March 28th, 2014
2014 Atrial Fibrillation Guideline Incorporates New Oral Anticoagulants, Catheter Ablation
Larry Husten, PHD
A new guideline for atrial fibrillation (AF) was released on Friday by the American Heart Association, the American College of Cardiology, and the Heart Rhythm Society. Among other features, the 2014 Guideline for the Management of Patients With Atrial Fibrillation incorporates important new information about the new oral anticoagulants and catheter ablation for the treatment of AF symptoms.
Perhaps the biggest change since the previous 2006 guideline has been the introduction of new oral anticoagulants, which can be used in some patients instead of warfarin for stroke prevention. The new guideline includes recommendations for the use of dabigatran, rivaroxaban, and apixaban. Warfarin continues to be indicated for the treatment of AF in patients who have mechanical heart valves. The new agents are strongly recommended for use in patients with nonvalvular AF who are unable to maintain a therapeutic INR level with warfarin.
Catheter ablation also gets a strong recommendation when a rhythm control strategy is desired in patients with symptomatic AF refractory to at least one antiarrhythmic drug. “As experience with RF ablation grows, there has been an increased recognition that it can be used effectively as an atrial fibrillation treatment,” said Craig T. January, the writing committee’s chair, in a press release.
January also highlighted as significant the guideline’s recommendation to use a more comprehensive thromboembolic risk calculator, the CHA2DS2-VASc calculator, to estimate stroke risk. “Most previous guidelines used a simpler risk calculator,” January said. “We recommend a more detailed risk calculator that provides more information.”
Another important difference from the earlier guideline is the diminished role of aspirin, which was previously used for stroke prevention in low-risk patients.”But data showing that aspirin decreases stroke risk is weak,” said January.
The Guideline for the Management of Patients With Atrial Fibrillation will be published in the Journal of the American College of Cardiology (www.cardiosource.org), Circulation (www.americanheart.org), and Heart Rhythm (www.hrsonline.org).
March 28th, 2014
How Sure Can We Be About Optisure?
Edward J. Schloss, MD
On March 24, St. Jude Medical announced the global launch of the Optisure family of ICD leads. It’s been a while since a new ICD lead was launched, and I’m probably not the only one who was caught by surprise. I’d like to explore why this approval is important for the ICD community. First, a brief history of ICD leads from St. Jude.
FROM RIATA TO DURATA
St. Jude Medical developed its own line of ICD leads after it purchased the former ICD vendor Ventritex in 1996. The first-generation Riata lead, approved in 2001, was succeeded by the Riata ST line in 2006. These leads were distinguished, in part, by their thin diameter, permitting implantation through a 7 Fr introducer sheath. In that era, implanting physicians’ interest in a thin lead was very strong. Even the high-profile failure of the 7 Fr Medtronic Fidelis ICD lead didn’t seem to dampen that enthusiasm.
Both of St. Jude’s Riata lead families later developed problems. Reports of subacute perforation soon after implant in the Riata ST line arose in the late 2000s. A year or two later, the internal core structure of both the Riata and Riata ST leads was discovered to break down in 25% and 10%, respectively, of these leads, as evident on fluoroscopic evaluation — a process called externalization. This problem, along with noted increased electrical failures of this lead, prompted an FDA class I recall of both product lines in December 2011, in addition to intense scrutiny and discussion in the lay press, investor press, blogosphere, and academic literature.
By the time the Riata and Riata ST leads were recalled, St. Jude had already gotten approval and marketed the successors: Riata ST Optim and, later, the Durata lead. Both these leads shared design similarities with the Riata ST lead, but additional modifications were intended to prevent the failures that the predecessor lines had exhibited. To mitigate the perforation risk specifically, changes in the Durata lead were intended to minimize tip pressure to the myocardium. And both new leads had a new insulator wrapping around the silicon core from Riata ST. This Optim insulation, shown to be more resistant to abrasion, has apparently been successful at preventing the fluoroscopic externalization that had occurred with the earlier leads.
The failure of the Riata leads has been shown to be time-dependent, so the device community has expressed some concern about Durata’s future performance. In addition, FDA has continued to apply pressure, with a January 2013 warning letter about this lead, specifically noting problems detected during a California plant inspection. Early active registry studies of Durata have been highly favorable, but a limited number of Durata problems have been discussed in case reports. Noted ICD critic Dr. Robert Hauser has also reported on a series of Durata failures from the FDA MAUDE database.
