November 3rd, 2012
Rivaroxaban Gains FDA Indications for Treating and Preventing DVT and PE
Larry Husten, PHD
The FDA has expanded the indication for rivaroxaban (Xarelto, Johnson & Johnson) to include the treatment of deep-vein thrombosis (DVT) and pulmonary embolism (PE) and to reduce the risk for recurrent DVT and PE.
The oral anticoagulant is already approved to reduce postsurgical risk for DVT and PE after hip- and knee-replacement surgery and to reduce the risk for stroke in people with atrial fibrillation. The new indication was granted under the FDA’s priority review program.
“Xarelto is the first oral anti-clotting drug approved to treat and reduce the recurrence of blood clots since the approval of warfarin nearly 60 years ago,” said Richard Pazdur, director of the FDA’s Office of Hematology and Oncology Products, in an FDA press release.
November 2nd, 2012
FDA Investigation Finds No Excess Bleeding Risk for Dabigatran
Larry Husten, PHD
In its latest assessment of a highly controversial issue, the FDA has found no indication that bleeding rates for dabigatran (Pradaxa, Boehringer-Ingelheim) are any higher than the bleeding rates for warfarin. The FDA investigation was in response to the large number of post-marketing reports of bleeding in people taking dabigatran. Click here to for the full FDA statement. Here is the first paragraph of the statement:
The U.S. Food and Drug Administration (FDA) has evaluated new information about the risk of serious bleeding associated with use of the anticoagulants (blood thinners) dabigatran (Pradaxa) and warfarin (Coumadin, Jantoven, and generics). Following the approval of Pradaxa, FDA received a large number of post-marketing reports of bleeding among Pradaxa users. As a result, FDA investigated the actual rates of gastrointestinal bleeding (occurring in the stomach and intestines) and intracranial hemorrhage (a type of bleeding in the brain) for new users of Pradaxa compared to new users of warfarin. This assessment was done using insurance claims and administrative data from FDA’s Mini-Sentinel pilot of the Sentinel Initiative. The results of this Mini-Sentinel assessment indicate that bleeding rates associated with new use of Pradaxa do not appear to be higher than bleeding rates associated with new use of warfarin, which is consistent with observations from the large clinical trial used to approve Pradaxa (the RE-LY trial).1 (see Data Summary). FDA is continuing to evaluate multiple sources of data in the ongoing safety review of this issue.
November 1st, 2012
DOJ Investigating Abiomed for Improper Marketing of Impella Circulatory Support System
Larry Husten, PHD
The U.S. Attorney’s Office is investigating Abiomed’s marketing and labeling of the Impella 2.5 circulatory support device, the company announced on Thursday.
Abiomed also said that it believed that the FDA would begin a review to possibly reclassify its Impella devices as Class III devices, which would require FDA clearance using the more stringent premarket approval (PMA) process instead of the current, less demanding 510(k) premarket notification process. Whether because of the DOJ investigation or the FDA announcement, the stock price of Abiomed dropped 25% with the news.
This is not the first time Abiomed has run into trouble with the FDA. In June 2011, Abiomed received a warning letter from the FDA about improper marketing of Impella for unapproved indications.
As previously reported here, in December 2010, the company issued a press release announcing — and spinning — the results of the PROTECT II trial comparing Impella to the intra-aortic balloon (IAB) in high-risk PCI patients. Although the trial was stopped early for futility, the press release downplayed the negative findings and instead emphasized positive trends and encouraging subgroup analyses. Last month, when the trial was finally published in Circulation, the company issued a much more restrained press release, perhaps a reflection of the company’s efforts to avoid further problems with the FDA.
October 31st, 2012
PCSK9 Inhibitor Enhances Cholesterol-Lowering Effect of Atorvastatin
Larry Husten, PHD
When added to low-dose atorvastatin, a much-discussed new monoclonal antibody to PCSK9 significantly lowers cholesterol more effectively than atorvastatin alone, according to a phase 2 study published in the New England Journal of Medicine. Earlier this year, in March, the findings of three phase 1 trials demonstrating the cholesterol-lowering effects of the drug in healthy volunteers and in people with familial or nonfamilial hypercholesterolemia were also published in NEJM.
