April 14th, 2014
Selections from Richard Lehman’s Literature Review: April 14th
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 10 Apr 2014 Vol 370
Spironolactone for Heart Failure with Preserved Ejection Fraction (pg. 1382): Human beings are programmed to die. One very common mode of dying is called heart failure. About half of people dying from heart failure do not show any diminution in the percentage of their left ventricular volume that they expel during systole, and in the clumsy jargon of the present, they are said to have HFPEF, heart failure with preserved ejection fraction. This is often referred to as “diastolic” HF, but in reality the mechanisms behind it are not confined to diastolic filling patterns but are far more complex. Let’s leave it at that, and consider what you might want to happen if you had a stiff, failing old heart. My main wishes would be to be looked after compassionately, not to be a burden on my loved ones, to get symptomatic relief for my breathlessness, and to avoid having to go into hospital. Knowing that this was how I would probably die, I might reach the point where I wanted it to happen quickly. These may not be everybody’s aims: some might wish to hang on to life as long as possible, but this seems a very odd assumption to turn into a primary outcome for trials in heart failure, as it invariably is. The median age in the TOPCAT trial was 68, at least a decade younger than most patients with HFPEF. This was essentially a rerun of the trials of spironolactone in systolic heart failure done over the last 20 years. In heart failure with an ejection fraction of 45% or more, spironolactone did not reduce the primary composite outcome of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure. My plea would be for researchers to start looking at other end-points, centred on the quality of dying.
Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism (pg. 1402): Ever had a pulmonary embolus? Don’t answer no, because in truth you have no idea. Thousands of tiny clots could have passed through your pulmonary circulation without you being any the wiser. The lung is a sieve, and pulmonary embolism is a matter of degree. For lesser degrees of PE, we generally use long-term anticoagulation, but if there is a threat to life, it becomes urgent to remove the clot physically or by fibrinolysis. And then there is a middle category: “normotensive patients with intermediate-risk pulmonary embolism” who have evidence of cardiac strain but are haemodynamically stable. A large French trial randomized them to receive either tenecteplase plus heparin or placebo plus heparin. There was a non-significant reduction in death in the fibrinolytic group but a significant increase in major bleeds including stroke.
JAMA 9 Apr 2014 Vol 311
The New Cholesterol and Blood Pressure Guidelines: Perspective on the Path Forward (pg. 1403): Harlan Krumholz, who is on sabbatical leave, has only two important editorials in the top journals this week. His reflection on the new US Cholesterol and Blood Pressure Guidelines is a classic and needs to be downloaded by anyone interested in the future of medical practice. The radical importance of these latest guidelines is that they refocus attention on what guidelines are really for. Here is the conclusion: “While it is important to advocate for health and promote healthy environments and behaviors on the broader scale, for medical decision making, it is even more important to ensure informed choice with the full participation of the person who will incur the risks and benefits of the decision. When viewed through this lens, the controversies about the guidelines become less contentious and the focus shifts to refining the evidence and producing better ways to communicate what is known for decision-making purposes. By directing attention to that message, already firmly embedded in these guidelines with their bold recommendations and deference to patient preference, they may have accomplished more than they ever envisioned.”
April 14th, 2014
The Uncertain Future of Renal Denervation
Larry Husten, PHD
Following the spectacular crash and burn of the SYMPLICITY HTN-3 trial at the American College of Cardiology (ACC) meeting two weeks ago, the future of renal denervation (RDN) — the once highly promising catheter technology that many thought would cure resistant hypertension — appears in doubt.
Although the device has not been approved in the U.S. — and will not be approved without further clinical trials — in Europe and other places it remains on the market. So the questions about the technology’s future revolve around the future direction of research in the field and how the existing renal denervation market will be affected by the trial results.
The uncertainty and confusion is driven by the very wide disparity between the findings of the SYMPLICITY HTN-3 randomized controlled trial, which found a vanishingly small blood pressure lowering effect for RDN when compared to controls who underwent a sham procedure, and the SYMPLICITY global registry, which found a very large effect similar to that seen in all the other previous uncontrolled or poorly controlled trials.
