This post is authored by Michael Scherlag, MD, FACC, governor of the Oklahoma chapter of the ACC.

As a pious devotee to evidence-based therapies, forgive me for reciting the (unproven in large trials) litany of diseases which have been benefited from renal denervation (RDN): hypertension, congestive heart failure, diabetes, sleep apnea, ventricular tachycardia, atrial fibrillation, PVCs, SVT, rapid ventricular response with atrial fibrillation, diastolic dysfunction, anxiety, depression, etc. Whenever it is shown to regrow hair, you can count me in. However, it is quite clear that resistant hypertension is dramatically reduced following RDN.

The procedure is easy to perform and assuming the Symplicity HTN 3 trial is positive, and assuming that the U.S. Food and Drug Administration approves it, and assuming that Centers for Medicare & Medicaid Services will reimburse it...our patients will no longer be subjected to drugs that are unproven/difficult to take. Irrational exuberance aside, as with any new therapy, it must be carefully evaluated, tested, analyzed and distributed in a standardized fashion. The ACC is in the best position to develop a registry to ensure that appropriate patients are being treated and these patients are followed for side effects which may in some cases be beneficial and hopefully not detrimental.

The science sounds pretty simple. An electrode catheter is placed against the wall of the artery and radio frequency ablation heats the nerves leading to their inactivation. In essence, disconnecting the sympathetic afferents/efferents of the kidneys from the brain thereby decreasing blood pressure. This would be simple, but it is also probably incomplete. There is still a lot to learn about the basic science. The ACC will encourage the dissemination of this science as it is uncovered.

Indulge me with some predictions for RDN. If my understanding of the physiology is correct, this should be effective for inappropriate sinus tachycardia, possibly neurologic movement disorders, or even Takotsuboʼs cardiomyopathy. Could RDN or an offshoot of this procedure supplant a significant number of implantable cardioverter-defibrillators? Will this be the first time a new technology actually lowered the cost of health care? Could reflex sympathetic dystrophy be treated with denervation of blood vessels to the affected limb? With this potential, one thing is certain: it is an exciting time to be a cardiologist.

Check out a recent article in CardioSource Interventional News: “Resistance is Futile: Renal Denervation Takes on Hypertension.”

This post was authored by James Fasules, MD, FACC, senior vice president of Advocacy for the ACC.

Just when you thought you’d learned enough healthcare acronyms to understand what we should care about as cardiologists, they add another one. This time, it’s the UFAs – the User Fee Acts, the quick way insiders refer to the Prescription Drug User Fee Act (PDUFA), the Medical Device User Fee Act (MDUFA) and the new generic drug and biologic user fee programs. Collectively, these programs help to fund the congressionally-mandated mission of the Food and Drug Administration, which is necessary given the dichotomy between what is expected of the FDA and what Congress appropriates for the FDA to achieve those expectations. The first of the programs, PDUFA, came out of the HIV-AIDS crisis when it became clear that the FDA did not have the necessary resources to review new drug applications quickly enough. Industry pays certain fees to have their applications reviewed. In exchange, the FDA commits to reviewing and coming to decisions (approval or otherwise) within certain timeframes.

The programs, created by Congress, sunset every five years, and it is up to Congress to decide whether to reauthorize the program. Thus, without Congressional action, PDUFA and MDUFA are set to expire on Sept. 30. To put it in perspective, funding from the PDUFA program is so important to the Agency today that approximately 2,000 staff reviewers will lose their jobs in the event that PDUFA is not reauthorized and the application review process will come to a grinding halt. Because of differences between the two programs and the two industries, the expiration of MDUFA would lead to the loss of between 200 and 300 jobs for device reviewers.

So why should cardiologists care? After all, if it’s just about approvals for devices and drugs, shouldn’t that be industry’s problem?  Well, if you think the FDA is slow at reviewing applications now, imagine how slowing things would move without all of those individuals reviewing the applications. New devices and pharmaceuticals would take even longer to get to market and even fewer patients would have access to them. Just think about how much further behind Europe we would be. It’s not just about TAVR; it’s about all of the new interventions that have been developed in recent years and have helped to reduce mortality resulting from cardiovascular disease.

Over the last two years, ACC’s Advocacy team has been meeting with members of Congress and their staff on these issues, as well as agency officials, industry representatives, consumer groups and public health advocates. Additionally, the ACC is working with a number of physician organizations to promote the passage of the UFAs, as well as legislation pertaining to related issues.

