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A federal appeals court stays a ban on U.S. sales of Medtronic’s CoreValve replacement heart valve “pending further notice” in a patent infringement battle with Edwards Lifesciences and its Sapien transcatheter aortic valve implant.
A federal appeals court today put a hold on the impending ban on U.S. sales of Medtronic‘s (NYSE:MDT) CoreValve replacement heart valve “pending further notice,” as Medtronic’s patent infringement war with rival Edwards Lifesciences (NYSE:EW) and its competing Sapien valve grinds on.
Earlier this month Judge Gregory Sleet of the U.S. District Court for Delaware granted a preliminary injunction to Edwards, limiting U.S. sales of the CoreValve transcatheter aortic heart implant to patients deemed unsuitable for Edwards’ rival Sapien device.
Medtronic promptly appealed the ban, slated to begin April 23, to the U.S. Court of Appeals for the Federal Circuit, drawing a rebuke from Sleet.
But the appeals court today granted Medtronic’s bid to stay the injunction indefinitely, with 2 of the Federal Circuit’s 3 judges agreeing to hold the sales ban on CoreValve, according to court documents.
“The district court’s injunction is stayed pending further notice by this court,” according to the documents.
But Federal Circuit Judge Pauline Newman dissented, citing a deal between Medtronic and Edwards that would have allowed limited CoreValve sales to patients deemed unsuitable to receive the Sapien device.
“I would deny the motion to stay subject to the terms of the recent agreement between Edwards and Medtronic that Medtronic may provide its devices pending this appeal,” Newman wrote.
“We believe this ruling is good news for patients who need the CoreValve device, and our primary objective has been to work closely with physicians to ensure that their patients are able to get the therapy they need,” Medtronic structural heart president Dr. John Liddicoat said in a statement.
“We have always made every effort to ensure patients receive the treatment they need and will continue to seek a durable solution that benefits physicians and their patients. We’re proud of the track record and large amount of clinical data supporting the performance of the Sapien family of valves, making them the preferred choice for doctors treating their patients around the world,” Edwards chairman & CEO Mike Mussallem said in prepared remarks.
Edwards initially filed the infringement claim in 2008 against CoreValve, then an independent entity (Medtronic acquired CoreValve in 2009). A federal jury ruled in 2010 that the CoreValve device willfully infringes Edwards’ “Andersen” patent, also known as the ‘552 patent. The U.S. Court of Appeals affirmed that decision in 2012 and the Supreme Court last year refused to hear Medtronic’s appeal. Earlier this year the FDA approved the CoreValve system for sale in the U.S.
The legal battle is also happening overseas, where the European Patent Office in October 2013 issued a preliminary, non-binding ruling that an Edwards’ patent was invalid, allowing CoreValve back on the German market after a temporary ban. The EPO last month finalized that ruling, entirely invalidating and revoking the so-called “Spenser patent” at the heart of the overseas dispute.
The Edwards SAPIEN transcatheter heart valve is an investigational device which is placed either through a transfemoral (RetroFlex 3 Transfemoral Delivery System) or transapical (Ascendra Transapical Delivery System) approach. The Edwards SAPIEN valve is being evaluated in the treatment of patients with severe calcific aortic stenosis who are considered to be high-risk for conventional open-heartvalve replacement surgery.Cohort A of the PARTNER (Placement of AoRTic traNscatheterER valves) Trial is designed for patients with severe calcific aortic stenosis who are considered to be high-risk for conventional open-chest valve replacement due to the risk surgery might pose to them. These patients may be eligible to participate in a new, investigational transcatheter valve replacement procedure that is performed without
The Edwards SAPIEN transcatheter heart valve is an investigational device which is placed either through a transfemoral (RetroFlex 3 Transfemoral Delivery System) or transapical (Ascendra Transapical Delivery System) approach. The Edwards SAPIEN valve is being evaluated in the treatment of patients with severe calcific aortic stenosis who are considered to be high-risk for conventional open-heartvalve replacement surgery.