In the new trial, Eli Roth and colleagues studied 92 patients with LDL levels of 100 mg/dL or higher despite taking atorvastatin 10 mg. Patients were randomized to 8 weeks of treatment with 80 mg atorvastatin plus the PCSK9 inhibitor SAR236553, 10 mg atorvastatin plus SAR236553, or 80 mg atorvastatin plus placebo. SAR236553 was administered as an injection once every 2 weeks.
PCSK9 inhibition significantly improved LDL reduction. LDL decreases from baseline were as follows:
- atorvastatin 80 mg + SAR236553: 73.2%
- atorvastatin 10 mg + SAR236553: 66.2%
- atorvastatin 80 mg + placebo: 17.3%
The investigators reported that 100% of patients in the two groups that received SAR236553 achieved target LDL levels of less than 100 mg/dL, compared with only 52% who received atorvastatin plus placebo.
The results, write the authors, suggest that SAR236553 “may benefit patients in whom LDL cholesterol has not been reduced to recommended levels, either because of an inadequate lipid-lowering response with high-dose statins alone or because of unacceptable side effects with high-dose statins.”
James Stein told CardioExchange:
“These results are very promising. What we need now are larger studies of SAR236553 with a longer duration, to determine its safety and tolerability. If it is safe and effectively lowers total and LDL cholesterol over long periods of time, it would be expected to reduce cardiovascular disease risk, but of course outcomes studies eventually will be needed to prove that.”
In July the companies developing SAR236553, Sanofi and Regeneron, announced a large phase 3 program for the drug, including an 18,000-patient outcomes trial. Next Monday, at the American Heart Association scientific sessions, the results of two more phase 2 studies of SAR236553 will be presented, as well as a study with another PCSK9 monoclonal antibody from Pfizer, RN316 (PF-04950615).
October 30th, 2012
Ablation for Treatment-Naive A-Fib Patients?
CardioExchange Editors, Staff
For this post, CardioExchange invited the authors of MANTRA-PAF study (Radiofrequency Ablation as Initial Therapy in Paroxysmal Atrial Fibrillation) to elucidate their findings.
The Trial
In this study, Danish researchers randomized 294 treatment-naive patients with paroxysmal atrial fibrillation to receive either radiofrequency catheter ablation or standard therapy with class IC or class III antiarrythmic drugs. At 2 years, the burden of a-fib was significantly lower in those receiving ablation than in those receiving antiarrythmic drug therapy (90th percentile, 9% vs. 18%; P=0.007). Three patients in the ablation group had cardiac tamponade related to the procedure. One patient in the ablation group died from a procedure-related stroke. About a third of the patients in the drug treatment group underwent supplementary ablation. An accompanying editorial can be found here.
How does your study change which patients with A-fib you consider for ablation in your own practice?
The MANTRA-PAF trial documents that antiarrhythmic drug treatment is pretty effective in a large proportion of patients with paroxysmal a-fib, most notably relatively young patients without much comorbidity. Therefore, we still advise the majority of our patients to try at least one antiarrhythmic drug as the initial therapy. However, the study also shows that radiofrequency ablation is at least as effective as drug therapy. Thus, we offer ablation as initial therapy as an option for younger, healthier patients. Further analysis of these data may help to clarify which patients are most suitable for initial therapy with ablation versus drug therapy.
Are these results generalizable given the evolving ablation techniques (your study focused on reduction of atrial electrograms versus the new method of focusing on electrical isolation of target regions) and differences in outcome that can be seen between centers and between experts?
We recognize that ablation techniques have changed significantly since this study was initiated. Outcomes after ablation may well be significantly better today using more effective procedural techniques and verifying complete isolation of the pulmonary veins. Despite the now dated methods used in the study we still found significantly improved quality of life and a trend towards less atrial fibrillation after two years with initial ablation. The findings therefore support that ablation could be considered as initial treatment.
The procedures in this study were performed by qualified electrophysiologists, but the centers involved had differing levels of experience in performing ablation. Whether better results can be achieved at larger centers and by electrophysiologists doing a higher number of procedures is unknown.
