October 24th, 2012
TCT: Impressive Survival Benefit for TAVR in Inoperable Patients at 3 Years
Larry Husten, PHD
At the TCT meeting in Miami, Murat Tuzcu presented the latest findings from the PARTNER B trial comparing transcatheter aortic valve replacement (TAVR) with standard therapy in patients who are not considered eligible for surgical valve replacement. At 3 years, the mortality advantage continued to grow for TAVR over standard therapy.
All-cause mortality at 3 years:
- 80.9% in the control group versus 54.1% in the TAVR group (HR 0.53, CI 0.41-0.68, p<0.0001)
The difference between the groups has increased from an absolute difference of 20.1% at 1 year (50.8% vs. 30.7%), to 25% at 2 years (68% vs. 43%), to 26.8% at 3 years. Here are the other endpoints reported by Tuzcu:
Rehospitalization at 3 years:
- 75.7% versus 42.3% (HR 0.39, CI 0.28-0.54, p<0.0001)
Mortality or rehospitalization at 3 years:
- 93.1% versus 66.3% (HR 0.46, CI 0.36-0.58)
Mortality or stroke at 3 years:
- 80.9% versus 57.5% (HR 0.60, CI 0.46-0.77, p<0.0001)
The 3-year results, concluded Tuzcu, “continue to support the role of TAVR as the standard-of-care for symptomatic patients with aortic stenosis who are not surgical candidates.” In addition, the results “underscore the importance of patient selection before TAVR and the need for aggressive management of illnesses after TAVR.”
October 24th, 2012
Syncope Patients with a Normal ECG Are Unlikely to Have Structural Heart Disease
CardioExchange Editors, Staff
In a recent study, no syncope patients admitted with a normal electrocardiogram had any abnormality on transthoracic echocardiogram.
Although the differential diagnoses for syncope are myriad, most patients who present with syncope and are evaluated in an emergency department (ED) observation unit are discharged with no diagnosis and no identified cause of the syncopal episode. In a recent Annals of Emergency Medicine study, researchers conducted a retrospective chart review of 323 consecutive patients admitted to a single ED observation unit after a syncopal episode in order to evaluate the utility of structural evaluation of the heart by echocardiography.
Overall, 294 patients (91%) underwent echocardiography (transthoracic in 270, stress in 24). Of 267 patients who presented with normal electrocardiogram (ECG) results, 235 underwent transthoracic echocardiography and none had structural heart disease identified on echocardiogram. One patient had a positive troponin, two patients showed evidence of ischemia on stress echocardiogram, and two patients exhibited transient dysrhythmia while being monitored. Of 56 patients who presented with abnormal ECGs, 35 underwent transthoracic echocardiography and 7 (20%) were abnormal.
Comment: In patients who present with syncope with a normal ECG and who rule out for acute coronary syndromes do not need an echocardiogram as part of their evaluation.
Reprinted with permission from Journal Watch Emergency Medicine
October 24th, 2012
Four CV Risk Factors Predict Most of Peripheral Artery Disease Risk in Men
Nicholas Downing, MD
Four common cardiovascular risk factors account for most of the risk for peripheral artery disease (PAD) in middle-aged and older men, according to a JAMA study.
Some 45,000 U.S. male health professionals, aged 40 to 75 and without histories of CV disease, were followed prospectively for nearly 25 years. During that time, 537 developed clinically significant PAD.
In adjusted analyses, smoking (past or current), hypertension, hypercholesterolemia, and type 2 diabetes were all independently associated with PAD. Risk for PAD increased with each additional risk factor, with the absolute incidence among men with all four risk factors being 3.5 per 1000 person-years. Over 95% of PAD cases had at least one risk factor at diagnosis.
The researchers call for more research “to determine whether aggressive risk factor modification in patients with multiple atherosclerotic risk factors can reduce the incidence of clinically severe PAD.”
Reprinted with permission from Physician’s First Watch
October 23rd, 2012
Setback for Trial Studying Dabigatran After Mechanical Valve Surgery
Larry Husten, PHD
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 a newer oral anticoagulant has suffered a setback.