Cohort A of the PARTNER (Placement of AoRTic traNscatheterER valves) Trial is designed for patients with severe calcific aortic stenosis who are considered to be high-risk for conventional open-chest valve replacement due to the risk surgery might pose to them. These patients may be eligible to participate in a new, investigational transcatheter valve replacement procedure that is performed without
In a move that calls into question the future of transcatheter valve competition in the United States, a jury in the Federal District Court of Delaware decided Jan. 15 the Medtronic CoreValve infringes on transcatheter device patents held by Edwards Lifesciences Corp. Medtronic said it intends to appeal the decision.
Medtronic anticipates U.S. regulatory approval of the CoreValve transcatheter aortic valve replacement (TAVR) system for extreme risk patients by the end of 2014 to enter the U.S. market.
The jury found that Edwards’ United States Cribier transcatheter heart valve patent (U.S. Pat. No. 8,002,825) is valid and that Medtronic CoreValve LLC willfully infringes it. Edwards said it plans to move to enforce this verdict and intends to seek a permanent injunction. The jury also awarded Edwards $394 million in damages. Edwards may seek increased damages of up to three times that amount, in addition to attorneys’ fees.
“While we are disappointed in the jury’s verdict, we continue to believe that this decision will be overturned on appeal,” said Neil Ayotte, vice president and acting general counsel at Medtronic. “Medtronic has prevailed against Edwards in several legal actions related to a European counterpart to this patent and others, and believes the Federal Circuit Court of Appeals will find no merit to Edward’s infringement claim. Today’s jury verdict does not impose an injunction, and Medtronic will oppose any requests for an injunction by Edwards. “
The patent involved in this suit is part of the Cribier family of patents and expires in December 2017. This case was tried in the U.S. District Court for the District of Delaware and is directed at the manufacture and sale of the CoreValve ReValving System in the United States, as well as the worldwide sales of valves assembled in Medtronic’s Tijuana, Mexico, facility using U.S. made components.
“Edwards invests in promising early technologies. As a result, Edwards holds a number of important patents in transcatheter valve technology, and we intend to continue to defend this intellectual property when it is used by others without permission,” said Larry L. Wood, Edwards’ corporate vice president, transcatheter heart valves.
The Rocky Road Ahead
As with the “stent wars” in the late 1990s through the past decade where key stent vendors were involved in extensive patent litigation and counter suits to block competition, a similar pattern has developed with TAVR devices.
Edwards Lifesciences currently has the only U.S. Food and Drug Administration (FDA)-cleared TAVR device on the U.S. market, the balloon-expandable Sapien Valve. The FDA approved the Sapien in November 2011. It has indications for the treatment of inoperable patients and high-risk surgical patients. The CoreValve is expected to become the second FDA-cleared TAVR system, but litigation may hinder its U.S. market launch.
In 2010, a federal jury found that Medtronic CoreValve LLC willfully infringed on another Edwards patent, the U.S. Andersen transcatheter heart valve patent, and awarded damages to Edwards. The Anderson patent was set to expire in 2011. That finding was upheld on appeal and an initial payment of $84 million was made by Medtronic to Edwards in 2013. A decision on Edwards’ request to enjoin Medtronic’s entrance into the U.S. market and additional damages is still pending. Because some of the sales have been found to infringe both the Andersen and Cribier patents, a portion of the damages awarded in the Cribier case could be reduced, Edwards said in a statement.
Edwards challanged CorValve in German courts and succeeded in getting an injunction against the sale of the device.However, in November 2013, a German court ordered the discontinuation of a prior court ruling that prohibited Medtronic from commercially marketing or selling the CoreValve system in Germany since Aug. 26, 2013. The Higher Regional Court of Karlsruhe explained that, due to the European Patent Office (EPO) preliminary opinion, the Edwards Lifesciences’ EP2055266 Spenser patent claims are not valid, and it could not assume “with sufficient likelihood” that the Spenser patent is valid. Metronic has since resumed sales in Germany.
