November 3rd, 2011
FDA Advisory Committee Recommends Approval of Vytorin for Pre-Dialysis CKD Patients
Larry Husten, PHD
The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee on Wednesday strongly supported the combination of ezetimibe and simvastatin (Vytorin, Merck) to prevent cardiovascular events in pre-dialysis chronic kidney disease (CKD) patients. But the panel voted against recommending Vytorin for patients with end-stage renal disease on dialysis. The votes were 16-0 in favor of the pre-dialysis indication and 10-6 against the dialysis indication.
The votes were based on the FDA review of the SHARP trial, which found a highly significant 16% reduction in the rate of major vascular events with Vytorin compared with placebo. However, the beneficial effect was much larger in the subgroup of 6247 patients who were not on dialysis at the time of randomization (22% risk reduction) than among the 3023 patients who were receiving dialysis at randomization (6% risk reduction).
The committee did not vote on an indication that would have included the entire pre-dialysis and dialysis population included in SHARP. One veteran FDA observer, Michael McCaughan, a reporter for the RPM Report, tweeted his belief that the committee would have voted in favor if there had been such a vote.
The panel also had no concerns about safety issues associated with Vytorin.
November 3rd, 2011
Sapien Transcatheter Aortic Heart Valve Gains FDA Approval
Larry Husten, PHD
After much anticipation and drama, the FDA has approved the Sapien transcatheter heart valve (THV). The news was announced late Wednesday afternoon by the FDA and by Edwards Lifesciences, the manufacturer of the device.
Details about the approval are scarce. The FDA said the Sapien THV has been “approved for patients who are not eligible for open-heart surgery for replacement of their aortic valve and have a calcified aortic annulus (calcium build-up in the fibrous ring of the aortic heart valve).” In addition, the product label “advises that a heart surgeon should be involved in determining if the Sapien THV is an appropriate treatment for the patient.”
In its announcement, the FDA noted that although patients in the pivotal PARTNER B trial who received Sapien had two and a half times the number of strokes and eight times as many vascular and bleeding complications as medically treated controls, after 1 year 69% of patients in the Sapien group were alive, compared with only 50% of controls.
The FDA also said that Edwards “will continue to evaluate the outcomes with the Sapien THV through a national Transcatheter Valve Therapy (TVT) registry,” which is under development by the Society of Thoracic Surgeons and the American College of Cardiology, in conjunction with the FDA and CMS. In its statement, Edwards said it would also continue to follow patients enrolled in the PARTNER trial.
November 2nd, 2011
FDA Approves Abbott’s Xience Prime Drug-Eluting Stent
Larry Husten, PHD
Abbott announced on Tuesday that it had received FDA approval for its Xience Prime everolimus-eluting stent. The cobalt chromium stent is designed to be delivered more easily to complex lesions and will be available in long lengths up to 38 mm. Approval of Xience Prime was based on the SPIRIT Prime clinical trial, an open-label registry trial of 500 patients. According to the company, the trial reached its primary endpoint and demonstrated at 1 year low rates of target lesion failure and stent thrombosis. Full results of the trial will be presented on November 8 at the TCT (Transcatheter Cardiovascular Therapeutics) meeting in San Francisco.
November 1st, 2011
No Increased Risk for CV Events with ADHD Drugs, Large Study Finds
Larry Husten, PHD
A large new study may help lay to rest concerns that the widely prescribed ADHD drugs may increase the risk for cardiovascular (CV) events.
In a study funded by the Agency for Healthcare Research and Quality and the FDA and published in the New England Journal of Medicine, William Cooper and colleagues analyzed data from 1.2 million children and young adults between 2 and 24 years of age who were enrolled in four health plans; 373,667 person-years of current ADHD drug use were included.
The investigators found a low rate of serious CV events (3.1 per 100,000 person-years) and no increase in risk for those taking ADHD drugs (adjusted HR 0.75, CI 0.31-1.85). The authors concluded that although their results did not find any increased risk, due to the wide confidence interval they were unable to rule out the possibility of a doubling in risk. “However,” they wrote, “the absolute magnitude of any increased risk would be low.”
November 1st, 2011
Hand-Held Metal Detectors Used in Airport Screening ‘Probably Safe’ for Patients with Implanted Cardiac Devices
Nicholas Downing, MD
Hand-held metal detectors, used frequently at airports, are “probably safe” for patients with pacemakers or implantable cardioverter-defibrillators (ICDs), according to an Annals of Internal Medicine study.
Researchers in Germany examined the effects of two types of widely used hand-held metal detectors on cardiac device function in some 390 patients with pacemakers or ICDs. Each detector was set at the highest possible magnetic field and then passed over the patient’s chest for 30 seconds during ECG monitoring. Over 60 cardiac device models were tested.
There were no ECG abnormalities either during or after exposure to the metal detectors.
The researchers say their findings are consistent with those from previous studies of metal-detector gates, but call for confirmatory research because of various limitations to their own study (e.g., they used a convenience sample of patients).