Recently, both the House and Senate overwhelmingly passed their respective versions of bills reauthorizing the UFAs.  Over the next month, Committee staff from both chambers will work together to iron out differences between both House and Senate bills before voting on final legislation and sending to the president for his signature.  It’s an exciting time to be an UFA!

The prestigious Institute of Medicine (IOM) earlier this month opined concerned that most medical devices are cleared for sale without sufficient evidence that they are safe and effective -- even though we tend to delay approvals of devices far longer than the EU, Canada and most of the developed world. IOM’s assessment should give everyone pause -- particularly because they declared the current regulatory approach (related to the FDA 510K approval process) to be so messed up that we should scrap it and start over. FDA reacted immediately that they disagreed, stating they would instead work to fix the problems acknowledged in the 510K regulatory system.

The IOM committee found no major new horror stories related to existing devices on the market, but worried that FDA and the public have no good way to determine where risk may exist because there is virtually no good clinical data to rely on. Hello. The NCDR has the clinical data they seek; and if we could get the feds to offer incentives to help us diffuse the PINNACLE Registry across more outpatient practices, we could track post-approval performance and look for even low-signal adverse events incredibly effectively!

The IOM committee commented specifically on what they termed "highest-risk" CV devices, such as implantable defibrillators and replacement heart valves. They noted that clinical trials with relatively few enrolled patients are used to demonstrate safety and effectiveness of such devices, deeming that they afford only a “moderate risk,” based on having the manufacturer show that they are “substantially equivalent” to devices previously cleared. The added concern is that those devices in turn may have been cleared because they were “substantially equivalent” to earlier devices that may no longer be in use -- a ‘house of cards’ process.

IOM deserves credit for spotlighting the issues. But, not only the FDA objected to IOM’s recommendations: the device industry, already frustrated with the cumbersomeness of the 35-year old 510K process, are yet even more worried about and opposed to completely scrapping the process. They want to see it streamlined instead. What we need to do is show FDA, IOM and industry what the broad use of registries could do to carefully track ALL patients who are device recipients. That’s what needs to happen! Upcoming FDA hearings on the IOM recommendations and the future of the 510K process will give us an opportunity to promote this potential of using our registries to provide more rigorous and effective surveillance of CV devices after they are on the market.

Pediatric devices get a lot less attention than is deserved. On Thursday, the FDA Circulatory System Devices Panel considered a request for a humanitarian device exemption of Berlin Heart, Inc. for its EXCOR Pediatric Ventricular Assist Device (VAD). While the literature documents potential risks to the implantation of VADs in the pediatric population, it also indicates opportunities to extend the time limits of existing therapy.

The ACC submitted comments in advance of the meeting, which note the importance of device manufacturers venturing into the field of pediatric devices because of the limited number of treatment options for pediatric cardiology patients in need of a bridge to transplant.  The ACC also attended the meeting.

The panel voted unanimously to in favor of all three questions posed:

1.       “Is there reasonable assurance that [it] is safe for use …?”

2.       “Is there reasonable assurance that [it] provides probable benefit …?”

3.      “Do the benefits … outweigh the risks …?”

The panel’s recommendation of a humanitarian device exemption for the EXCOR device is a breakthrough for pediatric cardiology. The device is really the only one small enough to use in infants and small children. The FDA still must adopt the panel’s recommendations, but we are pleased with the outcome and will continue to work with FDA to support these efforts.

With 2010 quickly coming to a close, I'd like to end the year by highlighting the range of topics we've covered on the ACC in Touch Blog. Below are the top 10 most popular blog posts of 2010.

10. Reform-O-Rama: In March I outline the chronology of the health reform law by year. 

9. SHOCKING! Use of Medical Services Dropping: I discuss how use of medical services among U.S. residents appears to be dropping during this ongoing recession. 

8. An Opportunity for ACC Leadership: Blog Co-author and ACC President Ralph Brindis, MD, FACC, discusses the ongoing allegations of stent overuse in Maryland and the opportunity for professional associations like the ACC to lead. 

7. Another Setback for Triple Therapy for ACS: CardioSource Science and Quality Editor-in-Chief Chris Cannon, MD, FACC, discusses the discontinuation of the Phase 3 APPRAISE-2 clinical trial in ACS patients treated with apixaban.