CoreValve’s Positive Clinical Results
The first results from the CoreValve U.S. pivotal trial were very positive. The data on the self-expanding TAVR device was presented as a late-breaking clinical trial session of the 25th annual Transcatheter Cardiovascular Therapeutics (TCT) conference last October. The trial met its primary endpoint in patients who were considered too ill or frail to have their aortic valves replaced through traditional open-heart surgery, with a rate of death or major stroke at one year of 25.5 percent. This result is highly significant (p < 0.0001) as it was 40.7 percent lower in patients treated with the CoreValve system than was expected with standard therapy.
Clinical Trials on Transcatheter Aortic Valve Replacement (TAVR) to be conducted by American College of Cardiology and the Society of Thoracic Surgeons
Curator: Aviva Lev-Ari, PhD, RN
UPDATED on 11/24/2013
Second Generation Transcatheter Aortic Valve Shown to Successfully Address TAVR Complications
Results of the REPRISE II trial reported at TCT 2013
November 4, 2013 — In a clinical trial of the Boston Scientific Lotus valve, a second-generationtranscatheter aortic valve, the device demonstrated low rates of complications that are sometimes seen in transcatheter aortic valve replacement (TAVR), including challenges with positioning, post-procedure paravalvular aortic regurgitation, vascular complications and stroke.
The findings were presented at the 25th annual Transcatheter Cardiovascular Therapeutics scientific symposium (TCT 2013).
The valve studied in REPRISE II is fully retrievable and repositionable with an adaptive seal intended to minimize paravalvular regurgitation, a complication that has been associated with higher mortality among patients undergoing TAVR. In this prospective, single-arm, multicenter study, symptomatic patients at high risk for surgery received the Lotus valve to treat calcific aortic stenosis.
The trial enrolled 120 patients; mean age was 84.4±5.3 years, 56.7 percent were female and 75.8 percent were considered New York Heart Association (NYHA) Class III or IV. The mean Society of Thoracic Surgeons score was 7.1±4.6 percent and all patients were confirmed by their site heart team to be at high risk for surgery due to frailty or associated comorbidities.
The valve was successfully implanted in all 120 patients with valve repositioning and retrieval performed as needed. There was no embolization, ectopic valve deployment or need for implantation of a second prosthetic valve.
The primary device performance endpoint was the mean aortic valve pressure gradient at 30 days compared to a performance goal of 18 mmHg; the primary safety endpoint was 30-day mortality. The primary device performance endpoint was met with a 30 day mean aortic valve pressure gradient of 11.5±5.2 mmHg; mean effective orifice area was 1.7±0.4 cm2.
All cause mortality and disabling stroke were low at 30 days (4.2 percent and 1.7 percent, respectively). Additional clinical event rates were consistent with those reported for other valves. Aortic regurgitation at 30 days was negligible in 99 percent of patients (78.3 percent none, 5.2 percent trace and 15.5 percent mild). The total stroke rate, disabling and non-disabling, was 5.9 percent, which is the same as the rate as the Edward’s Sapien valve’s performance in the PARTNER trial.
“These findings suggest this valve, which is a differentiated, second generation TAVR device, will be a valuable addition for the treatment of severe aortic stenosis,” said Ian Meredith, MBBS, Ph.D., director, Monash HEART, executive director, Monash Cardiovascular Research Centre, professor of medicine, Monash University in Melbourne, Australia, and lead investigator of the study.
