March 29th, 2013
FDA Approves First SGLT2 Inhibitor for Diabetes
Larry Husten, PHD
The FDA said today that it had approved canaglifozin (Invokana, Johnson & Johnson), the first of a new class of diabetes drugs known as sodium-glucose co-transporter 2 (SGLT2) inhibitors. Canaglifozin is indicated, in conjunction with diet and exercise, to improve glycemic control in adults with type 2 diabetes. The drug has been studied as monotherapy and in combination with other common treatments for type 2 diabetes, including metformin, sulfonylurea, pioglitazone, and insulin.
The FDA said it was requiring J&J to perform five postmarketing studies with canaglifozin, including a cardiovascular outcomes trial; an enhanced pharmacovigilance program to monitor for malignancies, serious cases of pancreatitis, severe hypersensitivity reactions, photosensitivity reactions, liver abnormalities, and adverse pregnancy outcomes; and a bone safety study.
Vaginal yeast infections and urinary tract infections are the most common side effects associated with canaglifozin. The FDA said canaglifozin should not be used to treat people with type 1 diabetes or in people with diabetic ketoacidosis or severe renal disease.
In clinical trials in over 10,000 patients with type 2 diabetes, canaglifozin was shown to improve hemoglobin A1c levels and fasting plasma glucose levels.
March 28th, 2013
Case Report Of Durata Lead Failure Raises Fresh Concerns
Edward J. Schloss, MD
A case report of a failed St. Jude Medical Durata ICD lead was published yesterday, raising suspicions that this lead may share some of the same potential failure mechanisms of its troubled predecessor, the Riata lead.
St. Jude’s ICD lead troubles date back to early case reports involving the Riata and Riata ST leads that ultimately led to FDA recall in December 2011. These leads have since been well documented to be subject both to increased electrical failures and structural breakdown of the lead as has been previously reported.
St. Jude’s Durata lead was designed as a successor to the Riata ST lead and continues to be marketed and implanted. The Durata lead shared a similar design to the predecessor Riata ST lead with the most notable difference being the addition of a outer coating made of the proprietary co-polymer Optim. This design modification has been promoted to improve abrasion resistance. It is hoped that this modification, would prevent the most prominent failure mechanism of the Riata family, inside-out abrasion and cable externalization.
St. Jude has staunchly defended the Durata lead and continues to promote its reliability. Although individual case reports and MAUDE database analysis have shown Durata failures, a pattern has not developed implicating similar failure mechanisms to the Riata family. Last month, Liu and colleagues reported favorable Durata lead survival data, although they recognized the limitations of the shorter follow up of this lead as compared to Riata and Riata ST.
Yesterday’s Heart Rhythm Journal case report from Swerdlow and colleagues at Cedars Sinai Heart Institute is the first detailed analysis of a Durata lead with inside-out abrasion leading to electrical failure. The lead, a Durata model 7121 was implanted in January 2008 and began to exhibit signs of electrical failure in July 2010. The patient initially declined operative intervention, but ultimately the lead was extracted and replaced in January 2013. There was no fluoroscopic externalization of the lead cables. Analysis of the lead after removal showed several area of insulation degradation. There were areas of visible abraded internal silicon and ETFE insulation under the distal shocking coil that resulted in electrical oversensing due to contact between the ring sensing cable and coil. In addition, several areas of degradation of the Optim outer insulation were found at sites of lead flexion. Based on detailed failure analysis, the investigators concluded that the lead failed due to inside-out abrasion of the silicon inner core of the lead. The analysis took care to exclude damage from the extraction process itself and included detailed photomicrographs in support of their conclusions.