INSIDE THE DURATA
The Durata and Riata ST may share some failure mechanisms. In particular, the Swerdlow case report revealed inside–out abrasion under the distal shocking coil, resulting in a short between that coil and the ring-electrode cable, and consequent oversensing. Swerdlow and the Hauser MAUDE study have suggested that a similar form of insulation failure at the proximal shocking electrode could result in failure to defibrillate. (Because Durata and Riata ST have essentially the same internal design and materials at the level of the shocking coils, it is possible that this failure mechanism will occur with the newer leads.)
Moreover, Swerdlow found evidence of disruption of the Optim layer, which he hypothesized was due to Optim degradation, possibly related to hydrolysis of the polymer and cyclical stresses during the 4 years of lead service. The long-term biostability of Optim is critical, because without the Optim layer, the Durata leads are quite similar to Riata ST.
St. Jude has staunchly defended Durata, citing the favorable active registry data and additional testing in a large bibliography on its website. The company’s independent engineering analysis concluded that Swerdlow’s lead was damaged externally as a result of the extraction tools, not Optim degradation (counter to Swerdlow’s assertion).
THE BASICS ABOUT OPTISURE
St. Jude released Optisure this week, its first new ICD lead line since Durata. The product literature describes Optisure as “providing an additional system enhancement for addressing lead complications and improving system reliability.” The company says the slightly thicker 8 Fr lead is “for physicians who prefer a larger lead diameter.”
According to St. Jude, Optisure is built on the basic design of Durata with these additional modifications:
- 8 Fr lead body
- additional Optim insulation at the proximal end of the lead
- new layer of Optim insulation under the SVC shocking coil
FDA filings show Optisure was submitted for approval as a PMA (pre-market approval) supplement on 10/24/12 and approved for release on 02/21/14. The filing links back to the original PMA for the Ventritex TVL lead issued in 1996. It does not appear that a human clinical trial was performed, as is common in PMA supplement approvals.
MY ANALYSIS OF OPTISURE
I’m happy that ICD companies continue to pursue process improvement. If we ever reach the point when we think we have a lead that is “good enough,” that will be really unfortunate. I’ve continued to have some concerns about Durata. ICD lead failures in the Riata lines have not become evident until 4 years of use, and we are only recently accumulating large numbers of Durata leads that have been implanted that long. Fortunately, Optisure’s design attempts to directly address two of the feared possible failure mechanisms of the Durata lead.
First, the increased Optim thickness in the proximal lead is likely to diminish the can/lead abrasion in the pocket, and perhaps in areas of cyclical stress. I find it really ironic and satisfying to read that St. Jude is promoting Optisure “for physicians who prefer a larger lead diameter.” Back in 2010, when I criticized thin ICD leads in an HRS debate, I had a hard time getting people to agree with me. Now, going thicker is a marketing strategy. Times really have changed.
Second, the Optim layer under the proximal shocking coil should help to prevent internal shorts that could cause lead failure. This type of short, if it involves the distal high voltage cable, is especially worrisome, as it may manifest only at the time of clinical or induced ventricular fibrillation. I fear that proximal coil HV shorting may be responsible for many of the Riata and Durata lead failures and deaths documented in MAUDE database entries, such as those published by Hauser (as well as this more recent report). Having a layer of Optim between the silicone core and the SVC shocking coil should help to prevent this shorting, just as it has prevented externalization. Unfortunately, this mitigation will not change the likelihood of shorting under the RV coil (as in Swerdlow’s case) but should help overall lead reliability. St. Jude seems to feel the same way, citing Optisure’s design as an “enhancement for addressing lead complications and improving system reliability.”
WHAT’S NEXT FOR ICDs?
Getting a pacemaker or ICD lead designed, approved, and built is an enormous undertaking. The process has only become more difficult because of increasing regulatory barriers. The formerly common process of PMA supplement approval has come under greater scrutiny. ICD and LV leads that formerly might have been approved under PMA supplement now require large U.S. trials. The trials’ costs, coupled with the fear of another Fidelis or Riata debacle, appear to have stifled lead innovation. Given the development of two new of leadless pacemakers (now being implanted in Europe) and the U.S.-approved subcutaneous ICD, we may be at the beginning of the end of the era of transvenous cardiac leads.