Medtronic, which manufactures the Symplicity RDN system and sponsored the SYMPLICITY HTN-3 trial, said that it “remains committed to advancing renal denervation.” The trial “confirmed the profound safety of the Symplicity system,” the company said. “We do not believe… that this trial proves renal denervation does not work; further clinical research is needed to confirm this hypothesis.” The company said that “a panel of independent experts made up of global physicians and researchers… affirmed that Medtronic should continue to provide access to the Symplicity system as long as the company continues to study it, which we intend to do. Medtronic believes physicians should make clinical decisions based on the totality of evidence, including their own independent experience.”
Boston Scientific said its own RDN technology is “highly differentiated” from Medtronic’s and is “supported by compelling clinical evidence and a strong clinical program.” The company has yet to determine its next steps.
Michael Böhm, who presented the registry findings at the ACC meeting last month, supports the continued clinical use of the device, especially in carefully chosen patients with uncontrolled hypertension who have exhausted other options and when performed by experienced operators. The operators in the registry, he said, had far more experience with the procedure than the operators in SYMPLICITY HTN-3. Along with others, he noted that there are currently no objective ways to measure the technical success of the procedure. It is possible, he said, that the greater experience of the registry operators produced better results.
Many commenters at the ACC meeting struggled to strike a delicate balance. There was wide agreement that research in renal denervation should continue, but many thought use of RDN outside of a clinical trial was hard to justify. But since the device remains on the market in many countries, and since there is little precedent for removing a product from the market once it has gained approval in the absence of a safety issue, some believe that the decision to employ RDN should be left to the individual physician.
Not Steve Nissen. “I think sales should be suspended,” Nissen told Reuters. “You (now) have a trial with no evidence it works.” PK Shah told Reuters that physicians in Europe “would be better off doing the right clinical trials and perhaps putting a short-term moratorium” on RDN except in the context of a clinical trial.
The new president of the ACC, Patrick O’Gara, said he thought that some patients may have benefited from RDN. “We need to convene a group of experts to weigh the positives and negatives of a moratorium,” O’Gara told Reuters.
Speaking on behalf of the European Society of Cardiology, François Schiele told me that RDN “should not be used except in clinical trials,” but he was clearly unhappy with the current situation. As a former strong believer in RDN, he said “it is difficult for me to understand that it doesn’t work.”
At a Late Breaker Deep Dive session, Robert Califf said that physicians should “hold off on clinical use until someone can produce rigorous supportive data using God’s gift of randomization.” He also said it “would be good to have a functional assay” to measure the effect of the catheter procedure.
Milton Packer defended the use of sham procedures because “there’s so much bias in the wonderment of having done something to somebody.” “Procedures,” he said, “are fundamentally a religious experience.”
Darrel Francis, who predicted early on that SYMPLICITY HTN-3 would not meet its primary endpoint, said that the registry does send “a resoundingly clear message” that Symplicity “is safe, which is of paramount importance for patients.” But the results of SYMPLICITY HTN-3 “teach crucial lessons in human behaviour, underlining for us why we must do blinded randomized controlled trials on these questions if we want the real answer.”
We need to look carefully through the SYMPLICITY 3 data to help design future trials that will have a better chance of detecting effects that are smaller than we hoped, and may be more variable than we guessed. I hope we are witnessing the origin of a new interest in meticulous methodology.”
April 9th, 2014
Putting TOPCAT in Perspective
Bertram Pitt, MD, Marc A. Pfeffer, MD and Clyde Yancy, MD
CardioExchange’s John Ryan poses questions about the TOPCAT trial to its first two authors, Bertram Pitt and Marc Pfeffer, and to regular CardioExchange contributor Clyde Yancy. The study is published in The New England Journal of Medicine.
THE STUDY
Researchers randomly assigned 3445 patients with symptomatic heart failure and a left ventricular ejection fraction >=45% to receive either spironolactone (15 to 45 mg daily) or placebo. At a mean follow-up of 3 years, incidence of the primary outcome — a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for heart failure — was statistically similar in the spironolactone and placebo groups (18.6% and 20.4%, respectively; hazard ratio, 0.89; 95% CI, 0.77–1.04; P=0.14), although the incidence of hospitalization for heart failure was significantly lower with spironolactone than with placebo (12.0% vs. 14.2%; HR, 0.83; 95% CI, 0.69–0.99; P=0.04). The incidences of all-cause mortality, all-cause hospitalization, MI, and stroke were similar in the two groups.