Lev-Ari, A. 2/12/2013 Clinical Trials on transcatheter aortic valve replacement (TAVR) to be conducted by American College of Cardiology and the Society of Thoracic Surgeons
Lev-Ari, A. 6/22/2012 Competition in the Ecosystem of Medical Devices in Cardiac and Vascular Repair: Heart Valves, Stents, Catheterization Tools and Kits for Open Heart and Minimally Invasive Surgery (MIS)
Lev-Ari, A. 6/19/2012 Executive Compensation and Comparator Group Definition in the Cardiac and Vascular Medical Devices Sector: A Bright Future for Edwards Lifesciences Corporation in the Transcatheter Heart Valve Replacement Market
Lev-Ari, A. 6/22/2012 Global Supplier Strategy for Market Penetration & Partnership Options (Niche Suppliers vs. National Leaders)in the Massachusetts Cardiology & Vascular Surgery Tools and Devices Market for Cardiac Operating Rooms and Angioplasty Suites
Acute Myocardial Infarction: Curations of Cardiovascular Original Research A Bibliography
Curators: Aviva Lev-Ari, PhD, RN and Larry H Bernstein, MD, FCAP
This article covers CURATIONS on one topic in Cardiology: Acute Myocardial Infarction. It represents a Bibliography on the subject matter using the Methodology of Curation.
The e-Reader is advised to read the article that describes what is this methodology and what makes it particularly appropriate for analysis, synthesis, interpretation and exposition of Medical Research Findings.
conceived: NEW Definition for Co-Curation in Medical Research
MicroRNA in Serum as Bimarker for Cardiovascular Pathologies: acute myocardial infarction, viral myocarditis, diastolic dysfunction, and acute heart failure
Atherosclerosis Independence: Genetic Polymorphisms of Ion Channels Role in the Pathogenesis of Coronary Microvascular Dysfunction and Myocardial Ischemia (Coronary Artery Disease (CAD))
Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination?
Why should Quality Assurance be difficult and awkward? Take a strategic view on achieving compliance (focus on ISO 13485)
Reporter: Dror Nir, PhD
Converting life-science innovations into useful products involves allocation of significant resources to handling of regulatory processes. A typical approach that makes the management of these processes difficult and awkward is starting your project and later patching it with a QA system. It then becomes a source of sever headaches to many people who need to live and operate according to such patch.
I hope that the following post by Rina will inspire you all.
It is all too easy to dive into the list of requirements contained within the ISO 13485 and achieve compliance by just ticking the boxes: looking at one requirement or one area at a time and making sure you have put in place something to address that requirement. This may easily result in a quality system that feels like a patchwork. Compliant, perhaps, but most certainly awkward and difficult to sustain.
The second most common mistake is to not ask yourself how software tools can help in setting up the quality system. “We already have MS Word, MS Excel, email, and we can always print a document and have it signed.” This is only a solution if you think that the quality system is a one-off activity. In the longer run, the system turns out to be a constant struggle with non-integrated elements that have no cohesion.
A better way to address compliance is to:
Accept the fact that the quality system is a long term commitment and that it is very demanding.
Assume that the right software tools do help.
Think strategically, reviewing the whole standard, and try to identify the different areas, in respect to what type of software would help address those.
Real life example: A company maintains an Excel list of all corrective actions. The date of effectiveness check is filled in manually. A QA engineer needs to review the Excel spreadsheet once a week to identify which effectiveness checks are due. Last audit revealed that in most cases, effectiveness checks were not followed up.
Real life question: Meetings and other events are registered in a calendar and you are reminded when they are due. Wouldn’t it be easier if effectiveness checks due dates were also linked to a calendar? Putting those dates in Excel does not make more sense than putting your meetings in Excel…..
What follows is how we can divide the ISO-13485:2003 in regard to the type of software features which can help us. You do not need to be an IT expert to follow the logic or the explanation – if you know the standard and see my examples hopefully you will get the idea.
In any case, I put here the complete mapping of the ISO into the different categories I describe. I also mention the main Atlassian tools we use to address each area. In future posts we will dive deeper into each of those categories and provide more details on exactly how we achieve easy and sustainable, compliance.
So, as promised, these are the various categories that appear in the ISO 13485:2003:
Document management: These are the various requirements relating to the procedures, manuals, and device related documents you need to have, and how they should be handled within the organization. The ISO elaborates in quite a detailed manner about how the controlled documents needs to be approved, who should access them, etc. Confluence is the key tool we use to handle all these requirements.