The cardiac electrophysiology community has watched carefully for any signals that the Durata lead may exhibit failure similar to its predecessors. Last summer, a single case report of a Durata failure with lead externalization resulted in a 6% stock drop, as Wall Street reacted harshly to the news. That lead was later analyzed by St. Jude and reported in an investor press release to have failed due to outside-in abrasion from contact with another ICD lead. Last fall a study from scientists at rival Medtronic and University of Minnesota questioned the long-term biostability of Optim insulation in the body environment. More negative attention came this past winter as an FDA warning letter was released arising from inspections at the Durata manufacturing facility.
This most recent ICD lead failure suggests that the Durata lead can fail in a manner similar to the recalled Riata and Riata ST leads. The fundamental problem of inside-out abrasion does not appear to be fully prevented by Optim insulation. This is a failure mechanism predictable based on the design of the lead, but not reported until now. St. Jude has not yet commented publically on this most recent lead failure. All eyes will be watching to see if this is an isolated event or an early sign of systemic trouble for this lead.
March 27th, 2013
Left to Our Many Devices, Which One Do We Choose?
Mark Dayer, MD PhD FRCP and James Fang, MD
A 63-year-old male smoker with type 2 diabetes presents for the first time with chest pain and shortness of breath at rest. He has no recent history of viral infection and no family history of heart failure or sudden cardiac death.
Initial laboratory testing documents negative troponin, normal calcium, normal serum angiotensin-converting-enzyme (ACE) activity, and a negative HIV test. He has no hilar lymphadenopathy.
After being managed with intravenous diuretics and stabilized with ramipril 1.25 mg once daily and furosemide 40 mg twice daily, the patient still has significant limitations and mobilizes comfortably only around the bed. His systolic blood pressure (about 95 mm Hg) prevents the introduction of a beta-blocker. His intermittently high potassium level (up to 6.1 mmol/liter) precludes use of an aldosterone antagonist.
Other Findings
Electrocardiogram: left bundle-branch block, QRS duration 120 msec, and first-degree heart block (PR interval, 220 msec).
Echocardiogram: dilated left ventricle (end-diastolic diameter, 5.8 cm); LV ejection fraction, using Simpson’s biplane, of 16%; mildly dilated and significantly impaired right ventricle; elevated pulmonary artery pressure (about 50 mm Hg).
Coronary angiography: normal coronary arteries
MRI: no late gadolinium enhancement
Cardiac monitoring: periodic 2:1 heart block (<10% of the time)
All of the clinicians who considered the patient’s case agree that a device is warranted.
Which device should this patient receive as chronic therapy?
1. Dual-chamber pacemaker. The patient currently does not pace >40% of the time, and his expected progress is hard to determine. His device can be upgraded if he stabilizes in NYHA class III or better (although not according to current UK guidelines) and if optimal medication does not improve his left-ventricular function.
2. Cardiac resynchronization therapy–pacemaker (CRT-P) device. The patient’s ventricular function is poor and is unlikely to recover significantly. Furthermore, his conduction disease will progress, and he is likely to become dependent on pacing during the lifetime of the device. Given that he is arguably still in NYHA class IV, albeit ambulatory, he is currently not eligible for a defibrillator.
3. CRT–defibrillator (CRT-D) device. The patient is improving and with good medical therapy is likely to improve further. He has very poor ventricular function, and his conduction disease raises the possibility of a laminopathy, further increasing his risk level.
4. Another option
Response:
April 11, 2013
This patient has several worrisome clinical features, including advanced symptoms despite maximal tolerated therapy, the inability to titrate to target doses of heart-failure medications, pulmonary hypertension, and conduction-system disease. In light of these issues, it is not clear to me that he is “likely to improve further.” Ivabradine is not available in the U.S. but could be considered to augment his modest medical therapy without risking exacerbation of his atrioventricular (AV) block.
I do agree that device therapy is indicated (and guideline supported) in this situation; in fact, device therapy may enable initiation of beta-blockade, which the patient’s current AV block (but not his BP) does not permit. Notably, device therapy provides a “bridge” to advanced therapies, as the natural history of this patient is likely to be inexorable progression of heart failure. The worrisome 2:1 AV block with a baseline left bundle-branch block also requires dual-chamber pacing, preferably biventricular (e.g., with a cardiac resynchronization therapy–defibrillation device).