I have to agree with Zheng and Redberg that the PMA supplement process for medical device approval is problematic. The fact that leads from Riata to Optisure were approved on the basis of a dissimilar lead developed by a different company nearly 20 years ago should be ample evidence of this argument. Should Riata leads have gone through a clinical trial? Answering yes may seem logical. The unfortunate reality, however, is that no pre-market clinical trial would have picked up this lead’s late and novel failure mechanism. Even today, I would argue that careful industry engineering and close post-market scrutiny (including FDA-mandated registries) are doing far more to help our ICD patients than any pre-market trial ever could.
Nevertheless, it is critical to improve existing products, especially ICD leads. Most of us agree these are the “weak link in the chain.” I fear that a more highly regulated environment is having the paradoxically adverse effect of forcing us to settle with what we already have. That’s why I tweeted on March 24 that the quick approval of Optisure “both surprises and pleases me.” I wonder if this lead would even have been developed if it had been forced through a long, expensive clinical trial. Would that outcome have been a good thing?
Share your thoughts with me here on CardioExchange. I want to hear where you agree and where you think I’m wrong.
March 27th, 2014
FDA Advisory Panel Recommends Against Approval of Novartis Heart Failure Drug
Larry Husten, PHD
The FDA’s Cardiovascular and Renal Drugs Advisory Committee voted unanimously (11-0) against approval of the biologics license application (BLA) for serelaxin (proposed trade name, Reasanz). The novel drug from Novartis was intended to be used in patients with acute heart failure (HF). The once highly promising drug, which received a ”breakthrough therapy” designation from the FDA last year, was also turned down for approval in Europe earlier this year.
FDA reviewers and committee members expressed no significant concerns over the safety of the drug. But they were troubled by the seemingly impenetrable results of the pivotal RELAX-AHF trial. Throughout the day the Novartis speakers, including HF specialists Milton Packer and RELAX-AHF investigator Barry Greenberg, tried to explain and justify the complex trial, which only met one of its two co-primary endpoints.
But panel members remained skeptical. They found that flaws in trial design made it impossible to accurately assess the effect of the drug. They did not completely reject the surprising finding of a mortality reduction at 180 days in RELAX-AHF, but because it was not a prespecified endpoint they said it needed to be tested in a followup study.
After the vote most of the panelists advised the company to continue development of the drug since it may ultimately help address an important unmet medical need.
Novartis sent the following statement after the panel meeting:
“Recognizing the urgent patient need, today we presented what we believe to be a persuasive picture of the evidence for RLX030 so far – compelling results from our Phase II and III trials with no significant safety concerns,” said Tim Wright, Global Head of Development, Novartis Pharmaceuticals. “The discussion provided important information that we will address with the FDA as it completes its review. In the meantime we’ll continue to drive our robust clinical trial program and build upon the already established body of evidence.”
March 27th, 2014
What’s Behind the Decline in Nuclear MPI Use?
Kim Williams, MD and John Ryan, MD
A new JAMA study shows a sharp decline since 2006 in the use of nuclear myocardial perfusion imaging (MPI). Edward McNulty and colleagues examined trends in MPI use within a large, community-based population. MPI was used for 302,506 patients at 19 facilities. From 2000 until 2006, MPI use increased by a relative 41%. However, between 2006 and 2011, it declined a relative 51%. Declines were greater for outpatients than for inpatients (58% vs. 31%) and for those younger than 65. This decrease could not be explained by an increase in other imaging methods.
CardioExchange’s John Ryan asked Kim Williams, Vice President of ACC and Chief of Cardiology at Rush University School of Medicine, to give us his perspective on this decline in MPI use, particularly whether he’s surprised by the decline, if it’s reflected outside of the study population, and what it means for patients.