October 31st, 2011
FDA Gives Favorable Review to SHARP Ahead of Vytorin Advisory Panel
Larry Husten, PHD
In preparation for Wednesday’s meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, an FDA reviewer has generally endorsed the positive interpretation of the SHARP trial of Vytorin (ezetimibe and simvastatin) in chronic kidney disease (CKD).
Based on the results of SHARP (Study of Heart and Renal Protection), Merck is seeking an expansion of its indication for Vytorin to include the reduction of major cardiovascular events in patients with CKD. The proposed label from Merck would include a statement noting that any added benefit for the combination of ezetimibe and simvastatin over simvastatin alone “has not been definitively established.”
Currently there are no drugs specifically available to CKD patients that reduce the high risk of CV events in CKD, although statins sometimes have been used. Previous studies have shown that statins are not beneficial in patients with end-stage renal disease, but the potential benefits in patients at earlier stages in the disease – including two thirds of patients in SHARP – had not been tested until now.
SHARP was the subject of discussion and controversy when it was first presented last November.
The analysis of SHARP by the FDA reviewer found that the combination of ezetimibe and simvastatin reduced the rate of major vascular events by 16% (p=0.001) compared with placebo. This result appeared robust, holding up to a number of different secondary and exploratory analyses.
The beneficial effect was much larger in the subgroup of 6,247 patients who were not on dialysis at the time of randomization (22% risk reduction) than in the subgroup of 3,023 patients on dialysis at randomization (6% risk reduction). The test for heterogeneity did not find a significant difference in treatment effect based on dialysis status, however (p=0.08).
The reviewer raised no red flags about safety. Cancer, which had been a subject of intense concern in the past, was not an issue. The rate of incident cancer was 9.4% with ezetimibe-simvastatin group versus 9.5% with placebo, although there were 18 more cancer deaths in the intervention group than in the placebo group (132 [2.8%] versus 114 [2.5%]).
October 28th, 2011
Belgian Study Supports Use of FFR to Guide Therapy in Intermediate LAD Lesions
Larry Husten, PHD
A study published in JACC: Cardiovascular Interventions suggests that fractional flow reserve (FFR) may be safely used to guide treatment in patients with an intermediate left anterior descending coronary artery (LAD) stenosis.
Olivier Muller and colleagues report on 730 patients at a single center in Belgium who had a 30% to 70% stenosis in the proximal segment of the LAD and received treatment based on FFR. Overall, 564 patients who had an FFR of 0.80 or higher were treated medically, while 166 with an FFR below 0.80 underwent revascularization. In the revascularization group, 13% underwent surgery and 87% had PCI.
Estimated 5-year survival was 92.9% in the medical group and 87.4% in the revascularization group (p=0.03). Estimated 5-year survival free of death, MI, and target vessel revascularization was 89.7% and 68.5%, respectively (p<0.0001).
The authors write that their findings indicate that “patients with an angiographically dubious, but hemodynamically nonsignificant, isolated stenosis in the proximal LAD (as assessed in the catheterization laboratory by FFR measurements) have a favorable long-term outcome without mechanical revascularization.” They note that although current recommendations call for functional testing to demonstrate ischemia prior to revascularization, a number of common factors “in daily practice” mean that this recommendation is frequently overlooked. As an alternative, “FFR makes it possible to obtain both anatomic and functional data during the same examination.”
The study, they conclude, “supports the strategy of deciding about revascularization based on both anatomic and functional information obtained simultaneously in the catheterization laboratory.”
October 28th, 2011
FDA Advisory Panel Votes 8-2 Against Approval of Medtronic AF Ablation System
Larry Husten, PHD
An FDA advisory panel has recommended against approval of Medtronic’s Ablation Frontiers Cardiac Ablation System for the treatment of symptomatic, drug refractory, persistent atrial fibrillation (AF) or longstanding persistent AF of up to four years in duration.
In an 8-2 vote, members of the Circulatory System Devices Panel said that the risks of the device outweighed its benefits. Earlier the panel had unanimously agreed that the device was effective in combating AF, but voted 9-1 that it was not safe.
In a report prepared for the committee, the FDA reviewers had expressed grave concerns about the safety of the system, focusing particular concern on the high stroke rate.
In his Twitter feed, Mark McCarty, of Medical Device Daily, pointed out that all catheter ablation for AF other than paroxysmal is off-label. The panel, he said, sent a signal to electrophysiologists that they should continue using other devices off label.
The Wall Street Journal quoted panel chair Clyde Yancy, who is holding out hope for eventual approval of the device: “I hope what you heard today is not a no, but a not yet.”
October 28th, 2011
Joining the Fishbowl
Shengshou Hu, M.D.
CardioExchange welcomes this guest post, reprinted with permission, from Dr. Westby Fisher, an electrophysiologist practicing at NorthShore University HealthSystem in Evanston, Illinois, and a Clinical Associate Professor of Medicine at University of Chicago’s Pritzker School of Medicine. This piece originally appeared on his blog, Dr. Wes.