6. Is a New Study on ARBs and Cancer Risk Cause for Alarm?: Jeffrey Anderson, chair-elect of the ACC/American Heart Association Task Force on Practice Guidelines and Vice Chair of the 2010 UA/NSTEMI Focused Update, talks about a July article in Lancet Oncology on the cardiovascular effects of ARBS. 

5. New ACCF/AHA Clinical Alert Addresses Clopidogrel Warning: Brindis discusses the ACCF/AHA clinical alert that was released in June on the clopidogrel black box warning. 

4. The Patient with a Left Ventricular Assist Device: Past ACC President Fred Bove, MD, MACC, discusses former U.S. VP Dick Cheney's decision to have an LVAD implanted. 

3. Does CV Imaging Increase Cancer Risk?: Brindis discusses a study that came out in JACC in July finding that cardiac imaging procedures increased risk of radiation exposure and effective doses for those in the study. 

2. Dabigatran: Good news (and Odd News from FDA): Cannon discusses the approval of dabigatran and hypothesizes why the specific dosages were chosen to be approved. 

And for our most popular blog post of the year ... [drum roll, please] ...

1. Do Interventionalists Need to PARTNER with the FDA on TAVI?: Brindis sums up the findings of the PARTNER trial, presented at TCT 2010, and its implications for the TAVI procedure.

Tomorrow I leave for the holiday break. With the ACC closed until Jan. 3, the blog will be dark during this period. Here's wishing you and yours a wonderful holiday season! We'll see you in 2011!

I had the distinct honor of being named the Disruptive Women in Health Care’s November “Man of the Month.” The blog interviewed me on my thoughts on innovation. Here are some highlights:

Q: Can you elaborate on the relationship between innovation and patient safety?

Today’s regulatory agencies in the US have become more conservative than in the EU, UK, and elsewhere in the world....  From the point of view of CMS and the federal government, the focus is so fixed on cost containment that the agencies don’t think about how to jump beyond the problem of rising costs by reducing the need for outdated therapies and diagnostic devices and replacing them with better ones that essentially reduce morbidity and decrease overall costs.... 

Q: What are some promising innovations in the field of cardiology?

Promising innovations include the TAVI percutaneous valve replacements as well as new devices that provide ventricular assistance and support, and new short-term uses for ventricular assist devices.  Cardiovascular genetics and cardiovascular cell therapies are also an expanding frontier.... 

Q: It seems innovation is disruptive; is the disruption it causes positive or negative in your opinion?

The disruption of innovators can be both positive and negative. Anytime there is rapid progress there is the risk that valuable elements of the present can be left behind.  Disruptive innovators challenge the status quo, which is critically important.  The US could be headed towards mediocrity if we choose to drive into the future with our eyes on the review mirror. We need to embrace change and seek a better future through innovation, while making sure we retain what works in the past and present of health care as we speed into the future.

There’s a lot more than is featured here, so make sure to read the full post over at the Disruptive Women in Health Care blog.

The ACC has secured representation at a somewhat historic meeting of the regulatory pharma-device agencies of the EU, UK (NICE), and US (FDA) in France on Jan 27-28, 2011. Mitch Krucoff, MD, FACC, of Duke, and Doug Weaver, MD, MACC, of Henry Ford, are our representatives. The idea is to collaborate on these efforts and speed up approvals and innovation of new cardiovascular technological advancements. In addition, its goals are to establish:

• General principles of clinical efficacy and patient safety for the use of diagnostic and therapeutic devices in cardiovascular medicine
  
  
• Recommendations for the clinical evidence (criteria) and systems that should be required by regulatory authorities before granting approval to new devices in cardiovascular medicine
  
  
• Recommendations for the monitoring of the performance of medical devices after they have been granted regulatory approval

A meeting with such an esteemed panel of representatives from these major agencies has never occurred before. Lessons learned from this conference with our European colleagues should be very helpful for the FDA and the U.S. cardiovascular community to become more forward-thinking in the diffusion of innovative CV technology while at the same time not relinquishing our well-known high standards for safety and efficacy evaluations of such. With Dr. Krucoff’s expertise with his leading role in FDA’s Critical Path Initiative and Dr. Weaver’s role as past president of the ACC and chair of the CathPCI NCDR steering committee, we indeed are well represented.