A Lyme titer should be checked if the patient’s history warrants it. There is little circumstantial evidence for sarcoid, despite the AV block. (Laminopathy, as noted, is a good thought as well and would be supported by a family history.)
Follow-Up:
April 18, 2013
We implanted a cardiac resynchronization therapy–pacemaker device with a high-voltage lead in the right ventricle. In the UK, the use of implanted cardioverter–defibrillators (ICDs) for a dilated cardiomyopathy is still much debated. NICE guidelines are expected to clarify the issue in 2014. We have referred the patient for genetic testing for a laminopathy and have tested him for Lyme serology (it is not something we usually overlook in the rural area where I practice).
When I examined the patient very recently, his clinical presentation was, perhaps surprisingly, much better. He walked up four flights of stairs to the cardiology clinic, although he was breathless at the top. He now takes ramipril 2.5 mg daily, and his blood pressure remains below 100 mm Hg. He is keen to go back to work (as a machine operator).
I will see him again in 2 months, when I will order a repeat echocardiogram to assess remodeling. He and I talked about the option of an upgrade to an ICD, but he is concerned about possible effects on his employment and about the (perhaps) increased risk for interactions between the ICD and the machines he operates at work.
March 26th, 2013
Controversial NIH Chelation Trial Published in JAMA
Larry Husten, PHD
Final results of the troubled NIH-sponsored Trial to Assess Chelation Therapy (TACT) testing chelation therapy for coronary disease have now been published in JAMA. Last November, when the preliminary results were presented at the American Heart Association meeting, the positive finding in favor of chelation therapy surprised many observers, though the investigators and senior AHA representatives expressed considerable caution about the proper interpretation of the results. Full publication of the main results should now allow for a more thorough consideration of the trial.
TACT was initially funded by the NIH more than a decade ago to test chelation therapy with EDTA, an alternative medicine therapy received by more than 100,000 people every year but with no evidence base for support. The highly controversial trial was temporarily suspended in 2008 in response to ethical concerns, but was then allowed to resume. The trial was also hampered by slow enrollment, eventually resulting in a downsizing of the trial population. To maintain the trial’s power to achieve a meaningful result, the follow-up time was increased. (Because of this change, and because the data and safety monitoring board reviewed the data multiple times over the course of the study, the threshold for statistical significance was lowered to 0.036.)
TACT was a double-blind study testing active or placebo infusions of chelation in 1,708 stable patients with a history of MI. The primary endpoint of the trial — the composite of death, MI, stroke, coronary revascularization, or hospitalization for angina — was significantly lowered in the chelation group:
- 26% in the chelation group versus 30% in the placebo group (HR 0.82, 0.69-0.99, p=0.035)
There were no significant differences in the individual components of the endpoint. Two subgroups — patients with diabetes and patients with anterior MI — appeared to benefit most from chelation therapy:
- Diabetes: HR 0.61, CI 0.45-0.83
- Anterior MI: HR 0.63, CI 0.47-0.86
The authors concluded that chelation therapy “modestly reduced the risk of adverse cardiovascular outcomes, many of which were revascularization procedures.” But, they cautioned against using the results as an endorsement of the clinical use of chelation therapy: “These results provide evidence to guide further research but are not sufficient to support the routine use of chelation therapy for treatment of patients who have had an MI.”
Although the TACT trial has been, and may well continue to be, the subject of intense controversy, so far the medical community has circled the wagons and been in substantial agreement about its practical implication. The AHA, the NHLBI, and two JAMA editorials (by the JAMA editors and Steve Nissen) have all expressed agreement with the authors that the results do not support the clinical use of chelation therapy. Writes Nissen: “the findings of TACT should not be used as a justification for increased use of this controversial therapy.”