Last year, Boehringer Ingelheim announced the launch of the RE-ALIGN trial, a phase 2, open-label, 12-week randomized comparison of warfarin and dabigatran (Pradaxa) in 400 patients who received a mechanical valve. There were two arms in the trial. The first arm randomized patients during their initial hospital stay. The second arm randomized patients more than 3 months after their surgery.
Now, following the advice of the trial’s Data Safety Monitoring Board, Boehringer Ingelheim has discontinued the first arm of the trial, the post-surgery arm, due to “lower than projected plasma levels of dabigatran in this population, and an imbalance in reports of thromboembolic events (primarily strokes).” The trial’s second arm is unaffected by this decision and will continue as planned.
Boehringer-Ingelheim says that the news about RE-ALIGN does “not affect the positive benefit/risk profile of Pradaxa 150 mg for the current labeled indication” of stroke prevention in patients with nonvalvular atrial fibrillation. “RE-ALIGN is evaluating a different patient population and different doses than were studied in the RE-LY trial.”
Dabigatran has been approved in Europe, but not in the U.S., for venous thromboemoblism (VTE) prevention after knee and hip replacement surgery. Rivaroxaban (Xarelto) has been approved for both VTE prevention in the U.S. 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.”
One clinical cardiologist who did not wish to be identified offered the following perspective:
This is similar to the case reports (with all the usual caveats) where we have seen this signal with the novel anticoagulants…. it’s not intuitively clear why this is the case. It may be that the dose is not optimized for mechanical valves. It is worth noting that the drug levels in patients with mechanical valves were lower than anticipated based on pharmacokinetic calculations. Maybe patients with mechanical valves have a different metabolism of the drug versus those that don’t have mechanical valves? There may be an interaction with von Willebrand factor in the pharmacokinetics of dabigatran. Or maybe the dose is just too low and patients with mechanical valves need higher doses, just as we use a higher INR in patients with mechanical valves? The science keeps evolving!
Sanjay Kaul made a similar point:
The anticoagulant dose requirement for mechanical valves is higher even for warfarin (INR targeted for 2.5 to 3.5) compared with atrial fibrillation or VTE indication (Target INR of 2 to 3). It is likely that the dabigatran dose tested in RE-ALIGN was not sufficiently effective early post surgery when the thrombotic risk is the highest.
Here is a letter sent by Boehringer Ingelheim to members of its speakers bureau:
Dear Valued Speaker:
Boehringer Ingelheim is committed to communicating ongoing, timely information regarding Pradaxa® (dabigatran etexilate esylate) to members of the speaker faculty. The purpose of this letter is to provide an update on the RE-ALIGN clinical trial.
RE-ALIGN™ is a phase II trial designed to validate the dosing algorithm for dabigatran etexilate compared to warfarin in patients who have received a mechanical heart valve. This multi-center, prospective, randomized, open-label, active comparator, two arm study is evaluating the safety and pharmacokinetics of 12 weeks treatment of oral dabigatran etexilate in patients who have undergone mechanical heart valve replacement.
In consultation with the Data Safety Monitoring Board, Boehringer Ingelheim has made the decision to discontinue the post-surgery arm of the trial. Interim analysis indicates that the studied dosing algorithm delivers lower than projected plasma levels of dabigatran in this population, and an imbalance in reports of thromboembolic events (primarily strokes) has been identified. The second arm, which includes patients who underwent surgery more than three months prior to enrollment in the trial, will continue.
RE-ALIGN is the first clinical study to evaluate an oral direct thrombin inhibitor (DTI) as an alternative to warfarin for use in patients with mechanical heart valves requiring anticoagulation therapy. Patients have been enrolled in the RE-ALIGN trial at investigational sites in Europe and Canada. No U.S. study sites have been initiated and randomization of patients has been suspended pending protocol amendment.
At Boehringer Ingelheim, patient safety is our top priority. All regulatory authorities, clinical trial investigators, and patients involved in the RE-ALIGN trial are currently being informed and information will be updated on www.clinicaltrials.gov. Pradaxa® (dabigatran etexilate mesylate) capsules are not approved for the prevention of thromboembolic complications in patients with mechanical heart valves.
The changes to the RE-ALIGN protocol do not affect the positive benefit/risk profile of Pradaxa 150 mg for the current labeled indication: reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. RE-ALIGN is evaluating a different patient population and different doses than were studied in the RE-LY trial.