Procedures and records are the evidence that the organization lives up to its quality system: The various procedures and work instructions should be followed consistently on a daily basis, forms or other records should be collected as evidence. Some examples (with reference to the standard section):
Training( 6.2.2).
Customer complaints: (8.5.1).
Corrective and preventive actions: (8.5.2, 8.5.3)
Subcontractor approvals( 7.4.1)
Purchasing forms( 7.4.1).
Those records may be created as electronic or physical paper forms which need to be completed by the authorized person. However, a much better way is to implement an automatic workflow that makes it easier for the team to create, follow, and document all the various tasks they need to do. Such a workflow can automatically schedule tasks, remind and alert, thus triggering better compliance to the quality system and at the same time automatically creating the required records. This is a double win. JIRA® is our tool of choice and it provides a state-of-the-art solution to everything related to forms and workflows.
Design control: Some of the issues covered by section 7 of the ISO 13485 require quite advanced control along several phases of design and development. The risk mitigation measures and the product requirements should be, for example, verified in the product verification stage. This verification, or the test file, could be written as a simple Word or Excel document, but a far better implementation is to create it within JIRA. The advantage of JIRA here is the various reporting that it allows once the data is in and the fact that it can connect directly into the work scheduling of the various team members. JIRA is the principal tool we use for design control. Confluence can be used in some advanced implementations. If the medical device involves software, then the development suite from Atlassian can be implemented to provide a complete software life cycle management suite.
Manufacturing and product traceability: Some requirements relate to your manufacturing setup. Depending on the scale and type of manufacturing, specialized ERP may be the best option. When manufacturing is more basic and does not call for a full blown manufacturing facility, JIRA can handle the requirements of the standard.
Monitoring and improving: A key theme of the standard is the need of the organization to measure and improve (for example, section 8.2.3). The nice thing is that the framework we have put in place to support the other categories, if done correctly, should provide us with the reports, alerts, and statistics we need. Indeed, all the processes we have implemented in JIRA, as well as the various elements we have implemented in Confluence, may easily be collected and displayed in practically endless variations of reports and dashboards.
Requirement (Article)
Requirement type
4.Quality management system – 1.General requirements
Non specific
4.Quality management system – 2.Documentation requirements – 1.General
Document management
4.Quality management system – 2.Documentation requirements – 2.Quality manual
Document management
4.Quality management system – 2.Documentation requirements – 3.Control of documents
Document management
4.Quality management system – 2.Documentation requirements – 4.Control of records
6.Resource management – 2.Human resources – 2.Competence, awareness and training
Procedures and records
6.Resource management – 3.Infrastructure
Manufacturing and product traceability
6.Resource management – 4.Work environment
Non specific
7.Product realization – 1.Planning of product realization
Design control
7.Product realization – 2.Customer-related processes – 1.Determination of requirements related to the product
Design control
7.Product realization – 2.Customer-related processes – 2.Review of requirements related to the product
Design control
7.Product realization – 2.Customer-related processes – 3.Customer communication
Design control
7.Product realization – 3.Design and development – 1.Design and development planning
Design control
7.Product realization – 3.Design and development – 1.Design and development input
Design control
7.Product realization – 3.Design and development – 3.Design and development outputs
Design control
7.Product realization – 3.Design and development – 4.Design and development review
Design control
7.Product realization – 3.Design and development – 5.Design and development verification
Design control
7.Product realization – 3.Design and development – 6.Design and development validation
Design control
7.Product realization – 3.Design and development – 7.Control of design and development changes
Design control
7.Product realization – 4.Purchasing – 1.Purchasing process
Procedures and records
7.Product realization – 4.Purchasing – 2.Purchasing information
Procedures and records
