TAVR market now appears poised for greater growth. In addition to the new CoreValve indication, Edwards’ second generation TAVR system is expected to gain approval soon. Further, the recent settlement of a seemingly endless series of patent disputes between Medtronic and Edwards should allow the companies to focus on medical issues without worrying about legal threats.
June 10th, 2014
Major Medical Organizations Establish Ambitious Diabetes Registry
Larry Husten, PHD
Our knowledge of diabetes today is a bit like the way blind men understand an elephant. With a myriad of isolated perspectives it’s nearly impossible to gain a broad overview. Now, a new initiative from a group of major medical organization will seek to provide the tools to better see a full picture of the elephantine problem of diabetes.
The American College of Cardiology, the American Diabetes Association, the American College of Physicians, and the Joslin Diabetes Center announced today that they will launch the Diabetes Collaborative Registry, which they say is “aimed at tracking and improving the quality of diabetes and cardiometabolic care across the primary and specialty care continuum.”
Diabetes patients today “receive treatments across medical specialties for a multitude of related conditions,” according to the announcement. “The Diabetes Collaborative Registry will allow for a longitudinal study of diabetes presentation, progression, management and outcomes, even as patients receive treatment from multidisciplinary care teams.”
The Diabetes Collaborative Registry will utilize technology from the ACC’s PINNACLE Registry, which can bring together electronic medical records created by primary care physicians, endocrinologists, cardiologists, and other health care providers. But the new registry will go beyond PINNACLE and incorporate a broader range of data “to include additional measures relevant to a wider group of providers who are involved in the coordinated care and treatment of diabetes.”
On a practical level, the registry will enable “practices, providers and patients… to track adherence to performance measures at the provider and practice level, compare performance to national benchmarks, target quality improvement areas and ultimately transform the quality of care provided to patients.” Researchers will also now be able to utilize data from different outpatient providers.
“Cardiovascular disease is the leading cause of death among people with diabetes, and there is a clear need for cross-specialty management of diabetes patients,” said the ACC President Patrick O’Gara, in the announcement. “By consolidating patient data, this registry will allow primary care physicians and specialists who treat patients with diabetes to compare data and access real-time metrics on patients in all stages of the disease.”
“Diabetes is not one disease but a complex set of diseases and too often leads to serious and potentially life-threatening complications, such as cardiovascular and kidney disease, as well as nerve damage, amputation, blindness and a multitude of other health problems,” said the ADA’s Chief Scientific and Medical Officer Robert Ratner. “We hope that a cross-specialty, clinical registry will ultimately allow us to improve the quality of care — and therefore quality of life — for all people living with diabetes by giving researchers a clearer picture of what’s happening to patients at various stages of their disease. Improved data collection should help us improve patient outcomes.”
The founding sponsor of the registry is AstraZeneca. The registry expects to announce additional partners in the coming months and is open to accepting additional sponsors.
June 9th, 2014
Selections from Richard Lehman’s Literature Review: June 9th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint this selection from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.
NEJM 5 Jun 2014 Vol 370
Rosuvastatin for Sepsis-Associated Acute Respiratory Distress Syndrome (pg. 2191): It was once the same with statins: while they could earn big money, new ones kept appearing. And I don’t mind that, because often there are useful differences within drug classes, as you can see from the latest Cochrane review of thiazides for blood pressure lowering. From the start, about 30 years ago, statins have had their fans and their detractors. It became obvious from an early stage that they had actions well beyond lipid lowering, and that these so-called “pleiotropic” effects included reduction of inflammation. This week’s NEJM tests this in two groups of patients with respiratory disease. In acute respiratory distress syndrome (ARDS), inflammation in the lungs and other organs can cause life threatening organ failure. A randomised trial aimed to recruit 1000 patients with ARDS and give them either rosuvastatin or placebo. It was stopped early for futility. In fact, the statin may have contributed to hepatic and renal organ dysfunction.
Simvastatin for the Prevention of Exacerbations in Moderate-to-Severe COPD (pg. 2201): There is a strong suggestion, based on retrospective observational evidence, that statins can decrease the rate and severity of exacerbations, the rate of hospitalisation, and mortality in chronic obstructive pulmonary disease (COPD). What’s not to like? Unfortunately, however, this large prospective randomised controlled trial, conducted at 45 sites across North America, shows that simvastatin 40mg daily does not decrease the rate and severity of exacerbations, the rate of hospitalisation, and mortality in high risk COPD patients. Another good teaching paper showing why RCTs are necessary.