This post is authored by Christopher P. Cannon, MD, FACC, editor-in-chief of the Science and Quality section of CardioSource.org and an associate physician in the Cardiovascular Division at Brigham and Women's Hospital in Boston. He also is an associate professor of medicine at Harvard Medical School and a senior investigator of the Thrombolysis in Myocardial Infarction (TIMI) Study Group.

********************

For the first time in over 50 years – we have a new oral anticoagulant to use in place of warfarin!  This past week, the FDA approved the oral thrombin inhibitor dabigatran (Pradaxa) for the prevention of stroke or systemic embolism. The approval was based on the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, which found that dabigatran, an agent that does not require monitoring of the INR, was as safe and effective, and at the 150-mg twice daily dose, actually superior to warfarin.

Although few people were surprised by the approval of the drug, what was surprising was that only one of the two doses tested in the RE-LY are the doses that the FDA approved. The RE-LY trial tested the effectiveness of 110- and 150-mg twice daily doses. However, the FDA approved only the 150-mg dose (with 75 mg pills also available) – but not the 110 mg dose.

I queried the FDA, and they wrote back to me saying they would soon post an explanation of their rationale. They did explain the 75-mg dose (which wasn’t included in the RE-LY trial) as wanting a treatment option for patient with severe kidney impairment.

SO – what about the 110-mg b.i.d. dose? This dose was seen to be as effective as warfarin. The topline result from RE-LY found that dabigatran 110-mg vs. warfarin had a relative risk of 0.91 and 95% confidence interval [CI] of 0.74 to 1.11 (p<0.001) for noninferiority. So the trial has a pre-specified endpoint and analysis plan, and meets it with p<0.001, and yet FDA doesn’t approve it? I honestly don’t understand. The key is that there is a lower rate of major bleeding: 3.36% per year for warfarin and 2.71% with 110-mg of dabigatran (p = 0.003) and a significantly lower rate of intracranial hemorrhage! So, we have a drug regimen that is equivalent to our current treatment – but safer, and doesn’t require monitoring. With the FDA’s key focus on safety, how could they not approve this safer dose of the drug?

Thoughts on Why
For now we don’t know why. The agency could say that the 150-mg dose is better, so there is no need to approve a dose that is not as efficacious, but I would counter that is true for a lot of medications. Atorvastatin has an 80-mg dose that is proven to be better than 10-mg, but all doses are still on the market!

Some have said that because it was an open-label trial (actually partially blinded to the dabagatran dose) that this makes it harder to be 100% sure that there was not bias in assessing bleeding. But that really doesn’t hold either since the dose of dabigatran was blinded and, thus, neither the physicians nor patient knew which dabigatran dose they were getting and yet the FDA approved the higher dose. We will learn more soon, but I hope that this dose can continue to be discussed and ultimately approved.

The reason is: I think about all the patients I have treated in the past month with AFib – they are all very old, and most have risks for bleeding. For example, I admitted a patient recently for AFib and bradycardia. He is over 90, has trouble walking and falls often. He has been treated with warfarin, but the team admitting him was fearful that he might fall and get an intracranial hemorrhage. Wouldn’t it be nice to have a safer dose for this patient? I could name many other patients just like him – probably half of my Afib patients have stories like this where having a safer alternative to warfarin would be the optimal choice for therapy.

FDA apparently will soon offer some insight, but I hope that the 110-mg dose will continue to be discussed. It is available in Europe – and one physician from Turkey spoke to me yesterday at the Cardiometabolic Health Congress, where he said has over 100 patients on the 110-mg dose – and he has been very happy with their clinical course. I just hope that all the trial nit-picking can end and people look at the big picture and see this new treatment option for what it is worth – a major new advance in treating patients with AFib.

Why do you think the FDA did not approve (at least yet... people know I am ever the optimist) the 110-mg dose?

Arguably the hottest trial at last week’s Transcatheter Cardiovascular Therapeutics (TCT) conference was PARTNER. The PARTNER trial compared outcomes between standard therapy for patients with inoperable severe aortic stenosis and transcatheter aortic valve implantation (TAVI). TAVI is a new procedure where a bioprosthetic aortic valve is inserted either femorally or transapically by catheter and then implanted within the native aortic value. Previous to the release of PARTNER, the assessment of efficacy and safety of TAVI was confined to registries and various modest-sized Phase I trials.