The editorial by the JAMA editors is itself evidence of the extraordinary sensitivity of the TACT trial. The JAMA editors, in a highly unusual situation, discuss their detailed review of TACT and explain their decision to publish the trial. Although they acknowledge multiple limitations of the trial, they defend its value: “reports of rigorous investigations should not be censored because of preexisting ideological positions,” they write.
In his editorial, Steve Nissen agrees with the JAMA editors’ decision to publish the trial but issues a fierce indictment of the trial and its conduct. The TACT paper, Nissen writes, “represents a situation in which many important limitations in the design and execution of a clinical trial compromise the reliability of the study and render the results difficult to interpret. Unfortunately, the efforts of these investigators fell short of the minimum level of quality necessary to adequately answer the question they sought to investigate.”
Nissen questions the reliability of the trial since “more than 60% of patients were randomized at enrolling centers described as complementary and alternative medicine sites.” “Whether a high-quality RCT can be performed at such sites is questionable,” he writes. The major flaw in the trial is that 18% of patients were lost to followup, most of whom because of withdrawal of consent, which occurred significantly more often in placebo patients than in chelation patients (174 versus 115, HR 0.66, p=0.001).
Since in general withdrawals should occur more often in the active treatment group due to toxicity or adverse effects, Nissen speculates that “a logical explanation is unmasking of treatment assignments. If either the investigators or the patients knew who was receiving chelation, patients assigned to the placebo group would likely be influenced to withdraw or stop study treatment, particularly when some investigators were advocates for chelation therapy.” This “substantial nonretention of study participants is sufficient to compromise the validity of the study results.”
TACT investigator Daniel Mark provided CardioBrief with the following detailed response to Nissen’s criticism. (Nissen declined to respond to Mark.)
In his editorial, Dr. Nissen asserts that the “logical” explanation for the greater withdrawals in the placebo group is that patients were unblinded. He further implies that the CAM sites were more likely to be responsible for such unmasking.
His editorial is written from the perspective of someone who is absolutely sure that the trial results are wrong and his mission is to identify where the flaws originate.
Unfortunately, this perspective has blinded him to a more nuanced consideration of the extensive evidence presented in the paper and the appendices.
There is absolutely no indication in the data that placebo patients knew that they were not getting the active therapy. There is no indication in the data that CAM sites were unmasking their patients as Dr. Nissen implies. The AHJ 2012 TACT design paper describes the extensive lengths to which the TACT leadership went to ensure that unblinding of patients and investigators would not occur.
And most importantly, the differential loss of placebo patients would most likely introduce a conservative bias in our results. In other words, if these placebo patients had stayed in the trial and had events, the difference in favor of EDTA might have been even stronger than it was. Sensitivity analyses in the appendix (Table 8) show that the results are robust under a wide variety of reasonable assumptions about the outcomes of the withdrawals.
The idea that the CAM sites were somehow able to tip the results of TACT to favor the EDTA arm is at odds with the data in Figure 3 of the paper, which shows that the effect size for EDTA therapy was actually larger in the non-CAM sites (HR 0.72) than in the CAM sites (HR 0.89).
So basically Dr. Nissen has made assertions that are not empirically supported by anything in the data. The “logic” he sees is the logic of his own beliefs. And the most likely effect of the biases he asserts would actually strengthen not weaken the results of the study.
March 26th, 2013
Should the Use of IVC Filters be Filtered Until We Have More Data?
Behnood Bikdeli, M.D.
Preventing pulmonary embolism (PE) by interrupting the inferior vena cava (IVC), first introduced by Trousseau during the mid-1800s, has received growing attention lately with recent studies showing a remarkable increase in their use (e.g., Stein et al and Duszak et al). But what is the evidence base behind this mechanistically appealing approach? The largest randomized trial for the use of IVC filters was the PREPIC (Prevention du Risque d’Embolie Pulmonaire par Interruption Cave) trial. PREPIC enrolled 400 (of the anticipated 800) patients with proximal deep vein thrombosis (with or without PE), 94% of whom received anticoagulation for at least three months. Placement of IVC filters was associated with reduced risk of PE, but increased risk of deep vein thrombosis, with no mortality difference at 2-year or 8-year follow-up.