7.Product realization – 4.Purchasing – 3.Verification of purchased product
Procedures and records
7.Product realization – 5.Production and service provision – 1.Control of production and service provision – 1.General requirements
Procedures and records
7.Product realization – 5.Production and service provision – 1.Control of production and service provision – 2.Control of production and service provision: Specific requirements – 1.Cleanliness of product and contamination control
Manufacturing and product traceability
7.Product realization – 5.Production and service provision – 1.Control of production and service provision – 2.Control of production and service provision: Specific requirements – 2.Installation ativities
Procedures and records
7.Product realization – 5.Production and service provision – 1.Control of production and service provision – 2. – 3.Servicing activities
Procedures and records
7.Product realization – 5.Production and service provision – 1.Control of production and service provision – 3.Particular requirements for sterile medical devices
Manufacturing and product traceability
7.Product realization – 5.Production and service provision – 2.Validation of processes for production and service provision – 1.General requirements
Manufacturing and product traceability
7.Product realization – 5.Production and service provision – 2.Validation of processes for production and service provision – 2.Particular requirements for sterile medical devices
Manufacturing and product traceability
7.Product realization – 5.Production and service provision – 3. Identification and traceability – 1.Identification
Manufacturing and product traceability
7.Product realization – 5.Production and service provision – 3. Identification and traceability – 2.Traceability – 1.General
Manufacturing and product traceability
7.Product realization – 5.Production and service provision – 3. Identification and traceability – 2.Particular requirements for active implantable medical devices and implantable medical devices
Manufacturing and product traceability
7.Product realization – 5.Production and service provision – 3. Identification and traceability – 3.Status identification
Manufacturing and product traceability
7.Product realization – 5.Production and service provision – 4.Customer property
Non specific
7.Product realization – 5.Production and service provision – 5.Preservation of product
Procedures and records
7.Product realization – 6.Control of monitoring and measuring devices
Manufacturing and product traceability
8.Measurement, analysis and improvement – 1.General
Monitoring and ongoing improvement
8.Measurement, analysis and improvement – 2.Monitoring and measurement – 1.Feedback
Monitoring and ongoing improvement
8.Measurement, analysis and improvement – 2.Monitoring and measurement – 2.Internal audit
Procedures and records
8.Measurement, analysis and improvement – 2.Monitoring and measurement – 3.Monitoring and measurement of processes
Monitoring and ongoing improvement
8.Measurement, analysis and improvement – 2.Monitoring and measurement – 4.Monitoring and measurement of product – 1. General requirements
Design control
8.Measurement, analysis and improvement – 2.Monitoring and measurement – 4.Monitoring and measurement of product – 2.Particular requirement for active implantable medical devices and implantable medical devices
Procedures and records
8.Measurement, analysis and improvement – 3.Control of nonconforming product
Procedures and records
8.Measurement, analysis and improvement – 4.Aalysis of data
Monitoring and ongoing improvement
8.Measurement, analysis and improvement – 5.Improvement – 1.General
Monitoring and ongoing improvement
8.Measurement, analysis and improvement – 5.Improvement – 2.Corrective action
Procedures and records
8.Measurement, analysis and improvement – 5.Improvement – 3.Preventive action
Summary of Genomics and Medicine: Role in Cardiovascular Diseases
Author: Larry H. Bernstein, MD, FCAP
The articles within Chapters and Subchapters you have just read have been organized into four interconnected parts.
Genomics and Medicine
Epigenetics – Modifyable Factors Causing CVD
Determinants of CVD – Genetics, Heredity and Genomics Discoveries
Individualized Medicine Guided by Genetics and Genomics Discoveries
The first part established the
rapidly evolving science of genomics
aided by analytical and computational tools for the identification of nucleotide substitutions, or combinations of them
that have a significant association with the development of
cardiovascular diseases,
hypercoagulable state,
atherosclerosis,
microvascular disease,
endothelial disruption, and
type-2DM, to name a few.
These may well be associated with increased risk for stroke and/or peripheral vascular disease in some cases,
essentially because the involvement of the circulation is systemic in nature.