JAMA 4 Jun 2014 Vol 311
Kidney Function After Off-Pump or On-Pump CABG Surgery (pg. 2191): For a while, coronary artery bypass grafting was the commonest surgical procedure in parts of the developed world. Surgeons argued hotly about whether to do it on or off a cardiopulmonary bypass pump. Off-pump surgery was a badge of technical skill, and was supposed to produce less cognitive impairment in the post-op period. And as for the brain, so for the kidney. This massive multicentre CORONARY trial randomised 4752 patients to on- or off-pump CABG, and followed renal function in 2932 of these. There was less acute postoperative kidney injury in the off-pump group, but no difference in renal function at one year.
Association of Azithromycin With Mortality and CV Events Among Older Patients Hospitalized With Pneumonia (pg. 2199): Hmm. I’ve just told you that you can’t depend on retrospective observational evidence; but sometimes it’s all you can get. I suppose you could prospectively randomise thousands of older patients in Veterans’ hospitals to receive azithromycin-containing versus other drug regimens for pneumonia, and compare cardiovascular outcomes in the two groups. But this has not been done. Instead these investigators go through a complex process of propensity matching in 73 690 actual VA patients and conclude that: “Among older patients hospitalized with pneumonia, treatment that included azithromycin compared with other antibiotics was associated with a lower risk of 90-day mortality and a smaller increased risk of myocardial infarction.” Goddam it, this is a good mycin.
Lancet 7 Jun 2014 Vol 383
Diabetes as a Risk Factor for Stroke in Women Compared with Men (pg. 1973): Life is unfair. Men get a lot more cardiovascular disease than women. But once fasting blood glucose rises above about 6mmol/l, the reverse applies. The sugar effect may not be causal, but it’s a marker for something that is. Once it gets a bit higher, we call it diabetes, though I find this a perplexing term. Three authors have crunched through an immense amount of data from 64 cohort studies to discover what is known about the risk of stroke in women and men with diabetes. Women have a risk ratio of 2.28 for stroke if they are labelled diabetic, while for men the figure is 1.83. Not that this actually tells you anything about the risk of the person coming to see you: “we were unable to assess whether the excess risk of stroke in women with diabetes varied with different indices of glycaemic control or duration of diabetes because of insufficient data for these variables.”
Prevention and Management of Type 2 Diabetes: Dietary Components and Nutritional Strategies (pg. 1999): And everything conspires to make people enjoying peace and prosperity get fat in the first place. A review called “Prevention and management of type 2 diabetes: dietary components and nutritional strategies” whistles bravely in the dark. We don’t really know what works, but in the meantime we are told to stick to a diet rich in wholegrains, fruits, vegetables, legumes, and nuts; moderate in alcohol consumption; and lower in refined grains, red or processed meats, and sugar sweetened beverages. Has a familiar ring.
Cardiovascular Outcome Trials of Glucose-Lowering Drugs or Strategies in Type 2 Diabetes (pg. 2008): I may be older and fatter than I would like, but on the whole I am optimistic. I keep meeting brilliant young people who are brighter and kinder than most of my generation. The world has little need of me: it will be safe in their hands. And another pleasure is watching eminent authority figures changing their tune in line with evidence. Here is a review of cardiovascular outcome trials of glucose lowering drugs or strategies in type 2 diabetes. I was first author on two Editorials for The BMJ on this topic, and in 2010 the first one was not welcomed by the British diabetes establishment because it criticised the notion that HbA1c lowering below 7 was a worthwhile target in established T2DM. You can still see this idea going through its death pangs in the introduction to this article: “No trial results have shown unequivocal cardiovascular risk reduction with glucose lowering. However, results of the post-trial follow-up of the UK Prospective Diabetes Study, and of a meta-analysis of the four glucose-lowering outcome trials completed to date, suggest about a 15% cardiovascular relative risk reduction per 1% decrement in HbA1c.” I would lay a fair bet that the first bit of that came from Robert Califf and the “However” bit from Rury Holman. I don’t buy his suggestions of course, but I rejoice that almost all the rest of the piece is bang on, especially the conclusion calling for longer, better trials designed with patients.