This letter is meant to provide background, should you receive an unsolicited question related to the RE-ALIGN trial. Please do not share the content of this communication proactively during speaking engagements. Should you have any questions or concerns regarding the RE-ALIGN trial, please do not hesitate to contact your Boehringer Ingelheim Medical Science Liaison or Medical and Technical Information at 1-800-542-6257.
Best Regards,
Dr. John Smith, MD, PhD
Senior Vice President, Medical Affairs
Boehringer Ingelheim Pharmaceuticals
October 23rd, 2012
High Rate of Warfarin Discontinuation Observed in Study
Larry Husten, PHD
One of the many potential problems with warfarin-based anticoagulant therapy is the poor rate of adherence and persistence among patients who are prescribed the drug. Now an observational study published in the Archives of Internal Medicine raises the possibility that the problem may be even worse than many have suspected, as discontinuation rates in clinical trials appear to be much lower than in the real world.
Tara Gomes and colleagues analyzed data from more than 125,000 new users of warfarin in Ontario, Canada and found very high rates of discontinuation over time:
- 8.9% never filled a second prescription.
- 31.8% discontinued warfarin within 1 year.
- 43.2% discontinued warfarin within 2 years.
- 61.3% discontinued warfarin within 5 years.
People at higher risk for stroke, as assessed by the CHADS2 score, were more likely to continue taking warfarin over the course of the study.
In an invited commentary, Whitney Maxwell and Charles Bennett write that the results are consistent with previous observational studies but that warfarin discontinuation can be appropriate and is often initiated by the physician. “Appropriateness of anticoagulation discontinuation is perhaps a more important outcome to evaluate rather than absolute discontinuation rates,” they write. An additional plausible explanation for the finding is that few patients in Canada were treated at anticoagulation clinics.
Maxwell and Bennett write that any potential problem with anticoagulation discontinuation is not limited to warfarin. In the RE-LY trial, they note, more patients discontinued therapy in the dabigatran arm than in the warfarin arm, and a similar trend was observed with rivaroxaban in ROCKET AF.
October 22nd, 2012
Selections from Richard Lehman’s Literature Review: October 22nd
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint selections 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.
JAMA 17 Oct 2012 Vol 308
Favorable Lipid-Level Trends in U.S. Adults (pg. 1545): “Between 1988 and 2010, favorable trends in lipid levels have occurred among adults in the United States.” That may seem pretty amazing, but there is a lot we don’t understand about these things. Remember that cardiovascular disease is also falling steeply, even as the population gets more obese. The authors of the NHaNES analysis speculate that the cause of the fall in total cholesterol and LDL-cholesterol may be linked with a fall in sugar consumption and smoking. Greater use of lipid-lowering drugs has contributed very little to the overall decline.
Lancet 20 Oct 2012 Vol 380
Angiotensin Receptor Neprilysin Inhibitor for Patients with HF and Preserved Systolic Ejection Fraction (pg. 1387): Here is a truly obscure phase 2 trial of a drug which doesn’t yet have a name in a group of patients hitherto largely ignored by the cardiology community, especially in the UK—people with heart failure and preserved systolic ejection fraction. The drug is classed as an angiotensin receptor neprilysin inhibitor (ARNI)—I won’t try and explain but you can think of it as an angiotensin receptor blocker with bells on. The comparator was an ordinary ARB (valsartan), and the end point was N-terminal proBNP at 12 weeks. So far, so bad: what is this trial doing in The Lancet, and why am I bothering to tell you about it? I don’t know the Lancet’s reason, but mine is that I want to go on about heart failure and BNP yet again. This hormone is an excellent marker for ventricular strain but it is very variable physiologically and not a reliable way to monitor treatment in individuals. So of course this trial is worthless in itself and needs to be followed by one that has hard end-points. BNP is raised equally in all patients with heart failure, whether or not they have reduced ejection fraction, and is an excellent predictor of death. It is high time that we used highly elevated BNP despite optimal treatment as an indicator that patients should receive palliative and supportive care. As for these new ARNI drugs and their place in the great scheme of things, you can learn more from the editorial by John Cleland and Andrew Clark, which usefully challenges the primacy of systolic ejection fraction as a measurement in heart failure.