The available expert statements and guidelines, including those by the AHA and the ACCP, however, recommend IVC filters mostly for cases with contraindications to anticoagulation or those with recurrent PE despite receiving anticoagulation; two reasonable recommendations for which we lack data from high-quality, comparative effectiveness studies.
Lack of convincing evidence, costs and expertise considerations, as well as local culture effects may lead into variations for use of IVC filters in the spectrum of patients with venous thromboembolism (VTE). Using the administrative data from 263 hospitals in California, White and colleagues recently showed a remarkable variation in use of IVC filters for acute VTE hospitalization across hospitals, from 0% to 38.96% (interquartile range: 6.23%-18.14%). Even among geographically close hospitals, such variations were remarkable. Of note, the hospital effect persisted even after extensive adjustment for clinical factors and comorbidities.
Despite the potential benefits, placing filters is costly and is not risk-free, making it a challenging decision for patients, physicians, and society, and the lack of high-quality evidence hampers the selection of the best possible decisions. There is a real need for definitive trials to answer the questions about the utility of IVC filters for the existing indications, as stated recently. I have heard that a group of investigators are about to launch a large, multicentric randomized trial in that regard. Until then, perhaps anticoagulation should remain the cornerstone of VTE treatment. While use of IVC filters is most plausible in patients with contraindications for anticoagulation, we simply lack high-quality comparative effectiveness data to support this appealing option.
What are your reflections on this issue? Where do you see the future of IVC filters?
March 25th, 2013
Selections from Richard Lehman’s Literature Review: March 25th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint selections from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.
JAMA 20 Mar 2013 Vol 309
Effect of Aliskiren on Postdischarge Mortality and HF Readmissions Among Patients Hospitalized for HF (pg. 1125): Is aliskiren a good drug for heart failure? Despite the negative result of this Novartis-funded trial (ASTRONAUT), I think the answer is probably yes. First of all, let me remind you that aliskiren is a direct renin blocker. In other words, it acts right at the start of the renin-angiotensin- aldosterone cascade. But unfortunately for alis and her sister kirens, these renin blockers have come on the scene too late. We already have perfectly good RAAS inhibitors in the form of ACE inhibitors, ARBs, and aldosterone blockers, and between them they do all that it is possible to do via RAAS inhibition in heart failure: which, by the way, is not much, since typical NNTs lie over 30. Now imagine a world where renin blockers were first on the scene, and we selected patients for heart failure trials on the basis of BNP rather than ejection fraction; then this trial would probably have been a resounding success. Because the ASTRONAUT groups were not well matched: the patients put on aliskiren had a mean NT-BNP of 4239 pg/ml compared with 2718 pg/ml in the placebo group: in other words, they were experiencing considerably worse ventricular strain. Yet they still had better outcomes than the less ill controls, albeit not to the point of statistical significance. If you removed all the ACE inhibitors, ARBs, and the amazing amount of mineralocorticoid blockade (57%) from these patients, there would probably have been a very significant benefit in mortality and readmission from aliskiren. But life is unfair, and Novartis may just have to face the fact that Alice has come too late to lead them into Wonderland: though a trial in heart failure with preserved systolic ejection fraction, but without diabetes, might be interesting.
Long-term Mortality After Stroke Among Those Aged 18 to 50 Years (pg. 1136): Having a stroke when you are young (under 50) increases your risk of dying over the next 20 years by 3-4 times. Which is sad, but hardly unexpected.