THE EXPERT PERSPECTIVES
John Ryan: Are you surprised that spironolactone failed to reduce incidence of the primary outcome?
Pitt & Pfeffer: We were surprised and disappointed by the result on the primary outcome. However, we did find a significant effect on one component of the primary outcome: hospitalization for heat failure.
Clyde Yancy: We should all be surprised because the hypotheses studied are sound, the conduct of the trial was exceptional, and the consistency of the efficacy of mineralocorticoid antagonism (MRA) has been unwavering. We ought to refrain from taking a binary approach to TOPCAT and simplifying the take-home message as “positive” (embrace the data) or “negative” (dismiss the trial). A much better approach is to declare that this was an informative trial that adds to our understanding of heart failure with preserved ejection fraction (HFpEF). In effect, we must respect the results, but we must also question everything in these data — especially the variation of disease as a function of geography — and notably, we should not hesitate to try again. The condition of HFpEF is of such heft now that it merits our most diligent efforts to discover a treatment strategy that modifies the natural history.
John Ryan: In the end, is the study underpowered? Many would consider the statistically nonsignificant difference to be clinically significant (NNT of about 50). Can we really conclude that spironolactone is ineffective in this group?
Pitt & Pfeffer: I do not believe the problem was overall underpowering. The problem, as I see it, is that about half of the patients (those from Russia and the Republic of Georgia) had a placebo event rate that was not compatible with what we understand from prior trials of HFpEF. Their placebo-group event rate is compatible with a risk factor such as hypertension without HF. Given the low event rate in Russia and Georgia, we were certainly underpowered in these countries. However, if you look at the results in the Americas (Canada, U.S., Argentina, Brazil), where the placebo-group event rate is compatible with that in prior HFpEF studies, spironolactone significantly reduced the primary outcome and its two major components: CV mortality and hospitalization for HF. However, this post hoc analysis is open to debate.
In the subset of patients randomized on the basis of elevated BNP, rather than a history of hospitalization (a major component of which was HF), spironolactone also resulted in a significant reduction in the primary endpoint. However, as we note in the paper, this was only one of several subgroups analyzed; therefore, the result is subject to chance.
Clyde Yancy: Is any clinical trial truly powered adequately? We make our best a priori approximation of power, but event rates are entirely predicated on the enrolled patient population and the comparative care in the control population. Ultimately, the signal here was simply not robust enough — but it was not absent. The HF hospitalization data are reasonable, and even more so when considered both in the North America cohort and again in the group stratified according to an elevated BNP. Moreover, the significant geographic variation (i.e., the Russian and Georgian cohorts) really speaks to a potential clinically important but not statistically significant advantage. Reducing heart failure hospitalizations, especially in HFpEF, is a good thing. Thus, in the interpretation of these data, perhaps we steer away from our purist inclinations and become more pragmatic. The clinical answer to be gleaned from these data is not a “no” vote for MRAs in HFpEF, but rather a reasonableness assessment that considers the safety of this approach with the likelihood of a favorable impact on HF hospitalizations. It’s not the home run we sought, and it won’t make the guidelines for heart failure today, but perhaps it’s good enough—at least for now. We’d be foolish to dismiss this approach altogether. In my own practice, I have and will continue to use MRAs in this setting.
John Ryan: The discussion mentions “the clinical challenges in diagnosing heart failure with a preserved ejection fraction.” What are those clinical challenges, and how can we overcome them when designing a clinical trial?
Pitt & Pfeffer: As we point out, the criteria for the diagnosis of HFpEF are rather subjective. It is likely that a number of patients with shortness of breath or dyspnea from causes other than HFpEF (e.g., obesity, COPD) may have been included. The baseline echo findings make it obvious that although many patients had mild diastolic dysfunction (a nonspecific finding that can occur in patients with hypertension without HF), others did not have any structural evidence of HF. I believe that the presence of an elevated BNP level helped to identify a subset of patients whose symptoms were due to HFpEF and who were at increased CV risk. As mentioned above, in that subset of patients, spironolactone seemed to work.