Part 1
establishes an important connection between RNA and disease expression. This development has led to
the necessity of a patient-centric approach to patient-care.
When I entered medical school, it was eight years after Watson and Crick proposed the double helix. It was also
the height of a series of discoveries elucidating key metabolic pathways.
In the period since then there have been treatments for some of the important well established metabolic diseases of
carbohydrate,
protein, and
lipid metabolism,
such as – glycogen storage disease, and some are immense challenges, such as
Tay Sachs, or
Transthyretin-Associated amyloidosis.
But we have crossed a line delineating classical Mendelian genetics to
multifactorial non-linear traits of great complexity and
involving combinatorial program analyses to resolve.
The Human Genome Project was completed in 2001, and it has opened the floodgates of genomic discovery. This resulted in the identification of
genomic alterations in
cardiovascular disease,
cancer,
microbial,
plant,
prion, and
metabolic diseases.
This has also led to
the identification of genomic targets
that are either involved in transcription or
are involved with cellular control mechanisms for targeted pharmaceutical development.
In addition, there is great pressure on the science of laboratory analytics to
codevelop with new drugs,
biomarkers that are indicators of toxicity or
of drug effectiveness.
I have not mentioned the dark matter of the genome. It has been substantially reduced, and has been termed dark because
this portion of the genome is not identified in transcription of proteins.
However, it has become a lightning rod to ongoing genomic investigation because of
an essential role in the regulation of nuclear and cytoplasmic activities.
Changes in the three dimensional structure of these genes due to
changes in Van der Waal forces and internucleotide distances lead to
conformational changes that could have an effect on cell activity.
Part 2
is an exploration of epigenetics in cardiovascular diseases. Epigenetics is
the post-genomic modification of genetic expression
by the substitution of nucleotides or by the attachment of carbohydrate residues, or
by alterations in the hydrophobic forces between sequences that weaken or strengthen their expression.
This could operate in a manner similar to the conformational changes just described. These changes
may be modifiable, and they
may be highly influenced by environmental factors, such as
smoking and environmental toxins,
diet,
physical activity, and
neutraceuticals.
While neutraceuticals is a black box industry that evolved from
the extraction of ancient herbal remedies of agricultural derivation (which could be extended to digitalis and Foxglove; or to coumadin; and to penecillin, and to other drugs that are not neutraceuticals).
The best examples are the importance of
n-3 fatty acids, and
fiber
dietary sulfur (in the source of methionine), folic acid, vitamin B12
arginine combined with citrulline to drive eNOS
and of iodine, which can’t be understated.
In addition, meat consumption involves the intake of fat that contains
the proinflammatory n-6 fatty acid.
The importance of the ratio of n-3/n-6 fatty acidsin diet is not seriously discussed when
we look at the association of fat intake and disease etiology.
Part 2 then leads into signaling pathways and proteomics.The signaling pathways are
critical to understanding the inflammatory process, just as
dietary factors tie in with a balance that is maintained by dietary intake,
possibly gut bacteria utilization of delivered substrate, and
proinflammatory factors in disaease.
These are being explored by microfluidic proteomic and metabolomic technologies that were inconceivable a half century ago.
This portion extended into the diagnosis of cardiovascular disease, and
elucidated the relationship between platelet-endothelial interaction in the formation of vascular plaque.
It explored protein, proteomic, and genomic markers
for identifying and classifying types of disease pathobiology, and
for following treatment measures.
Part 3
connected with genetics and genomic discoveries in cardiovascular diseases.
Part 4
is the tie between life style habits and disease etiology, going forward with
the pursuit of cardiovascular disease prevention.
The presentation of walking and running, and of bariatric surgery (type 2DM) are fine examples.
It further discussed gene therapy and congenital heart disease. But the most interesting presentations are
in the pharmacogenomics for cardiovascular diseases, with
volyage-gated calcium-channels, and
ApoE in the statin response.
This volume is a splendid example representative of the entire collection on cardiovascular diseases.