NEJM 21 Mar 2013 Vol 368
Still No Closure on the Question of PFO Closure (pg. 1083): I love to read about medical progress, which makes me a sucker for giving innovative treatments the benefit of the doubt. About 15 years ago I was really intrigued to learn that quite a few ischaemic strokes were likely to be paradoxical—and that you could actually demonstrate shift of clot from the right to the left heart via a patent foramen ovale. In fact I was about a century late, because this mechanism had been proposed in the 1890s. But although in those days they were very good at performing autopsies, they didn’t have transoesophageal ultrasound to look for functional right-to-left shift. The excellent editorial “Still no Closure on the Question of PFO Closure” puts this into perspective: “In approximately 30% of young survivors of stroke, no clear cause is identified despite a thorough evaluation. Patent foramen ovale is found on transesophageal echocardiography in about half of these patients, as compared with approximately 25% of the general population. Clinicians, then, often assume that the patent foramen ovale was the cause of the stroke, although it may be incidental in some patients.”
Percutaneous Closure of PFO in Cryptogenic Embolism (pg. 1083): So there’s really no way to find out if PFO closure works better than standard medical therapy without doing a randomised trial, and even this won’t tell you whether any given individual will benefit. This first trial was designed 14 years ago to try out the Amplatzer PFO Occluder (St. Jude Medical) versus antiplatelet or anticoagulant treatment. After a mean patient follow-up of 4 years, the triallists conclude: “Closure of a patent foramen ovale for secondary prevention of cryptogenic embolism did not result in a significant reduction in the risk of recurrent embolic events or death as compared with medical therapy.” In fact they are quite harsh on themselves, because the device was observed to reduce strokes and TIAs by a third, but was inadequately powered to reach statistical significance.
PFO Closure vs. Medical Therapy after Cryptogenic Stroke (pg. 1092): And now, oddly enough, we get the results from another St Jude-funded trial of the same device in a similar but larger group of patients. Again, there were fewer events in the PFO closure group—this time fewer than half—but the authors seem reluctant to trumpet the fact. “In the primary intention-to-treat analysis, there was no significant benefit associated with closure of a patent foramen ovale in adults who had had a cryptogenic ischemic stroke. However, closure was superior to medical therapy alone in the prespecified per-protocol and as-treated analyses, with a low rate of associated risks.” This is all very admirable, but it makes you wonder what is going on. Is this the NEJM responding to criticism that it lets industry get away with too much sales pitching in its abstracts? Or is this industry itself indulging in what you might call “reverse marketing”—being so modest in its claims that people will rally to the defence of the product? Either way, I’m sure it won’t affect NEJM sales of reprints to St Jude.
Ann Intern Med 19 Mar 2013 Vol 158
Chlorthalidone vs. Hydrochlorothiazide for the Treatment of Hypertension in Older Adults (pg. 447): I always bridle when I see articles describing “diuretics” as a treatment for hypertension. Say thiazides if you mean thiazides. And also specify your thiazide: if in the UK, you probably mean bendroflumethiazide, in Canada you probably mean hydrochlorthiazide, and in the USA and other countries you might perhaps mean chlortalidone. Are they all the same? Irfan Dhalla and colleagues seek to find out by looking at the records of people started on chlortalidone at age 66 and over and comparing them with people started on hydrochlorthiazide. In up to five years of follow-up there was no difference in cardiovascular outcomes, but more hypokalaemia in the chlortalidone group. As for good old standard British BFZ, I suspect we just don’t know.
March 25th, 2013
Once Again FDA Rejects Oral Treprostinil for Pulmonary Arterial Hypertension
Larry Husten, PHD
For the second time the FDA has issued a complete response letter rejecting the new drug application (NDA) of oral treprostinil for the treatment of pulmonary arterial hypertension (PAH). The manufacturer of the drug, United Therapeutics, said in a press release that it planned to discuss the decision with the FDA.