The BMJ 7 Jun 2014 Vol 348
Effect of Fixed Dose Combination Treatment on Adherence and Risk Factor Control Among Patients at High Risk of CVD: A very recent Cochrane review of fixed dose combination pills for reducing cardiovascular risk concluded that: “Compared with placebo, single drug active component, or usual care, the effects of fixed-dose combination therapy on all-cause mortality or CVD events are uncertain; only few trials report these outcomes and the included trials were primarily designed to observe changes in CVD risk factor levels rather than clinical events.” So we don’t know what “polypills” of various similar kinds really do to real outcomes. And I don’t think the Cochrane reviewers would change their mind in the light of the latest trial, which comes from New Zealand. To be sure, many more people take their medicines if they are all rolled into one pill; they also get more adverse effects, and frequently discontinue them. It’s a shame that people are not more like sheep, who will follow each other into a pasture, feed on the same grass, and die at an appointed time. “Among this well treated primary care population, fixed dose combination treatment improved adherence to the combination of all recommended drugs but improvements in clinical risk factors were small and did not reach statistical significance. Acceptability was high for both general practitioners and patients, although the discontinuation rate was high.”
Time to Treatment with rtPA and Outcome of Stroke in Clinical Practice: A study of outcomes after administration of thrombolysis for stroke, in a population of 4 million Germans, concludes that treatment with recombinant tissue plasminogen activator within the first 1.5 hours after onset is highly effective, with a NNT of 4.5. The inconsistencies within this study are neatly explored in two rapid responses. Thrombolysis is a treatment of zero or marginal benefit for the great majority of stroke patients.
June 9th, 2014
Wide Range of Radiation Dose in Children Undergoing Cardiac Procedures
Larry Husten, PHD
Children with heart disease are at increased risk for developing cancer later in life due to their exposure to radiation during imaging procedures. Since an ever-growing number of children with heart disease now reach adulthood, this may become an increasingly important public health issue.
A new study published in Circulation offers some reassurance in finding that for most children the increased risk is low or negligible. But for some children who undergo more complex procedures, the increased risk is significant.
Jason Johnson and colleagues calculated the radiation dose received by 337 children who underwent 1 of 7 cardiac surgery procedures at Duke University. The median number of radiation-producing imaging procedures received by the children was 17. The median cumulative effective dose was 2.7 mSv, less than the annual background exposure of 3.0–3.5 mSv in the U.S.
There was a wide variation in radiation exposure. For 5 of the 7 procedures (atrial septal defect, ventricular septal defect, arterial switch operation, tetralogy of Fallot, and atrioventricular canal defect), the median annual dose ranged from 0.9 to 0. 29 mSv, which the authors said was “reassuringly low.” But children who underwent the most complex operations received much higher levels of radiation: the median dose was 20.08 mSv for children who underwent the Norwood operation and 42.54 for those who underwent cardiac transplantation.
Although cardiac catheterization represented only a small percentage (1.5%) of all imaging procedures, it was responsible for a majority (60%) of the total radiation exposure.
The lifetime attributable risk for cancer due to radiation was small for the less complex procedures, ranging from a median of 6-20 cases per 100,000 exposed. But the risk was much more elevated for the Norwood procedure (799 cases per 100,000) and cardiac transplantation (1677 per 100,000). Because of the expected impact of radiation on breast and thyroid cancer, girls had a significantly higher increase in risk than boys.
The authors write that their findings can be used in clinical practice: “To reduce long-term cancer risk, providers should target reducing radiation exposure in the highest-risk cohorts, including those children who will require repetitive high-exposure imaging and females because of their increased cancer risk. Providers can consider our relative exposure estimates when choosing between various radiation-producing imaging modalities.”
June 5th, 2014
An Adverse Event on Lisinopril: What Do You Say to Your Patient?
John Ryan, MD
This post is the third in our series “What Do You Say to Your Patient?” In this series, we ask members to share with us how they interpret a complex or controversial issue for patients. To review earlier posts, click
The following scenario stems from the recommendations from the JNC8 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults.