These data from the JAMA study may indeed be representative, with some busy centers claiming to have had a 40% drop in nuclear volume. This decrease was primarily due to
1) Appropriate Use Criteria being published and then publicized in 2005, leading to a marked decrease in testing of asymptomatic individuals, low-risk patients, and annual or semi-annual follow-up studies in asymptomatic individuals with coronary artery disease, often post-CABG or PCI;
2) Radiology Benefit Managers putting up barriers to imaging, not necessarily based on our appropriate use criteria; and
3) the Deficit Reduction Act of 2005, which reduced the technical component of imaging tests to that of the hospital outpatient prospective payment system (HOPPS), despite American Medical Association/Specialty Society Relative Value Scale Update Committee (RUC) surveys at that time indicating that payment should be higher in the Medicare Fee Schedule.
This latter issue was compounded in 2010 by a flawed RUC survey, which led to a further marked reduction in the technical component (with no 4-year phase-in, as was given to stress echocardiography), making it less feasible to practice outpatient nuclear imaging; and sending patients to other practitioners rather than one’s own lab brought up issues of liability and trust, reducing shift of the site of service to some hospitals.
It would be important to compare this decline in MPI use with stress echo volume over the same period; I suspect the downturn was not as dramatic, as some practitioners moved from “nuclear only” to using stress echo with greater frequency.
March 25th, 2014
Glucose Measurements Don’t Improve Cardiovascular Risk Assessment
Larry Husten, PHD
Although blood glucose and glycated hemoglobin (HbA1c) play a central role in diabetes, the value of these measurements to assess cardiovascular risk has been unclear. Now, in a paper published in JAMA, members of the Emerging Risk Factors Collaboration analyze data from nearly 300,000 people without known diabetes or cardiovascular disease who were enrolled in 73 prospective studies.
The authors found that adding glycemia measures to conventional cardiovascular risk assessment provided little additional prognostic information. Further, adding information about blood glucose did not result in a significant improvement in the classification of people used to help decide about preventive treatment.
One somewhat surprising finding was that four different measures of glycemia independently resulted in a J-shaped curve of cardiovascular risk — although lower glycemia levels were generally associated with lower levels of risk, at the extreme lowest level there was a rebound in risk. This finding “should encourage further studies to test whether very low glycemia levels are markers of ill health,” write the authors.
Another nonintuitive finding was that HbA1c measures were “at least equal” to fasting, random, and postload plasma glucose levels in assessing risk. “This finding challenges suggestions that postload glucose levels predict CVD incidence more strongly than do other glycemia measures,” they say.
The authors conclude: “Contrary to recommendations in some guidelines, the current analysis of individual-participant data in almost 300,000 people without known diabetes and CVD at baseline indicates that measurement of HbA1c is not associated with clinically meaningful improvement in assessment of CVD risk.”
March 25th, 2014
FDA Reviewers Recommend Against Approval for Novartis Heart Failure Drug
Larry Husten, PHD
Ahead of an important advisory panel FDA reviewers have recommended against approval of a novel drug for acute heart failure from Novartis. The once highly promising drug, which received a “breakthrough therapy” designation from the FDA last year, was turned down for approval in Europe earlier this year.
On Thursday, the FDA’s Cardiovascular and Renal Drugs Advisory Committee will discuss the biologics license application (BLA) for serelaxin injection (proposed trade name Reasanz) from Novartis. The indication is for the improvement of the symptoms of acute heart failure through reduction of the rate of worsening of heart failure. (The meeting was originally scheduled for February but was postponed due to weather.) Serelaxin is a recombinant form of the naturally occurring human hormone relaxin-2, which has been found to help women adjust to the cardiovascular changes that occur during pregnancy.
The FDA reviewers raised critical questions and concerns about the pivotal RELAX-AHF trial, which was published in the Lancet in 2012. The reviewers did not raise any safety concerns about the drug but stated that “there is insufficient evidence to support the proposed indication.”
Generally, the reviewer notes, the FDA requires two independent trials to demonstrate a drug’s efficacy. But the RELAX-AHF trial, the single trial in support of the BLA, was further hampered because it successfully met only one of its two primary endpoints. Further, although the trial “was designed to assess dyspnea… the proposed claim is to improve the symptoms of acute heart failure.” Acute heart failure symptoms other than dyspnea “were not systematically measured in this study,” wrote the reviewer, who went on to then question the reliability and relevance of the dyspnea findings.