“We remain confident that oral treprostinil will play an important role in treating PAH and we are committed to working collaboratively with the FDA to accomplish this goal in the most timely and appropriate manner,” said the company’s chairman and CEO.
Trepostinil is a prostacyclin vasodilator that is already approved for the treatment of PAH in an injectable form (Remodulin) and in an inhalable form (Tyvaso). The FDA initially rejected the NDA for the drug last October.
March 25th, 2013
Emerging Biomarkers: How Reliable Is the Evidence?
Larry Husten, PHD
Novel biomarkers are the subject of intense controversy, with a bewildering variety of factions and perspectives seeking to elevate or dismiss any of a large number of proposed new measures. Now a new examination of the literature published online in JAMA Internal Medicine suggests that the evidence base used to evaluate novel biomarkers may be seriously compromised by selective reporting bias.
John Ioannidis led a team of researchers who analyzed 56 meta-analyses of new candidate cardiovascular biomarkers. Of these, 49 had statistically significant results, but 9 studies were compromised by very large heterogeneity, 13 studies were compromised by small-study effects, and 29 studies had an excess of studies with statistically significant results. Only 13 studies had more than 1,000 cases, achieved statistical significance, and had none of the other deficiencies listed above. The meta-analyses that emerged unscathed examined the associations of glomerular filtration rate and albumin to creatinine ratio in general and high-risk populations with cardiovascular disease mortality and of non-high-density lipoprotein cholesterol, serum albumin, Chlamydia pneumoniae IgG, glycosylated hemoglobin, nonfasting insulin, apolipoprotein B/AI ratio, erythrocyte sedimentation rate, and lipoprotein-associated phospholipase mass or activity with coronary heart disease.
The authors summarized their finding as suggesting that “the effect of biomarkers is exaggerated because the largest studies — which one would expect to produce the most stable estimates — consistently showed smaller effects. In most meta-analyses, too many single studies had reported ‘positive’ results compared with what would be expected on the basis of the results of the largest studies. This suggests that small studies with ‘negative’ results remain unpublished or that their results are distorted during analysis and reporting to seem more prominent.”
In an invited commentary, Steve Nissen writes that evidence-based medicine has been put on a “golden pedestal” but publication basis “is a dark secret that corrupts nearly every aspect of our profession and undermines societal efforts to promote evidence-based medicine.” He cites carotid intima-medial thickness and apolipoprotein B as just two biomarkers in which “the magnitude of the association is probably much smaller than suggested by the definitive meta-analysis.”
Nissen urges investigators to register their studies with ClinicalTrials.Gov, but points out that the site does not support large data sets. “Therefore,” he argues, “society must consider funding the National Library of Medicine to create a public website where authors can post the detailed results of findings that they were unable to publish despite submitting to multiple journals. Finally, we must emphasize to colleagues and trainees that all studies contribute to scientific understanding. We have a moral obligation to our patients to make all research findings available to the broader scientific community.”
March 22nd, 2013
FDA Proposes Higher Regulatory Scrutiny for Automatic External Defibrillators
Larry Husten, PHD
Automated external defibrillators (AEDs) will have a more difficult time getting on the market if a new FDA proposal is finalized. The agency today proposed a new rule that will require AED manufacturers to submit pre-market approval (PMA) applications.
“Automated external defibrillators save lives,” said cardiologist William Maisel, deputy director of science and chief scientist at the FDA’s Center for Devices and Radiological Health, in an FDA press release. “However, the agency is concerned about the number of recalls and manufacturing problems that have been associated with these devices and we’re committed to working with manufacturers to address these issues.”
The FDA said that there have been “dozens” of AED recalls by manufacturers and that it had received approximately 45,000 adverse event reports between 2005 and 2012 relating to AED failures. FDA said that “the most common issues involve the design and manufacture of the devices and inadequate control of components purchased from other suppliers.”