Ablation is associated with rare but clinically significant risks. How do you recommend discussing these risks with patients who have not yet experienced treatment failure on anti-arrythmic drugs?
We recommend that risks and advantages of each treatment — antiarrhythmic drug or radiofrequency ablation — be discussed openly with the patients before deciding between the two.
What do you anticipate the CABANA trial adding to our understanding here and how is that distinct from your findings?
The CABANA trial includes a larger number of patients, and more of the patients will have concomitant heart disease or other comorbidities. It is also being conducted with current ablation methods that may be superior to those used during our MANTRA-PAF trial. The CABANA trial hopefully will add to our knowledge of whether initial ablation improves harder clinical outcomes that the MANTRA-PAF trial powered to analyze. It will also increase our understanding whether initial ablation is beneficial in a wider population of patients. The MANTRA-PAF results should not be extrapolated to elderly patients who have significant concomitant heart disease.
October 30th, 2012
The Research Agrees: Smoking Is Really Bad for You
Larry Husten, PHD
Four new studies offer powerful evidence of the dangers of smoking and the health benefits of quitting or not being exposed to secondhand smoke.
Smoking in the U.K. — Between 1996 amd 2001, the Million Women Study started following more than one million women aged 50 to 65 years of age. In a report published in the Lancet, trial investigators, including renowned epidemiologist Richard Peto, found that 12-year mortality was significantly higher in women with a history of smoking compared with women who never smoked (rate ratio 2.76, CI 2.71-2.81). Smokers, the authors calculated, lose 10 years of life. The good news is that stopping smoking before the age of 40 reduces the excess mortality by 90%.
Smoking in Japan — The Life Span Study, published in BMJ, was started in 1950 and has followed more than 65,000 men and women in Hiroshima and Nagasaki, Japan. The results were consistent with the Million Women Study in the U.K.: the rate ratio for mortality was more than doubled for smokers compared with nonsmokers both for men (2.21, CI 1.97-2.48) and for women (2.61, CI 1.98-3.44). The investigators also reported that stopping smoking before age 35 eliminated almost all of the risk associated with smoking.
Smoke-free legislation meta-analysis — Smoking is not just a personal decision that has individual health effects. A new meta-analysis published in Circulation found that smoke-free legislation results in immediate reductions in hospital admissions or deaths for coronary events (RR 0.848, CI 0.816-0.881), other heart disease (RR 0.610, CI 0.440-0.847), cerebrovascular accidents (RR 0.840, CI 0.753-0.936), and respiratory disease (RR 0.760, CI 0.682-0.846). The authors, Crystal Tan and Stanton Glatz, also report that the biggest reductions in events were associated with the most stringent smoke-free laws.
Smoke-free legislation in Minnesota — Here’s one more study to lend support to the above meta-analysis. In a paper published in the Archives of Internal Medicine, Richard Hurt and colleagues analyzed data before and after the implementation of a smoke-free law in Olmsted County, Minnesota. They found a significant, 33% reduction in the incidence of MI (from 150.8 to 100.7 per 100,000 people) and a trend in the reduction of sudden cardiac death by 17% (from 109.1 to 92.0 per 100,000 people). In an accompanying commentary, Sara Kalkhoran and Pamela Ling write that as “the evidence base documenting the positive health outcomes” of smoke-free legislation grows, “we should prioritize the enforcement of smoke-free policies, eliminating loopholes in existing policies as well as encouraging expansion of smoke-free policies to include multiunit housing, motor vehicles, casinos, and outdoor locations. Exposure to SHS [secondhand smoke] should not be a condition of employment, and all workers, including those of lower income and those in the service and hospitality industries, should have equal protection from SHS exposure.”
October 29th, 2012
L.A. Confidential: Preview of AHA Scientific Sessions 2012
Larry Husten, PHD
The American Heart Association scientific sessions, which start next weekend in Los Angeles, will be bigger than ever, with 853 separate sessions — 111 more than last year — and 27 late-breaking clinical trials — 6 more than last year. Elliott Antman, chair of the scientific sessions program committee, provided a preview of some of the highlights of this year’s late-breakers.