The FDA reviewer also cast doubt on the reliability of the surprising finding of a mortality reduction at 180 days in the serelaxin group. Although the result adds confidence to the safety of the compound, the endpoint was not prespecified and needs to be confirmed in a follow up study before gaining acceptance. The reviewer also thought that additional doubt was raised because the mortality benefit had not been observed at an earlier time point, despite the fact that the drug is used acutely. (Novartis is currently conducting a large outcomes trial to confirm the mortality result.)
March 25th, 2014
The Next Big Patient-Centered Initiative: Spiritual Care
Nicholas Bergfeld, BS, BA
“Lord, I am not worthy to receive you…,” my mother says as she offers the Eucharist, a wafer of unleavened bread consecrated by a Roman Catholic priest, to a frail 80-year-old woman who lies in her hospital bed. Terminal lung cancer and pneumonia have sapped the woman of her strength, but she can still muster the ritual response.
“But only say the word,” she whispers faintly, “and my soul shall be healed.” The woman parts her dry lips and expectantly opens her mouth, where my mother places the wafer.
“Please,” my mother says gently, “let it dissolve on your tongue before you swallow.” The woman complies, a mixture of relief and contentment on her face.
This patient’s desire to have this rite performed (and thereby, as her faith tells her, enter heaven in a state of purity) was so strong that she asked her family members to seek out my mother, and she pointedly requested an early swallow evaluation in preparation.
Spirituality will play an increasing role in the patient-centered healthcare model of the future, even though many providers are unaware of this trend. It will be difficult to ignore religion in healthcare settings, given data like these:
- 83% of surgery patients surveyed in Alabama want their surgeons to be aware of their religion and spirituality, and 64% would be more likely to trust a surgeon who takes a spiritual history of his or her patients.
- 72% of 921 surveyed Ohioans believe that a spiritual discussion with their doctor would increase physician-patient understanding.
- The 32% of University of Chicago Medical Center inpatients who reported having a discussion with a healthcare team member about religious and spiritual concerns were more likely than other patients to be highly satisfied with their care, whether or not they had initially desired such a discussion (41% did want the discussion initially).
The response from the healthcare profession has been mixed. In 2002, prayer was “the most commonly used complementary and alternative medical treatment in the United States,” and a full 43% of 31,044 people surveyed throughout the U.S. have reported praying for health reasons (. Advance Data 2004; 1). Of course, a 2007 Cochrane review on intercessory prayer showed a lack of benefit relative to standard care alone. One of the included trials assessed the benefit of prayer when the recipient was unaware of the intercessory act, a study design that some observers might consider insulting even if well-intended.
I think it’s time for the medical community to lead a patient-centered initiative rather than be dragged into one. Ezekiel Emanuel’s advocacy for end-of-life (EOL) discussions and early palliative care fell on deaf ears until the economic advantages became clear. Is it surprising, then, that the percentage of the U.S. population who believe that medical professionals should always do everything possible to save a patient’s life has doubled from 15% to 31% between 1990 and 2013? We healthcare professionals also ignored apologizing for our mistakes, a basic human courtesy, until it became a solution to the “medical liability crisis.”
Just like EOL discussions and apologizing, understanding your patient’s spiritual beliefs may one day show a quantifiable benefit. All three of these ideas center on communication — the lifeblood of social relationships. The difficulty in quantifying this resource has led to its exclusion in standard healthcare practice, and it is only being reintroduced in a piecemeal fashion.
Indeed, spiritual care is not being fully addressed even in medical fields that consider it to be important. For example, 87% and 80% of oncology nurses and doctors, respectively, surveyed at four Boston academic centers believe that spiritual care should be provided at least occasionally, but fewer than 15% of advanced cancer patients reported receiving it from either their nurses or physicians. Also worrisome is that physicians identify lack of time as the most common barrier to spiritual care, but this factor was not associated with whether the spiritual care was given — the strongest predictor was found to be previous training in spiritual care.
Let our professional organizations open up new discussions with all faiths to determine how to best pursue spiritual care for the 21st century. Let us not cede the humanistic high ground to lawyers and hospital administrators.
In reflecting on this topic, I’m reminded of a story about a beloved physician, practicing medicine in the 1960s, whose technique for always leaving his patients at ease was to start each encounter by offering and sharing a cigarette with the patient. The ritual action of smoking has a clear beginning and end, and the shared experience seems to stretch the perception of how much time has passed.