I believe we will have to let readers reach their own conclusions about whether spironolactone has an appropriate role in their patients with HFpEF. My personal view, for what it is worth, is that in patients with HFpEF and increased CV risk (e.g., those with elevated BNP or NT-proBNP), spironolactone is effective — and I would use it in my patients.
Clyde Yancy: This, I think, is the crux of the issue. For lots of reasons, we are inclined to be “lumpers” and think of diseases and patient cohorts in big buckets (e.g., hypertension, ACS, atrial fibrillation) — but for HFpEF (much like acute or hospitalized heart failure), we may need to be “splitters” and respect the very important within-group differences. How you get to HFpEF matters. We should let new science dictate how best to partition this patient population and then align future candidate therapies with targeted phenotypes.
Share your thoughts on the TOPCAT trial.
April 9th, 2014
TOPCAT Fails to Find Advantage for Spironolactone in HFPEF
Larry Husten, PHD
Although a significant portion of people with heart failure have preserved ejection fraction, none of the proven heart failure therapies has been shown to be beneficial in this important and growing heart failure subpopulation. Now a new NHLBI-funded study has failed to find a benefit in this group for spironolactone, which is a cornerstone of therapy for heart failure patients with reduced ejection fraction. But trial investigators and heart failure experts believe it is too early to dismiss hope that the drug may eventually be found to work in this population.
TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist), published in the New England Journal of Medicine, randomized 3,445 patients with heart failure with preserved ejection fraction (HFPEF) to either spironolactone, an aldosterone antagonist, or placebo. After 3.3 years of followup the primary outcome — a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure — occurred in 18.6% of the spironolactone group and 20.4% of the placebo group. This difference did not achieve statistical significance (hazard ratio 0.89, CI 0.77 – 1.04, p=0.14).
However, there was a statistically significant difference in one component of the composite endpoint. Hospitalization for heart failure was reduced from 14.2% in the placebo group to 12% in the spironolactone group (p=0.04).
The results were consistent across different subgroups, with one important exception. At the time of enrollment patients were stratified according to their eligibility criteria. 71.5% were enrolled because in the past year they had been hospitalized and the management of heart failure had been a major component of their care. 28.5% did not meet the hospitalization criteria but were enrolled because they had elevated BNP levels. The primary endpoint was significantly reduced in the BNP stratification but not in the hospitalization stratification.
Geographic differences may have played an important role in this discrepancy. Nearly half the patients in the trial were enrolled in Russia and George. These patients had lower event rates than subjects elsewhere and were much more likely to be enrolled in the hospitalization stratum. The authors wrote: “The discrepancy in event rates with placebo may have contributed to the observed treatment benefit in the Americas but not in Russia or Georgia (where low event rates would be difficult to reduce further) and the observed treatment benefit among patients enrolled in the BNP stratum but not among those enrolled in the hospitalization stratum (because most of the patients enrolled in Russia and Georgia were in the hospitalization stratum).”
In an accompanying editorial, John McMurray and Christopher O’Connor analyze this issue and end up questioning “whether some of the patients in the hospitalization stratum actually had heart failure with a preserved ejection fraction, not least because this is a diagnosis that is not straightforward and that relies on the ruling out of other potential causes of dyspnea and edema.”
In a discussion of the trial results on CardioExchange, principal investigators Bert Pitt and Marc Pfeffer said that although the trial as a whole was not underpowered, the low event rates in Russia and Georgia suggest that “we were certainly underpowered in these countries.” Furthermore, “if you look at the results in the Americas (Canada, US, Argentina, Brazil) where the placebo event rate is compatible with prior HFPEF studies, spironolactone significantly reduced the primary outcome and its two major components.” They warned, however, that this is “a post hoc analysis and therefore is open to debate.”
Clyde Yancy, who was not involved with the trial, also discussed the results on CardioExchange. Because of the absence of available treatments for HFPEF, Yancy said that TOPCAT should not be viewed as a “positive” or “negative” trial: “A much better approach to the TOPCAT data is to declare that this was an informative trial that adds to our understanding of HFPEF.”