Your patient is a 65-year-old woman with a BP of 150/90 mm Hg on hydrochlorothiazide (HCTZ) 25 mg. She is overweight and has obstructive sleep apnea but uses her continuous positive airway pressure machine every night. She is asymptomatic and keen to get her BP under control. You start her on lisinopril 10 mg once a day.
One week later you get a basic metabolic panel to assess renal function. Her potassium level is 6.8 mEq/L and her creatinine level is 2.1 mg/dL (up from 1.3 mg/dL at baseline).
In light of the increased postassium level, you refer the patient to the emergency department. She is treated for hyperkalemia and discharged the following day with a creatinine level of 1.8 mg/dL and a normal potassium level. She is discharged on HCTZ 25 mg only. Renal artery imaging did not show any renal artery disease.
She follows up with you in clinic one week later.
In this case, the patient has had a known adverse event. When you see her again, what do you say?
Do you apologize?
Do you tell her that this can happen and was not her fault?
Do you acknowledge that you were following guidelines?
How do you approach discussing the next medicine that you will consider starting for her BP?
June 4th, 2014
My Fellow Doctors, Are You Miserable?
Enrique Guadiana, MD
A few weeks ago, I read a Daily Beast article, titled “How Being a Doctor Became the Most Miserable Profession,” by Daniela Drake. The teaser at the top declares, “Nine of 10 doctors discourage others from joining the profession…” That is an unsettling fact. Are the leaders in our profession burned out, and are most of us too tired to care anymore?
As far as I can tell, we have taken many steps to enhance the quality of our profession, but almost every idea has been either hijacked or twisted. We develop guidelines to improve our practice, but now lawyers and insurance companies use them to justify suing us and denying payments to our patients. We decided to develop electronic health records in good faith, and now they want us to spend a lot of time filling in useless information and limiting our time to interact with patients. Also, many hospitals use practice guidelines for the unintended purpose of measuring physicians’ productivity. Many doctors now accept less compensation for their work, but the insurance companies, hospitals, and even the government don’t pass these savings on to patients.
The worst thing is that, for many different reasons, we doctors no longer have good standing in society. I always wonder why everybody is so worried about fraud, overspending, overtesting, and excessive referrals. Any profession can have a few bad apples, but to my eye ours isn’t particularly plagued by this wasteful behavior. Meanwhile, the system asks for perfection from members of our profession: no mistakes, long working hours, continuous availability, permanent training, and often inadequate compensation. These expectations, in the aggregate, are a fantasy. I don’t know of any other profession that has to accept such unrealistic terms.
Many people think that the new horizon for us will be “corporatization” and business consolidation, recognizing all the while that these features are fundamental to the problem. Shouldn’t we be concerned about the possibility of actually limiting free and true competition? We know what happens after that: Quality declines and prices rise. Remember, once you eliminate competition, it’s gone for good — so I think it is crucial to preserve competition at any cost.
A new analysis from Stanford University found that prices were most likely to increase when hospitals bought physician practices, rather than forming looser contractual relationships with physicians. Hospitals have increasingly bought physician practices during the past decade, arguing that it helps them to coordinate care and control costs. However, insurers and many economists say that the hospitals’ primary motivation is to negotiate higher prices with insurers and build referrals to increase admissions.
Excellent arguments abound on all sides, but the reality is that the system is not working overall. Sometimes people do the right thing for the wrong reasons and sometimes the wrong thing for the right reasons. What are we doing in this case? Is choosing the least of many evils our only option? If being a doctor has become a bad idea, what kind of talent is the profession is going to recruit? I see a very cloudy future ahead.
Do you think being a doctor is now the most miserable profession? What can we do to change the path we’re on?
June 4th, 2014
Air Pollution and Cardiovascular Disease in the U.K.: It’s Complicated
Larry Husten, PHD
Epidemiology studies have provided powerful evidence linking air pollution to cardiovascular disease, especially MI and stroke. By some estimates, air pollution may be responsible for 3.2 million deaths each year, most from cardiovascular causes.