Maybe instead of a pack of cigarettes, I’ll carry a small book of prayers chosen by a consensus of faith leaders and organizations. I’ll never be capable of engaging a patient in the same way my mother does, but I certainly can say the words, “Would you like me to pray with you?”
Do you share Nick Bergfeld’s perspective on the importance of spiritual care?
March 24th, 2014
Selections from Richard Lehman’s Literature Review: March 24th
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.
JAMA Intern Med
Nonleg Venous Thrombosis in Critically Ill Adults (OL): Almost all the deep venous thromboses we see in normal practice are in the legs, but in critically ill adults, nonleg venous thrombosis is not rare, despite the use of thromboprophylaxis. It is a particular risk in cancer patients. I might not have singled out this Australasian ICU study for comment, but I could not resist the title of the accompanying commentary piece “Upper Extremity Deep Vein Thrombosis: A Call to Arms.”
JAMA 19 Mar 2014 Vol 311
Age-Adjusted D-Dimer Cutoff Levels to Rule Out Pulmonary Embolism (pg. 1117): In the previous item, we encountered the new adjective “nonleg.” In this one, which is also about venous thromboembolism, we encounter “nonhigh.” It applied to the pre-test probability of a pulmonary embolism in a cohort of nonyoung European patients. The test, as you might expect, is D-dimer, and the rule, as you may already know, is to take the age of the patient and multiply it by ten to get the cut-off which excludes PE in patients with a low pre-test probability. So if you are 63, your cut-off is 630 μcg/L, and under that your risk of having a PE goes from nonhigh to practically nonexistent. This study was carried out at 19 centres in Belgium, France, the Netherlands, and Switzerland and confirmed this simple principle. Nonbad.
Factor Xa Inhibitors vs Warfarin for Preventing Stroke and Thromboembolism in Patients With Atrial Fibrillation (pg. 1150): Last week, an array of medical luminaries contributed to a Lancet paper extolling the merits of novel fixed-dose oral anticoagulants over warfarin in atrial fibrillation. I didn’t mention that many had ties with the manufacturers of these agents because that almost goes without saying. Here is a JAMA Clinical Evidence Synopsis on much the same topic—though it covers Factor Xa inhibitors only—by two authors who have only one slight industry connection between them. It reaches the same conclusion.
Lancet 22 Mar 2014 Vol 383
Association Between Change in Daily Ambulatory Activity and CV Events in People with Impaired Glucose Tolerance (pg. 1059): Two of the great truths of medicine are that levels of blood sugar are observationally related to cardiovascular risk, and that levels of physical activity, by contrast, are associated with decreased cardiovascular risk. Factor the two together and what do you find? “In individuals at high cardiovascular risk with impaired glucose tolerance, both baseline levels of daily ambulatory activity and change in ambulatory activity display a graded inverse association with the subsequent risk of a cardiovascular event.” If this comes as news to you, you need to get out more.
Pathophysiology and Treatment of Type 2 Diabetes (pg. 1068): Here is a review with the title “Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future.” Do read it if you can get access to it, but only in order to remind yourself of how little things have changed since these words were written: “In general, the treatment of mature diabetics would seem to be an example of the large-scale use of ineffective and possibly dangerous therapies in a particularly inefficient way. The cause of the sad situation seems to be the assumption that if some biochemical parameter is abnormally distributed in a defined group of people, “normalizing” the distribution must do more good than harm. In mature diabetics it may well be that the wrong parameter is being altered.” A.L. Cochrane Effectiveness and Efficiency 1973.
The Many Faces of Diabetes (pg. 1084): The next review is called “The many faces of diabetes: a disease with increasing heterogeneity.” That would not be my choice of title. Why not call it “Diabetes: heterogeneous diseases with a single label”? After all, diabetes is scarcely more heterogeneous now than it has ever been; it’s just that diabetes specialists are beginning to wake up to the fact. Let’s hope they may finally be recovering from “diabetologist retinopathy”—a condition which frequently blinds people to what is staring them in the face.