He continued:
Ultimately, the topline signal here was simply not robust enough. But it was not absent; the HF hospitalization data are reasonable and even more so when considered both in the North America cohort and again in the group stratified according to an elevated BNP. Moreover, the significant geographic variation, i.e., the Russian and Georgian cohorts, really speaks to a potential clinically important but not statistically significant advantage. Reducing heart failure hospitalizations, especially in HFPEF, is a good thing.
TOPCAT, said Yancy, is “not the home run we sought, and won’t make the guidelines for heart failure today, but perhaps it’s good enough—at least for now.” Yancy said that in his own practice “I have and will continue to use” aldosterone antagonists in HFPEF.
April 8th, 2014
NSAID Use Associated with Atrial Fibrillation in Older People
Use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the elderly is associated with an increased risk for atrial fibrillation (AF), according to a prospective study in BMJ Open.
Using a Dutch cohort designed to investigate risk factors of disease onset in the aged, researchers followed some 8400 people for 13 years. None had AF at baseline (when their mean age was 69 years).
Current use of NSAIDs for 15 to 30 days was associated with a higher AF risk, relative to never use (adjusted hazard ratio, 1.76). Use in the recent past (within the past 30 days) also brought increased risk (HR, 1.84). There was a suggestive dose-response relation, but it didn’t reach statistical significance.
The authors speculate that, in addition to possible effects on blood pressure, NSAIDs could cause fluctuations in serum potassium, possibly contributing to the observed association.
Adapted from Physician’s First Watch
April 8th, 2014
Study Suggests Link Between Viagra and Melanoma
Larry Husten, PHD
In recent years, researchers have uncovered a potentially important pathway whereby PDE5A inhibitors (which include sildenafil — Viagra — and other drugs used to treat erectile dysfunction and pulmonary hypertension) could potentially increase the risk for developing melanoma. Now a study provides early evidence showing an association between sildenafil and melanoma, though, like all observational studies, it is unable to demonstrate a cause-and-effect relationship.
The study, published in JAMA Internal Medicine, analyzed data from more than 25,000 men who participated in the Health Professionals Follow-up Study. Men who had recently used sildenafil had nearly twice the risk for developing melanoma after adjustment for other risk factors (hazard ratio 1.84, CI 1.04 – 3.22). Men who had used sildenafil at any time had a similar increase in risk. No increase in risk was observed for other skin cancers (basal cell carcinoma and squamous cell carcinoma) without known links to PDE5A inhibitors. In addition, there was no significant association between erectile function by itself and melanoma.
The investigators did not explore whether other PDE5A inhibitors, including tadalafil (Cialis) and vardenafil (Levitra), were associated with melanoma, since these drugs were not available at the start of the study. But in their discussion, they point out that because these drugs are longer-acting, they may potentially result in an even greater increase in risk for melanoma.
Because the study was a retrospective, observational study, the authors caution that their findings “should be interpreted cautiously and are insufficient to alter current clinical recommendations.”
In an accompanying editorial, June Robinson agrees with the authors that a prospective study will be required before clinical recommendations should be changed. But she sees little reason why physicians should not perform melanoma screening when writing a sildenafil prescription for older men who have a history of sunburns. Early detection, she noted, “may make melanoma a curable disease.”
April 8th, 2014
Some Thoughts on E-Communication and the Future of Medicine
Ahmad M Slim, M.D.
Picture this: It’s a usual Monday morning – one that involves trying to beat traffic in order to respond to pending emails and address administrative issues before the busy clinical day begins. Yet, prior to taking that first sip of much-needed caffeine, you receive an urgent email from a patient via your hospital’s electronic communications network. Five paragraphs later, you realize the patient is concerned about experiencing all the sides effects associated with statin therapy, two weeks after the therapy is initiated. Additionally, the patient feels he is currently taking too many medications, a conclusion he arrived at after reading information on the same secure website.