Two of the most interesting trials will be presented at the first late-breaking session on Sunday afternoon. Perhaps the most eagerly anticipated trial of the entire meeting is the NIH’s FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial, which will be presented by Valentin Fuster. The trial will evaluate the relative worth of CABG and PCI in patients with diabetes.
Immediately preceding FREEDOM on the program is another NIH-sponsored trial, TACT (Trial to Assess Chelation Therapy), testing the potential value of chelation therapy, a controversial alternative therapy. “We ought to take our hat off to the NIH for doing this trial, since industry was never going to fund this trial,” said Antman. Although most physicians have a skeptical view of chelation therapy, patients often express interest in it. TACT will finally provide real data about this approach.
Directly following the first session, the second late-breaking session will focus on economic and quality-of-life studies, including a quality-of-life TACT substudy and a cost-effectiveness FREEDOM substudy.
On Monday, two Italian trials will look at the role of omega-3 fatty acids for recurrent atrial fibrillation (FORWARD) and for the prevention of postoperative AF (OPERA). The Physicians’ Health Study II will examine the effect of multivitamins for cardiovascular endpoints. The UMPIRE study will test the feasibility of giving the polypill in 2000 patients for a period of 15 months.
The second late-breaker session on Monday will present the results of three phase 2 trials of PCSK9 inhibitors. The session will include a panel discussion and an overview of this fast-moving and much-anticipated new therapeutic area. Also at this session will be the results of the dal-OUTCOMES phase 3 trial of the CETP inhibitor dalceptrapib. Although the drug is no longer in clinical development, many observers are eager to see if the results will have implications for other CETP inhibitors.
A Tuesday morning session will be entirely devoted to stem cell regeneration trials. Antman said this was a “promising avenue of investigation” but acknowledged that we still don’t know if this whole approach might fail.
Later on Tuesday, Arthur Moss will present the results of the MADIT Randomized Trial to Reduce Inappropriate Therapy, comparing customized programming to standard programming for the reduction of ICD-induced inappropriate shocks. At the same session the results of RELAX-AHF will be presented, testing the novel agent relaxin in acute heart failure. Finally, the CARRESS-HF study will offer insight into the role of ultrafiltration in patients with acute decompensated heart failure and worsening renal function.
October 25th, 2012
TCT: Two PFO Closure Trials Miss Primary Endpoints
Larry Husten, PHD
Two trials presented today at the TCT meeting in Miami testing the benefits of PFO closure in patients with cryptogenic stroke have failed to convincingly demonstrate any significant benefit for the controversial procedure.
The RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) trial randomized 980 patients to PFO closure with the Amplatzer PFO Occluder device or medical therapy. According to lead investigator John Carroll, the rate of recurrent stroke was low in both arms of the trial: 1.6% in the closure group and 3% in the medical-therapy group.
This difference between the groups did not achieve significance in the intention-to-treat (ITT) analyses:
- ITT raw count: 46.6% risk reduction (p=0.157)
- ITT Kaplan Meier: 50.8% risk reduction (p=0.083)
However, statistical significance was achieved in the per-protocol and as-treated analyses:
- Per-protocol Kaplan Meier: 63.4% risk reduction (p=0.032)
- As-treated Kaplan Meier: 72.7% (p=0.007)
The investigators reported that there were very few device- or procedure-related complications. There was a similar amount of serious adverse events in the two groups (23% with the device and 21.6% with medical therapy).
The investigators concluded that “for carefully selected patients with history of cryptogenic stroke and PFO, the RESPECT Trial provides evidence of benefit in stroke risk reduction from closure with the AMPLATZER PFO Occluder over medical management alone.”
“The optimal secondary prevention strategy following a cryptogenic ischemic stroke in patients who are found to have a PFO has been unknown,” said Carroll, in a TCT press release. “This need to know is particularly intense for young stroke patients who have no or minimal traditional risk factors for ischemic stroke, yet face a risk of recurrent stroke for many decades. RESPECT makes progress in both removing the ‘unknown’ or cryptogenic cause of some strokes and providing high quality data from a large, long-term randomized trial.”