March 24th, 2014
ACC.14 Preview: Renal Denervation, TAVR Comparisons, and More
Larry Husten, PHD
The ACC begins this Saturday in Washington, DC. Here’s a preview of some of the most highly anticipated late-breaking clinical trials:
On Saturday morning at the opening session the world will finally learn more about the failure of Symplicity HTN-3, the Medtronic trial of renal denervation. Until recently, renal denervation was thought to be an extremely promising new technology. Many different companies were working on devices that, they hoped, would deliver a cure for resistant hypertension. But then earlier this year Medtronic announced that this trial — the first rigorous, well-controlled test of the technology — had failed to meet its primary endpoint. On Saturday the details will become clear.
One day later findings will be presented from the Global Symplicity Registry, including information about the real-world application of renal denervation in over 1,000 patients who have received the device in Europe, where it is currently approved for marketing.
In sharp contrast to renal denervation, transcatheter aortic valve replacement (TAVR) has had a markedly more successful introduction. PK Shah, co-chair of the ACC.14 program, told reporters at an ACC news conference that he believes TAVR will largely replace conventional surgery in coming years. The first results of two important new TAVR trials will be presented. The first, also on Saturday at the opening session, is the high-risk subset of the CoreValve pivotal trial, in which patients were randomized to the CoreValve or surgical aortic valve replacement. This trial will provide the basis for the FDA’s decision whether or not to expand the CoreValve indication into this important subgroup. CoreValve recently received initial FDA approval for use in patients who are not surgical candidates.
On Sunday comes CHOICE, the first head-to-head clinical trial to compare TAVR devices. Investigators in Germany randomized 240 patients to either the Sapien XT (Edwards’ next generation TAVR device) or the Medtronic CoreValve device.
In 2009 the MADIT-CRT trial demonstrated the benefits of cardiac resynchronization therapy in patients with mild heart failure. On Sunday the long-term mortality findings from the trial will be presented.
Other late-breakers at ACC.14 will provide information about the much-anticipated PCSK9 monoclonal antibodies, the failure of darapladib in the Stability trial, the role of colchicine in recurrent pericarditis, and the effects of bariatric surgery on glycemic control and diabetes.
March 20th, 2014
Pulmonary Embolism in a Patient with Acute Decompensated Systolic Heart Failure
Ian Neeland, MD and James Fang, MD
A 42-year-old man with a history of heart failure with preserved ejection fraction reports a one-day history of scant hemoptysis, cough, and right-sided pleuritic chest pain. During the past month, he has noted increasing exertional dyspnea, paroxysmal nocturnal dyspnea, lower-extremity swelling, and abdominal girth.
On examination, his blood pressure is 130/70 mm Hg, his heart rate is 110 beats per minute, and his oxygen saturation is 95% on room air. He has an S3 gallop, elevated jugular venous pressure, diminished breath sounds at the right lung base, and 2+ pitting edema to the knees.
Chest radiograph shows an enlarged cardiac silhouette and small right pleural effusion. His NT-proBNP level is 6328 pg/mL. Troponin T (TnT) is normal. Transthoracic echocardiography shows four-chamber enlargement, severe global hypokinesis, and severe biventricular systolic dysfunction with an LV ejection fraction of 15%.
The patient is hospitalized for further evaluation and treatment. Pharmacologic treatment is initiated for acute decompensated systolic heart failure. During the next few days, he has good diuresis and his lower-extremity swelling and abdominal distention improve; however, his chest pain is not relieved by analgesia, and his cough persists. He develops increased oxygen demands.
A CT scan of the chest reveals a large pulmonary embolus in the right pulmonary artery extending into all segmental and subsegmental branches, with pulmonary infarction in the right lower lobe. A repeat TnT test shows a concentration of 0.29 ng/mL. Blood pressure remains stable, exam results are not significantly changed, and a repeat echocardiogram is also unchanged. The patient is transferred to the intensive care unit, where a heparin infusion is begun.
Questions:
1. What would be your next step in managing this patient?
2. What factors would you consider in deciding how best to manage the pulmonary embolism?
3. Is there an appropriate role of advanced therapies, such as systemic or catheter-directed thrombectomy/thrombolysis, for this patient?