Six emails later – along with an extensive discussion, the distribution of pamphlets, and a total of three hours of electronic communication – you attempt to bring the patient in to review his case. He is reluctant, especially since you are unable to promptly answer all of his questions – a service that’s expected in today’s fast-paced information society. Finally, the patient comes in; after noting his history, conducting a physical exam, and asking focused questions, his symptoms are attributed to a viral syndrome that has abated.
This is not a made-up scenario or content for future coursework, but a true reality of the electronic communication system adopted by our industry. What started as a highway of free, abundant information to patients, along with the immediate electronic access to providers, has become more extensive than focused H&P examinations. The more we overwhelm the patient with medical information from different sources, the less focused the message delivered to the patient about the uniqueness of his or her condition will be.
The question remains then: Is electronic communication an expeditious method of healthcare delivery and does it really answer the health concerns of the patient? Or does it generate more queries due to the impersonal nature of digital messages, which are typically accompanied by either a paucity of information or a massive amount of data? Is the right financial course of action, during this era of budget constraints and limited reimbursements, actually hours of e-communication and the potential for legal action in the absence of a physical exam? Are we on the right path, especially when solidified guidelines based on the practice of telemedicine and the right advice when utilizing social media are lacking?
These are all unanswered questions, and yet true concerns remain as how to move forward in a society dominated by both e-communication and no single unifying idea as to what data is too overwhelming or too little for patients to understand. As the efficiency of this system is extremely debatable, since typically no digital conversations end with a single response, I believe we are not ready to move forward with email and web messaging as the primary source of communication with our patients. Unless we do the following: build the right data-sharing infrastructure, where the patient receives a focused message instead of the large medical data repository we call a pamphlet; develop the right guidelines detailing what constitutes as appropriate when using e-communication vs. in person; and standardize these rules across the industry, then our premature launch is a failure in the making. Though there are multiple of cases where e-communications have markedly and efficiently improved the delivery of care to our patients, all it takes is one case of a misdiagnosis or poor communication to demolish a system.
April 8th, 2014
Assessing the MRI Safety of New Pacemakers and ICDs
Promporn Suksaranjit, M.D.
An estimated 50% to 75% of patients with a pacemaker or implantable cardioverter-defibrillator (ICD) have a clinical indication for MRI during the device’s lifetime. Device safety during MRI scanning is therefore an important issue to explore.
The Evidence Thus Far
Early concerns about device dislodgement and overheating during MRI have abated, thanks to evidence that the maximal force and torque acting on modern pacemakers/ICDs at 1.5T are unlikely to dislodge leads anchored in the myocardium and that small measured rises in temperature pose minimal risk for thermal injury. Several reported adverse electrical events — including diminished battery voltage, increased capture threshold, decreased pacing-capture threshold on repetitive MRI, decreased sensing amplitude and pace impedances, power-on-reset, and oversensing of electromagnetic interference — do represent real potential risks. However, many of the electrical changes detected on device interrogation immediately after MRI scanning have proven to be transient and clinically inconsequential. In general, ICDs’ tachycardia-detection capabilities and therapy can be temporarily suspended by placing a magnet over the device to change the built-in reed-switch function; therefore, unpredictable reed-switch behavior in an MRI environment could cause inappropriate shocks. However, a large clinical trial has failed to reveal any adverse events from the inappropriate shock during 1.5T MRI.
Ongoing Efforts to Ensure Safety
Although no device-related major adverse clinical events have been documented during MRI scanning, device makers have been working on features to further improve safety. We now have MRI conditional devices, which are those shown to pose no known hazards in a specified MRI environment under specified conditions of use. In 2011, Medtronic released an MRI conditional pacing system, Revo MRI SureScan, the first FDA-approved pacemaker system available in the U.S.; approval of the second-generation Advisa MRI SureScan followed in 2013.
Clinical trials have tested the safety and efficacy of the Revo and Advisa MRI pacemaker generators with CapSureFix MRI conditional leads, in a dual-chamber pacemaker design. The evidence shows no reports of MRI-related complications; no disturbances of pacemaker function during or after MRI; no ventricular arrhythmia inductions; and minimal differences in pre- and post-MRI pacing threshold, impedance, and sensing (similar to results in a control [no-MRI] group). CapSureFix MRI conditional leads have an encouraging safety and efficacy profile, with no lead displacement and no cases of high pacing thresholds or inadequate sensing. Compared with conventional leads, the CapSureFix MRI leads show no clinically relevant difference in pacing threshold, sensing, or impedance.