PARTNER is a landmark trial in the management of patients with severe AS. Median survival time for patients receiving standard treatment is two years. TAVI resulted in 45% reduction in all-cause mortality and 61% reduction in cardiovascular mortality at 1 year in high-risk AS patients compared with standard therapy.  Further support of TAVI was that echocardiographic criteria such as aortic valve area and mean aortic valve gradients all improved as did symptom criteria such as the patients’ NYHA class.

Important cautions were noted in PARTNER: although the procedure can reduce mortality, there was a significantly higher risk of major vascular complications and major bleeding, and a trend towards a higher risk of major stroke in the TAVI arm.

Thus, while the overall results are very exciting, the high complication rate should temper overenthusiastic tendencies toward the aggressive use of TAVI. The results also should encourage the development and application of adjunctive intravascular techniques to diminish the stroke risk and, clinically, employ better case selection for either the femoral or transapical approach to minimize the vascular complications.

Thoughts
Although the findings of the study itself are clinically important, the regulatory background in which TAVI finds itself deserves special comment. TAVI is not yet approved as a treatment option in the U.S., although it is extensively used in Europe and other areas of the world.

This approval conundrum brings up two thoughts to mind:

1. TAVI already is highly in use in Europe. A TAVI registry in Great Britain for example already has over 1,200 patients enrolled. Is this an indication that the U.S. has lost its once-felt leadership in innovation and technology? The U.S. health care system, for all its flaws, has been considered the leading innovator in cardiovascular disease due to our highly skilled and visionary cardiovascular specialists working collaboratively with our industry partners.  Does this imply that our colleagues at the FDA should pursue additional avenues to foster innovation and assess safety and efficacy of new technology?  Are there ways the FDA could decrease the evaluation time necessary prior to the release of new technology into the marketplace if we had better post-market device surveillance routinely put into place?
   
   
2. Will the PARTNER trial alone be enough to earn FDA approval? And if (or as most of us feel when) approved, what can the FDA and  professional societies such as the ACC and SCAI do to help ensure patient safety with the diffusion of this new technology into the community? Clearly, interventionalists who perform TAVI will need special training, and the FDA likely will need to set out criteria for who can perform TAVI to ensure competence in this area. The ACC through its Interventional Council and competency and training documents -- along with our partners at SCAI and industry itself -- will all play an important role in ensuring patient safety as TAVI use is approved.
   
   FDA also will clearly need to monitor adverse outcomes and communicate how these adverse outcomes can be minimized.  Creating a TAVI registry within our NCDR suite could help implement the rigorous post-market surveillance desired as well as provide rich clinical information that could advise clinicians, the FDA, and payers for better patient selection for TAVI use. Participation in this registry might have additional appeal to interventionalists if it means they can have earlier access to TAVI’s innovative technology. The PARTNER trial well demonstrates the partnerships needed between industry, the FDA, professional societies and payers to be able to provide our patients with practice innovations in a safe and effective manner and in a timely fashion.

What are your thoughts on the trial and its implications? You can also comment on the CardioSource Trial Summary.

Big news for the last couple of weeks has been FDA’s proposed withdrawal of orthostatic hypotension drug midodrine hydrochloride from the market because its manufacturer didn’t complete post-approval studies verifying the clinical benefit (rather than surrogate end points) of the drug. The drug was approved in 1996 under an accelerated approval process and its manufacturer had agreed to conduct these studies contingent on approval. The company said it had already determined it would remove the drug from the market at the end of next month and had notified the FDA of that decision last year.

The drug, after it’s removed from the market, will be available through an expanded access program. On a case-by-case basis, expanded-access programs allow the use of a drug outside of a clinical trial to treat patients with a serious or immediately life-threatening disease or a condition that has no comparable or satisfactory alternative treatment options. Only about 100,000 use the drug.

The decision to propose to remove the drug from the market for failure to complete post-market studies is a new move for the FDA. The Government Accountability Office last year criticized the FDA for its hesitancy to use its withdrawal authority.

The ACC this week put out 2003 ACC/AHA/ESC Guideline for the Management of Patients With Supraventricular Arrhythmias, page 18), which remains appropriate as long as the drug is available. Should the drug become unavailable, an update will be posted and communicated expediently. The ACC will closely monitor the FDA proceedings and offer updated information as it becomes available.

This is really something to pass out about.