Long-Term Safety of the Zotarolimus-Eluting and Sirolimus-Eluting Coronary Stents (pg. 1396): Blimey. I thought that the Stent Wars were over, and that all sensible earthlings long since clambered into their starships and returned to the home planet. Not so, apparently: far out there, sirolimus and zotarolimus are busy eluting in competition with another, and their light beams are now reaching Earth. It’s an exciting draw: there is no difference in stent thrombosis: but the plaintive cry of the Medtronic-funded investigators is that “Time analysis suggests a difference in definite or probable stent thrombosis between groups is emerging over time, and a longer follow-up is therefore needed given the clinical relevance of stent thrombosis.” What, will the Stent Wars stretch out to the crack of doom?
October 22nd, 2012
NIH Trial of Lifestyle Intervention for Type 2 Diabetes Stopped for Futility After 11 Years
Larry Husten, PHD
The NIH today announced the early termination of a large randomized trial testing a lifestyle intervention approach to weight loss in type 2 diabetics.
More than 5,000 patients with type 2 diabetes were randomized to participate in an intensive lifestyle intervention program or a traditional program of diabetes support and education in Look AHEAD (Action for Health in Diabetes). In September, after 11 years of followup, the trial was stopped by the NIH after the data and safety monitoring board found no significant differences in cardiovascular events — the primary endpoint of the trial — between the two groups. According to the NIH, however, other benefits from the lifestyle intervention have been found in the course of the trial.
The NIH said that patients in the intervention group lost an average of 8% of their body weight in the first year and maintained a weight loss of nearly 5% at 4 years. By contrast, patients in the control group lost about 1% of their body weight at 1 and 4 years.
“Look AHEAD found that people who are obese and have type 2 diabetes can lose weight and maintain their weight loss with a lifestyle intervention,” said Dr. Rena Wing, chair of the study, in an NIH press release. “Although the study found weight loss had many positive health benefits for people with type 2 diabetes, the weight loss did not reduce the number of cardiovascular events.”
October 22nd, 2012
FDA Approves the Sapien Transcatheter Heart Valve for High-Risk Patients
Larry Husten, PHD
The FDA today approved an expanded indication for Edwards Lifesciences’ Sapien transcatheter heart valve (THV). The device can now be implanted in patients who are eligible for aortic valve replacement surgery but are at high risk for serious surgical complications or death. Previously the Sapien valve was approved only for use in patients who were not eligible for surgery.
The FDA also said the device could be delivered through both the transfemoral route and the transapical route. Previously the device could only be delivered through the transfemoral route.
“Any procedure to replace the aortic valve carries the risk for serious complications, but for some patients with coexisting conditions or diseases that risk may be especially high,” said the FDA’s Christy Foreman, in an FDA press release. “The THV serves as an alternative for some very high-risk patients.” The FDA requires that before being deemed eligible for the Sapien valve a patient must be evaluated by a heart team, which includes a heart surgeon.
The new approval in high-risk patients was based on findings from the PARTNER A trial. The earlier approval in non-operable patients was based on findings from the PARTNER B trial.
The FDA will continue to require Edwards to evaluate the Sapien device through a national registry.
October 22nd, 2012
The Highs and Lows of Fellowship Interviews
John Ryan, MD
At CardioExchange, we are very interested in our fellows’ experiences, and we understand how trying the fellowship application process can be. Now that the interview season is winding down and match lists are being prepared, we want to find out your thoughts about how your interviews have gone. We want to hear it all — the good, the bad, and the ugly. We can make posts anonymous if you feel it is necessary; if there is a program you really liked, we can highlight that too.
To get the ball rolling, we asked CardioExchange Associate Editor John Ryan about a stand-out experience that he had during fellowship interviews.
When I was interviewing for fellowship, I concentrated on programs that Irish people had matched at before. I did this for two reasons: (1) in most cases, the programs had positive experiences with their Irish trainees and (2) this history typically meant that the program would sponsor visas (I was on a J1 visa at the time).