MRI conditional pacemaker design addresses the theoretical concerns of MRI and device interaction. The limited amount of ferromagnetic material minimizes the magnetic-field interaction and, therefore, reduces the risk for device dislocation. The reed switch is replaced by a Hall sensor and, consequently, mitigates program switching from unpredictable reed-switch behavior in an MRI environment. Internal circuits have also been improved to prevent internal power-supply interruption and to reduce the potential for cardiac stimulation, thereby diminishing the risk for electrical reset and tachyarrhythmia. To address concerns about thermal injury, leads are being modified to reduce RF lead tip heating from transmitted RF power.
Making MRI Conditional Systems Practical
Implanting an MRI conditional pacing system has been made more practical by giving the pulse generator a size of 12.7 cm3 and a weight of 21.5 g (Revo MRI) or 22 g (Advisa MRI), similar to the average size and weight of a conventional pulse generator. CapSureFix MRI conditional leads have greater diameter and stiffness, but there is no difference in procedural and fluoroscopy time, and the implant success rate for an MRI conditional pacing system is 100%. Ideally, MRI conditional devices should be implanted in patients with an anticipated future indication for MRI. However, a patient-selection strategy needs to be developed, in part because an MRI conditional device is $1000 to $3000 more expensive than a standard device.
What About Image Quality?
Susceptibility artifacts from MRI conditional devices continue to affect image quality on cardiac magnetic resonance (CMR). Most image distortions and artifacts are within 10 cm to 15 cm around the device generator — and are pronounced in CMR, especially on steady-state and inversion-recovery sequences. The artifacts are substantially greater for ICD than for pacemaker generators and for left-sided than for right-sided systems. Using gradient-echo and wide-band sequences helps to improve quality on cine and viability images, respectively. With these imaging-sequence modifications, sufficient image quality can be obtained in most cases.
Translating What We Know Into Practice
MRI conditional devices are considered safe in specified MRI environments and conditions of use when standard safety protocols are followed. However, experience with conditional devices is still limited in CMR and in 3T MRI, and we have no postmarketing data on long-term adverse events. Given the current evidence, what would you do if a patient with a conventional device is scheduled for CMR? Should patients with conventional devices switch to an MRI conditional device? Would it be cost-effective to implant an MRI conditional device in all patients with appropriate clinical indications?
Please share your answers to these questions here.
April 7th, 2014
Selections from Richard Lehman’s Literature Review: April 7th
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 3 Apr 2014 Vol 370
A Controlled Trial of Renal Denervation for Resistant Hypertension (OL): From now on, teaching the crucial importance of proper design in randomized trials will be SYMPLICITY itself. I’ve already taken you through the essentials of this story, after being taken in myself, and there is a superb BMJ editorial as well. Here is the full report of the SYMPLICITY-3 trial which shows that after spectacular results in open label trials, renal denervation does not produce a significant drop in blood pressure which is persistently high after combined treatment with at least three drugs. Correction: it produces a very significant drop averaging 13mm Hg, whereas the sham control procedure produces a drop of nearly 12mm. Let’s just stop and think about that. If you lie a patient down and put a tube in an artery and pretend to fiddle about for half an hour, you can produce a long term reduction of their blood pressure nearly as great as if you actually ablate their renal nerve supply. Explanations on a post card please.
TAVR with a Self-Expanding Prosthesis (OL): Whereas by funding SYMPLICITY-3, Medtronic lost themselves a potential market running into tens of billions of dollars, with this one they may have gained themselves a small niche market in people with aortic stenosis who are borderline for open valve surgery. Patients like this can benefit from transcatheter aortic-valve replacement (TAVR) with a balloon-expandable device, but Medtronic claim superior results from an alternative transcatheter bioprosthesis comprising a self-expanding nitinol frame and trileaflet porcine pericardial valve (CoreValve, Medtronic). Doing device trials is quite tricky, because you need operators to climb a steep learning curve, and here the first three patients enrolled in the trial at each study site were considered to be “roll-in” participants. They did not count in the figures but were there to familiarize the operators with the procedure. The bottom line as stated in the abstract is that “In patients with severe aortic stenosis who are at increased surgical risk, TAVR with a self-expanding transcatheter aortic-valve bioprosthesis was associated with a significantly higher rate of survival at one year than surgical aortic-valve replacement.” But a lot must depend on patient selection; and how many “roll-ins” you’ve practised on.