The FDA announcement today is part of a broader FDA initiative to reclassify some medical devices that currently don’t require a PMA application. AED manufacturers would be required to submit clinical data demonstrating the safety and efficacy of the devices under the new rule. The FDA would also gain new authority to regulate and inspect the manufacturing process of AEDs.
If the new rule becomes final FDA said it would “exercise enforcement discretion” for a year and a half to give manufacturers time to file a PMA.
March 22nd, 2013
Europe and U.S. Diverge on Two New Drugs
Larry Husten, PHD
The U.S. FDA and Europe’s Committee for Medicinal Products for Human Use (CHMP) have taken opposite views of two important and controversial new cardiovascular drugs. Although earlier this month the FDA rejected — for the second time — an ACS indication for the oral anticoagulant rivaroxaban (Xarelto), CHMP announced today that it had adopted a positive opinion for the same indication. In contrast, although the FDA recently approved the new cholesterol-lowering agent mipomersen (Kynamro, Isis and Genzyme), CHMP, after reviewing its previous negative position, reaffirmed today that it would not recommend approval of the drug in Europe.
CHMP said it was recommending approval of a new, low dose of rivaroxaban for the following indication:
Xarelto, co-administered with acetylsalicylic acid (ASA) alone or with ASA plus clopidogrel or ticlopidine, is indicated for the prevention of atherothrombotic events in adult patients after an acute coronary syndrome (ACS) with elevated cardiac biomarkers.
The new indication would join the already-approved indications for higher doses of rivaroxaban for the prevention of venous thromboembolism (VTE) in patients undergoing elective hip or knee replacement surgery, for the treatment of (and prevention of recurrent) DVT and PE, and for stroke prevention in patients with atrial fibrillation. The new indication is based on results from the highly praised, but also much-criticized, ATLAS ACS 2-TIMI 51 trial.
Janssen recently announced the launch of a large expanded research program with rivaroxaban. The EXPLORER program will test new potential indications for rivaroxaban in heart failure, coronary artery disease, peripheral disease, and atrial fibrillation.
By contrast, despite the FDA’s recent approval of mipomersen, CHMP said that its earlier concerns about mipomersen remained unresolved. Some patients in Europe will be able to receive the drug, either because they are in clinical trials or through a compassionate use program. Here is the CHMP explanation for the mipomersen refusal:
What were the CHMP’s main concerns that led to the refusal?
In December 2012, the CHMP was concerned that a high proportion of patients stopped taking the medicine within two years, even in the restricted group of patients with homozygous familial hypercholesterolaemia, mainly due to side effects. This was considered an important limitation because Kynamro is intended for long-term treatment. The CHMP was also concerned by the potential long-term consequences of liver test results showing a build-up of fat in the liver and increased enzyme levels, and was not convinced that the company had proposed sufficient measures to prevent the risk of irreversible liver damage. Moreover, the Committee was concerned that more cardiovascular events (problems with the heart and blood vessels) were reported in patients taking Kynamro than in patients taking placebo. This prevented the CHMP from concluding that Kynamro’s intended cardiovascular benefit, in terms of reducing cholesterol levels, outweighed its potential cardiovascular risk. Therefore, at that point in time, the CHMP was of the opinion that the benefits of Kynamro did not outweigh its risks and recommended that it be refused marketing authorisation.
During the re-examination in March 2013, the CHMP’s concerns remained unresolved and were not fully addressed by measures proposed by the company. Therefore, the CHMP refusal was confirmed after re-examination.
NEJM Journal Watch — Recent Cardiology Articles- Diagnosing and Managing Kawasaki Disease
- Does TAVR Benefit Patients with Moderate Aortic Stenosis and Systolic Heart Failure?
- Reevaluating Genetic Associations in Hypertrophic Cardiomyopathy
- Does Use of Drug-Coated Devices Improve Outcomes in Chronic Limb-Threatening Ischemia?
- New Recommendations for Lipid Management in Patients with Acute Coronary Syndromes