There was one program in particular that I was very interested in, and I was excited when I got my invite. The interview was scheduled close to St. Patrick’s Day — I felt that maybe the luck of the Irish would shine on me. As is typical, all the applicants gathered in the cardiology conference room on the morning of the interview, the program director greeted us and gave us a talk about the program, and I thought to myself, “This is it. This is where I want to be.”
I went to my first interview; it was with the section chief. I took my seat, and the section chief opened up my file, looked at it, closed it, looked at me, and said, “You are on a visa, correct?” I answered, “Yes.” The section chief then said, “What you need to do is take a plane to Mexico and then try to come across the border that way ‘cos we don’t sponsor visas.” I did not know what to say and so simply said, “Okay.” I still do not know the best way to have answered. Suffice it to say that it was a fairly negative experience as well as a poor use of time and money, and I ended up not ranking this program.
Do you have a fellowship interview experience you want to share with us?
October 19th, 2012
“Aren’t You A Doctor, Baba? Can’t You Make Him Better?”
Paul S. Chan, MD, MS
Two-and-a-half years ago, my 5-year-old son, Jesse, and I walked by a homeless man sleeping on the sidewalk on a sunny morning near our home. For the rest of the day and the entire next week, he asked me whether I thought the man was all right. I admitted that I did not know, upon which he asked me, “Aren’t you a doctor, baba? Can’t you make him better?” Every day for the entire next week, Jesse asked me about the man and confided in me that he was thinking about him a lot.
His question was seemingly straightforward enough, “Is the man alright?” What I found deeply disturbing was that the man’s plight did not concern me as much as it did my son. “Can’t you make him better?” How many times had I been asked this question in the sterile confines of my clinic or hospital, and how many times had I responded by ordering diagnostic tests and treatments? Yet, outside of the hospital, I realized I had become complacent and removed from my earlier convictions and activism throughout college and medical school. Distant were the periods of my life when I had spent 6 years teaching literacy in Appalachian Kentucky, lobbying for the non-profit hunger group Bread for the World, and living and working on the Navajo reservation. I quickly realized that I needed to change, and fast.
So, I decided to hike in honor of those who struggle to make ends meet on a daily basis and because I was born a gifted hiker. On October 26, 2010, I embarked on a grand hike to raise money to support Church World Service: a non-denominational and non-missionary hunger organization) that implements programs worldwide to ensure food security for individuals and families in the U.S. who are barely able to put food on the table, provides emergency direct relief to refugees in war-torn nations, and implements sustainable rural health and development projects in developing countries. I decided to hike from the South Rim of the Grand Canyon through the bottom to the North Rim, and then back to the bottom and to the original starting point—traversing 50 miles in all and 22,000 feet in total elevation change—within a 24-hour period. I started out at 3 a.m. in sub-freezing temperatures and 20 mph winds and miraculously (at least to me), made it back 22 hours later at 1 a.m. in a moderate state of ketosis. I had figured if I could dream up a big enough effort that inspired others, people would respond in kind.
And how they have! We raised $34,000 that first year, and I never imagined I would do it again, especially since I spent the next 2 weeks limping on hospital ward rounds upon return. I was asked and encouraged by my supporters to repeat the trek last year, and I was able to complete it in 20-1/2 hours and in markedly better shape, raising $43,000. This coming Monday, October 22nd, I will be embarking on this 50-mile grueling journey for a third time, but this time with 4 other individuals who have committed to walk with me in solidarity for the cause. And this year, we have already raised over $60,000.
Once upon a time, I had considered the priesthood as my vocation. I thought seriously about it in college. I have found this trek in the Grand Canyon each year to be a spiritual and transforming journey. I have been changed, and my kids and I are involved in frequent discussions about social and economic justice. Having felt powerless, I now feel part of the solution for the enormous needs of our society. I have returned to my roots—to the very reasons as to why I chose medicine as a profession and a vocation in the first place. I now devote—in a more conscious way—my daily actions in solidarity with all people in our society, and I can finally tell my son Jesse that, while I may not be able to help each and every homeless person we meet on the street, we can greet them with dignity and friendship and we can be part of the solution. And I can look at him and answer yes: we can each make our world, however broken, a better place than when we entered it.
Click here to learn more about Dr. Chan’s trek in the Grand Canyon and to support his walk.