Survival with CRT in Mild Heart Failure (OL): If I get heart failure with left bundle branch block, I would like to have biventricular pacing (or cardiac resynchronization therapy, CRT). I would want nothing to do with implantable defibrillators. Sudden death—especially beyond the age of 70—seems to me greatly preferable to a decline into weakness, breathlessness, dependency, and repeated episodes of near-drowning. However, in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT), CRT alone was not on offer. You had to have the defibrillator, with or without CRT. Follow-up at a seven years confirms that CRT reduces all-cause mortality in people with mild systolic heart failure with LBBB from 29% to 18%, with a possibly harmful effect on those without LBBB. There is nothing here about symptom relief, which counts for more than survival to most people with HF.
Lancet 5 Apr 2014 Vol 383
Effect of High-Dose Simvastatin on Brain Atrophy and Disability in Secondary Progressive MS (OL): Statins, as I keep saying, are wonderful drugs. They should be offered to everybody and people should make up their own minds whether to take them, based on the evidence and their personal preferences. What I personally would not do, however, is take simvastatin at a dose of 80mg, because this maximizes the risk of adverse effects while producing a very small marginal benefit compared to a lower dose. But 80mg was the dose given to 70 patients with secondary progressive multiple sclerosis in a phase 2 placebo-controlled trial. The mean annualised rate of brain atrophy was significantly lower in patients in the simvastatin group (0•288% per year [SD 0•521]) than in those in the placebo group (0•584% per year [0•498]). How this 43% reduction in brain shrinkage converts into clinical benefit is uncertain from this relatively small and short RCT, but it certainly suggests that bigger trials with other statins are well warranted in a dreadful condition which is currently untreatable.
April 7th, 2014
Dabigatran Approved for Treatment of DVT and PE
Larry Husten, PHD
Boehringer Ingelheim announced on Monday that the FDA has approved dabigatran (Pradaxa) for the treatment of venous thromboembolism (VTE), which includes both deep venous thrombosis (DVT) and pulmonary embolism (PE), and to reduce the risk of recurrent DVT and PE in patients who have been previously treated.
All three of the new oral anticoagulants — dabigatran, rivaroxaban (Xarelto), and apixaban (Eliquis) — have now received FDA approval for the major indication of stroke prevention in patients with nonvalvular atrial fibrillation (SPAF). Rivaroxaban and dabigatran are also approved for the treatment of people who have or have had VTE, while rivaroxaban and apixaban are approved for DVT prophylaxis following hip or knee replacement surgery.
One significant difference between the drugs is that both apixaban and rivaroxaban were studied using a single-drug approach for acute use in the hospital and for continued use afterwards. By contrast, dabigatran was studied in patients after they had received parenteral anticoagulants and is indicated for use following treatment with a parenteral anticoagulant for 5 to 10 days. It can also be used in people who have been previously treated for VTE.
The new indication is based on results from four global Phase III studies evaluating the efficacy and safety of dabigatran in the treatment of DVT and PE: RE-COVER, RE-COVER II, RE-MEDY, and RE-SONATE.
NEJM Journal Watch — Recent Cardiology Articles- Major and Intracranial Hemorrhage Risk with Direct Oral Anticoagulants vs. Aspirin
- Chlorthalidone vs. Hydrochlorothiazide for Hypertension: Renal Outcomes
- Estimating Heart Failure Risk in the U.S. Population with the PREVENT Calculator
- Atrial Fibrillation and Stable Coronary Artery Disease — What Is the Optimal Anticoagulation–Antiplatelet Regimen?
- β-Blockers After Myocardial Infarction