4. What treatment options are available to prevent further episodes?
Response:
March 27, 2014
1. What would be your next step in managing this patient?
Managing the PE is the most pressing issue, and moving the patient to the ICU is appropriate in light of the background severe biventricular heart failure. The patient likely had a PE on admission and another event during his hospitalization. Although blood pressure is “stable,” I suspect that the patient has become more tachycardic, reflecting the hemodynamic consequences of the PE, and that he may become more unstable despite anticoagulation. Heart failure is known to be a hypercoaguable state, so a search for a thrombophilia is probably unnecessary. Risk stratification of this PE is prudent at this point. I wonder if the patient had received DVT prophylaxis on admission. Lower-extremity noninvasive testing should also be considered to assess further thrombus burden. Acutely holding vasodilators and diuretics is appropriate as well.
2. What factors would you consider in deciding how best to manage the pulmonary embolism?
The approach to PE should generally entail risk stratification in order to match the appropriate aggressiveness of therapy to the risk of immediate- and long-term sequelae. The cornerstone of PE risk assessment is the impact of the thrombus burden on RV function. In general, when there is significant RV dysfunction, the PE by definition becomes either submassive or massive. The hemodynamic consequences of RV dysfunction — not hypoxemia — generally define the PE’s acute risk to the patient. RV dysfunction can be assessed on physical examination (e.g., new tricuspid regulgitation, RV heave, jugular venous distention, RV S3), imaging (e.g., RV/LV size >1 on echocardiogram or CT), or elevated biomarkers (TnI, BNP). The newly positive TnT, progressive hypoxemia, and long-term sequelae of RV dysfunction in a young patient with “baseline” severe biventricular heart failure suggest that a more aggressive approach than simple heparin should be entertained. The “baseline” RV enlargement and dysfunction may, in fact, have reflected the severity of the patient’s presenting PE.
3. Is there an appropriate role of advanced therapies, such as systemic or catheter-directed thrombectomy/thrombolysis, for this patient?
Other therapeutic strategies, in addition to heparin, should always be at least entertained once a PE is considered massive or submassive. Randomized evidence has been equivocal (Goldhaber Lancet 1993; 341:507; N Engl J Med 2002; 347:1143;Circulation 2004; 110:744), but carefully selected patients may benefit (e.g., those with low risk for intracranial bleeding). The window for treatment may be as long as 2 weeks from symptom onset (Goldhaber Lancet trial); contemporary studies have shortened this window to <1 week. This patient’s recent hemoptysis and pulmonary infarction may temper the enthusiasm for systemic lytics; as an alternative, catheter-directed thrombolysis could be considered, and early studies (e.g., ULTIMATE) are promising. In the case of massive PE, surgical thrombectomy may be appropriate.
4. What treatment options are available to prevent further episodes?
Chronic anticoagulation with warfarin is the most appropriate therapy to prevent future events. Novel oral anticoagulants could be considered, but the evidence base to date is limited. I would not favor an inferior vena cava filter, as it has become increasingly clear that these devices can have significant long-term sequelae that are not outweighed by the acute benefits. The exception are the retrievable filters that can be placed until the risk for recurrent PE and/or bleeding risk has passed.
Follow-Up:
April 3, 2014
The patient was transferred to the ICU, and vasodilator and diuretic medications were withheld. Lower-extremity venous Doppler imaging showed no evidence of deep-vein thrombosis. Pulmonary specialty consultation was ordered, to help assess the risks and benefits of systemic or catheter-directed thrombolysis. Given the patient’s hemodynamic stability (despite persistent tachycardia) and the presence of pulmonary infarction, the decision was made to continue intravenous heparin but not pursue further thrombolytic therapy. An inferior vena cava filter was not placed because the patient was able to receive full anticoagulation. Repeat echocardiogram 2 days later did not show any significant changes.
During the next few days, the patient’s tachycardia resolved and his oxygen requirements lessened. He was transferred from the ICU to a monitored bed, and warfarin was started with a plan to bridge with heparin until a therapeutic INR was reached. His vasodilator and diuretic heart failure medications were slowly restarted and titrated up, as tolerated. He also underwent physical and occupational therapy to improve his functional status.
Ultimately, 2 weeks after initial diagnosis, the patient was well enough to return home. His discharge medications included furosemide, hydralazine/isosorbide dinitrate, lisinopril, and warfarin. He plans to follow up in the heart failure and pulmonary medicine clinics.
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