It’s a strange thing, this practice consolidation.
Imagine: one minute the guys over there are your competitors, then the next thing you know, they’re part of your group.
Before, you were SURE you offered patients something better (at least that’s what you told yourself). Now, they are us. How do you differentiate yourself any longer? Can you? Should you?
Before, you worked for your practice, them for theirs. People unhappy with them could come to you across town and vice versa. Where will your patients have to travel for an independent second opinion now? Or will those second opinions just occur with another colleague? As it stands now, we all work for One Practice and The Man. If the new guys screw up, we all screw up. They do well, we’ll do well. (At least that’s what’s promised, right?) And what if The Man screws up?
It can’t be easy being the new kids on the block: do you trust them? Do they trust you? Were there incentives to join? Were there not? What deal was cut? There was a deal, right? An now: what will be the impact of their presence be on patient volumes? On pay?
We’re like formerly incompatible tropical fish that are now being thrown in the same fishbowl. We look and feel so pretty now, don’t we? But you have to wonder: who will survive and who will die off when the fish food is in short supply? And as the bowl gets more crowded, will there be enough oxygen to support us all?
October 27th, 2011
The Art of Arriving at a Diagnosis
John E Brush, MD
A 55-year-old man came to the emergency room complaining of aching chest pain radiating to the back. The pain had started the day before and recurred several times. It seemed to worsen with exertion and resolve with rest. One resting episode was associated with diaphoresis. Exam, EKG, and cardiac enzymes were normal. A portable chest X-ray showed a slightly widened mediastinum. The ER resident ordered a CT scan of the chest, and the preliminary report was negative for aortic dissection but showed a small pericardial effusion. The patient was placed on aspirin, a beta-blocker, and heparin. A cardiology consultation was called, for presumed unstable angina.
I was on call and saw the patient that Saturday afternoon. After talking with him, I began to question the preliminary CT scan report. I asked an attending radiologist to go over the scan with me, and on careful review, a subtle dissection was noted. The heparin was stopped, and the patient underwent emergency aortic repair. The ER resident was stunned.
“What caused you to doubt the preliminary CT scan report?” he asked. “How did you know?”
“The scan result just didn’t fit,” I said.
Had I simply made a lucky guess? Perhaps. But after eliciting a history, examining the patient, and going over the other details, I formed a mental picture of the case that made me question the preliminary CT scan report.
How do experienced doctors “see” a diagnosis and start to solve a diagnostic problem? How do we begin to generate the “early hypotheses” that I discussed in my previous post? The answer, in my view, lies in pattern recognition.
The Way We Detect Patterns
During the first two years of medical school, we learn about causal reasoning — how basic biologic defects manifest in disease. Unfortunately, patients don’t come to us with an orderly textbook description of a condition. They present with signs and symptoms, forcing us to work backward in seeking a diagnosis. The philosopher Charles S. Peirce described this abductive reasoning as “regressing from a consequent to a hypothetical antecedent.” To begin to work backward, we have to recognize a pattern. The pattern may not be clear initially, or it may lack some key parts — but eventually one does emerge, and it starts us on the path of diagnostic evaluation.
Pattern recognition reinforces two traditional methods in medical practice: the use of narrative and the differential diagnosis. Kathryn Montgomery discusses the use of narrative in her book How Doctors Think. While in training, we physicians present cases repeatedly, practicing the art of developing stories that have meaning. The narratives are detailed, chronological, and structured by events. As we develop a narrative, we set ourselves up to detect patterns.
Judith Bowen has discussed how we transform the details of a patient’s case into a mental abstraction called a “problem representation” (N Engl J Med 2006; 355:2217). I like to think of this transformative step as being similar to solving an algebraic equation — sorting, factoring, canceling, and simplifying. The process starts with active listening, and it requires attentiveness and cognitive energy. We then compare the problem representation with “illness scripts” that are stored in our memory from past clinical decision-making experiences. When we find a match, we have a hypothesis or plausible conjecture that we test (usually against imaging or blood-test results) to work toward a final diagnosis.
But this process has its pitfalls. One is called post hoc, ergo propter hoc — a Latin phrase that describes the faulty assumption that temporal sequence implies causation. Another trap is confirmation bias, or selective use of facts to conform to a desired story. A third trap is anchoring, or placing too much weight on a particular aspect of a story. As we draw inferences from a particular case to arrive at a general principle or conclusion (i.e., as we reason abductively), we must of course avoid hasty generalizations or overgeneralizations. That’s where our training in differential diagnosis comes into play — it helps us entertain alternative diagnoses so that we don’t leap to erroneous conclusions.
Reflecting on how we think, how we generate hypotheses, and how we test them makes us more mindful about the art of arriving at a final diagnosis. In this era of imaging and biomarkers, do we need these diagnostic reasoning skills as much as we once did? To what extent has the art of diagnostic reasoning changed because of our new tools and tests?