A similar pattern occurred in the smaller PC (Percutaneous Closure of Patent Foramen Ovale versus Medical Treatment in Patients with Cryptogenic Embolism) Trial, in which 414 patients were randomized to PFO closure or medical therapy. The primary endpoint, the composite of death, nonfatal stroke, TIA, and peripheral embolism, occurred in 3.4% of the PFO closure group compared to 5.2% of the control group (relative risk reduction: 37%, p=0.34). The incidence of stroke was 0.5% versus 2.4% (relative risk reduction 80%, p=0.14).
Study investigator Stephan Windecker said that because of a lower-than-expected rate of events after a mean follow-up of 4 years, the trial ended up being underpowered to detect meaningful differences. He concluded that “the observed difference in stroke … may be clinically relevant if confirmed in further studies.”
“We need a definitive trial of this approach if it’s going to be broadly used for PFO closure,” said Deepak Bhatt, in an interview with Bloomberg News. “Anecdotally, there are patients who seem to benefit. It’s unfortunate that none of the trials have been able to absolutely nail that down.”
Earning Respect?
As reported here over the summer, during an earnings call St. Jude CEO Dan Starks told investors that the results of RESPECT were “favorable.” As I wrote then, the danger of this sort of statement is that the company’s initial evaluation of the results may clash with the eventual judgement of the medical community. Companies are simply in no position to be objective about their own products or trials. Caution in this case was particularly warranted because of the sorry history of negative trials in this area, as highlighted by the failed MIST trial of the STARFlex Septal Closure System. The results of the RESPECT and PC Trials demonstrate that the communication of medical information should not be left in the hands of industry. (St. Jude stock dropped 3.5% on the announcement of the trial results.)
October 24th, 2012
Atrial Fibrillation: Radiofrequency Catheter Ablation and Antiarrhythmic Drug Therapy Compared
Larry Husten, PHD
A trial comparing radiofrequency catheter ablation (RFA) to antiarrhythmic drug therapy (AAD) as initial therapy for paroxysmal atrial fibrillation (AF) found no difference in the overall burden of AF between the groups. But the trial also turned up evidence supporting the use of RFA as an initial treatment strategy in some patients.
In a paper published in the New England Journal of Medicine, European investigators report on 294 patients with paroxysmal AF with no previous use of AADs who were randomized in the MANTRA-PAF (Medical Antiarrhythmic Treatment or Radiofrequency Ablation in Paroxysmal Atrial Fibrillation) trial. Patients — age 70 years and younger and with no other major heart disease — were healthier than the general AF population.
The investigators found no significant differences in the cumulative burden of AF or the burden at 3, 6, 12, or 18 months. However, at 2 years, the AF burden was significantly reduced in the RFA group compared with the AAD group (90th percentile of AF burden: 9% vs. 18%, p=0.007). In addition, the percentage of patients with no AF and no symptomatic AF was higher in the RFA group than in the AAD group (85% vs. 71%, p=0.004; 93% vs. 84%, p=0.01, respectively). In the RFA group, there were three cases of cardiac tamponade in addition to one death after a procedure-related stroke. In the AAD group, 36% of the patients received supplementary RFA.
The overall results, write the authors, “support the current guidelines recommending antiarrhythmic drugs as first-line treatment in most patients with paroxysmal atrial fibrillation.” However, the positive findings for RFA, as well as the high number of crossovers from AAD to RFA, suggest that “a substantial minority of patients” treated with AAD “may eventually require ablation for adequate rhythm control.”
In an accompanying editorial, William Stevenson and Christine Albert mention the “substantial procedural risks” associated with RFA and warn that the results should not be extrapolated to different patient populations, since the MANTRA-PAF population was younger and healthier than the general AF population. They express hope that the much larger CABANA (Catheter Ablation versus Anti-arrhythmic Drug Therapy for Atrial Fibrillation) trial will provide more definitive evidence about RFA. RFA, they conclude, is “a reasonable option for patients with symptomatic paroxysmal atrial fibrillation before therapy with an antiarrhythmic drug.”