At first glance, a new study published in Heart appears to cast doubt on this association. Analyzing U.K. data from more than 400,000 MIs, 2 million hospital admissions, and 600,000 CV deaths, London-based researchers turned up conflicting and difficult-to-interpret findings concerning the effects of air pollution on cardiovascular health. Surprisingly, the researchers did not find a significant association between short-term exposure to air pollution and the risk for either MI or stroke. But they did turn up some significant associations. Nitrogen dioxide was linked to hospital admissions for CV disease, non-MI CV disease, arrhythmias, and heart failure. PM2.5 — particulate matter with diameters smaller than 2·5 μm — was linked to deaths from arrhythmias, atrial fibrillation, and pulmonary embolism.
But although the study failed to elucidate the pathways by which air pollution may lead to cardiovascular events, the confusing results may well reflect a broadly favorable trend in pollution reduction in the U.K. In an accompanying editorial, Anoop Shah and David Newby point out that air pollution in the study appeared to be quite moderate compared with “many of the megacities across the world,” which have PM2.5 levels 10-20 times the median level measured in the U.K. in the current study.
The title of their editorial is, “Less Clarity as the Fog Begins to Lift.” They conclude: “Some have suggested that associations with adverse cardiovascular events persist even at low pollutant concentrations, but as air quality continues to improve, the adverse impact on health will decline. The current lack of consistent associations with contemporary U.K. data may suggest that as the fog begins to clear, the adverse health effects of air pollution are starting to have less of an impact and are more difficult to delineate.”
June 4th, 2014
Transcatheter Mitral Valve Programs: No Volume Data
Richard A. Lange, MD, MBA and L. David Hillis, MD
The Society for Cardiac Angiography and Interventions (SCAI), the American Association for Thoracic Surgery (AATS), the American College of Cardiology (ACC), and the Society of Thoracic Surgeons (STS) recently joined together to provide recommendations for institutions that are considering starting and/or maintaining a transcatheter mitral valve (MV) program.
Unlike PCI, for which abundant data show a relationship between the volume of procedures and outcomes, the writing group acknowledged that little or no data exist regarding a volume-outcome relationship for transcatheter valve therapy.
Nevertheless, they recommend the following institutional and operator requirements:
INSTITUTION
- 1000 cath/400 PCI per year (with acceptable outcomes compared with NCDR benchmarks)
- At least 25 total MV surgeries per year for treatment of regurgitation (at least 10 with MV repairs)
OPERATOR
- 50 structural procedures per year (including ASD/PFO and transseptal punctures)
EXISTING PROGRAMS
- 15 transcatheter mitral procedures each year (total experience)
NEW PROGRAMS
- Because the indications are not defined, no volume criteria are proposed
What do you think of the requirements?
What is the minimum number of transcatheter MV procedures the operator should perform to (a) establish a program and then (b) maintain the program?
With each center performing a small number of procedures (~15/ year), are the outcomes data meaningful?
June 3rd, 2014
Prophylactic ICDs Appear Effective in Less Severe HF Patients
Larry Husten, PHD
Implantable cardioverter-defibrillators are routinely implanted in heart failure patients with ejection fractions of 35% and lower to prevent sudden cardiac death. However, the benefits in patients at the higher end of the spectrum — EFs between 30% and 35% — have not been well demonstrated in clinical trials, since few patients in this range have been enrolled in such trials.
Now a study published in JAMA suggests that the benefits in this group are similar to the benefits in heart failure patients with more severely depressed EFs.
Sana Al-Khatib and colleagues analyzed data from the National Cardiovascular Data Registry ICD registry and the Get With The Guidelines–Heart Failure database. They compared the mortality benefit associated with ICDs in patients with EFs between 30% and 35% with the benefit in those with EFs below 30%. At follow-up, the ICD-associated reduction in mortality was similar in both groups. At 3 years, among patients with EFs 30%-35%, adjusted mortality rates were 47.1% in those with ICDs versus 58.o% in those without ICDs. Among patients with EFs <30%, mortality rates were 46.1% and 57.o%, respectively. The hazard ratio for mortality among ICD patients with EFs 30%-35% was 0.83 (CI 0.69 – 0.99, p = .04). The HR among ICD patients with EF <30% was 0.72 (CI 0.65 – 0.81, p < 0.001).
The authors write that their findings “support guidelines’ recommendations to implant a prophylactic ICD in eligible patients with an LVEF of 35% or less.” Although “the difference in absolute risk by 3 years was not large (3.6% at 3 years),” the add, “it was significant and close in magnitude to what was observed in the clinical trials of prophylactic ICDs.”
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