These presentations covered several views of the utilization of cardiac markers that have evolved for over 60 years. The first stage was the introduction of enzymatic assays and isoenzyme measurements to distinguish acute hepatitis and acute myocardial infarction, which included lactate dehydrogenase (LD isoenzymes 1, 2) at a time that late presentation of the patient in the emergency rooms were not uncommon, with the creatine kinase isoenzyme MB declining or disappeared from the circulation. The world health organization (WHO) standard definition then was the presence of two of three:
1. Typical or atypical precordial pressure in the chest, usually with radiation to the left arm
2. Electrocardiographic changes of Q-wave, not previously seen, definitive; ST- elevation of acute myocardial injury with repolarization;
T-wave inversion.
3. The release into the circulation of myocardial derived enzymes –
creatine kinase – MB (which was adapted to measure infarct size), LD-1,
both of which were replaced with troponins T and I, which are part of the actomyosin contractile apparatus.
The research on infarct size elicited a major research goal for early diagnosis and reduction of infarct size, first with fibrinolysis of a ruptured plaque, and this proceeded into the full development of a rapidly evolving interventional cardiology as well as cardiothoracic surgery, in both cases, aimed at removal of plaque or replacement of vessel. Surgery became more imperative for multivessel disease, even if only one vessel was severely affected.
So we have clinical history, physical examination, and emerging biomarkers playing a large role for more than half a century. However, the role of biomarkers broadened. Patients were treated with antiplatelet agents, and a hypercoagulable state coexisted with myocardial ischemic injury. This made the management of the patient reliant on long term followup for Warfarin with the international normalized ratio (INR) for a standardized prothrombin time (PT), and reversal of the PT required transfusion with thawed fresh frozen plasma (FFP). The partial thromboplastin test (PPT) was necessary in hospitalization to monitor the heparin effect.
Thus, we have identified the use of traditional cardiac biomarkers for:
1. Diagnosis
2. Therapeutic monitoring
The story is only the beginning. Many patients who were atypical in presentation, or had cardiovascular ischemia without plaque rupture were problematic. This led to a concerted effort to redesign the troponin assays for high sensitivity with the concern that the circulation should normally be free of a leaked structural marker of myocardial damage. But of course, there can be a slow leak or a decreased rate of removal of such protein from the circulation, and the best example of this would be the patient with significant renal insufficiency, as TnT is clear only through the kidney, and TNI is clear both by the kidney and by vascular endothelium. The introduction of the high sensitivity assay has been met with considerable confusion, and highlights the complexity of diagnosis in heart disease. Another test that is used for the diagnosis of heart failure is in the class of natriuretic peptides (BNP, pro NT-BNP, and ANP), the last of which has been under development.
While there is an exponential increase in the improvement of cardiac devices and discovery of pharmaceutical targets, the laboratory support for clinical management is not mature. There are miRNAs that may prove valuable, matrix metalloprotein(s), and potential endothelial and blood cell surface markers, they require
1. codevelopment with new medications
2. standardization across the IVD industry
3. proficiency testing applied to all laboratories that provide testing
4. the measurement on multitest automated analyzers with high capability in proteomic measurement (MS, time of flight, MS-MS)
The Cost to Value Conundrum in Cardiovascular Healthcare Provision
Author: Larry H. Bernstein, MD, FCAP
Article ID #98: The Cost to Value Conundrum in Cardiovascular Healthcare Provision. Published on 1/1/2014
WordCloud Image Produced by Adam Tubman
I write this introduction to Volume 2 of the e-series on Cardiovascular Diseases, which curates the basic structure and physiology of the heart, the vasculature, and related structures, e.g., the kidney, with respect to:
1. Pathogenesis
2. Diagnosis
3. Treatment
Curation is an introductory portion to Volume Two, which is necessary to introduce the methodological design used to create the following articles. More needs not to be discussed about the methodology, which will become clear, if only that the content curated is changing based on success or failure of both diagnostic and treatment technology availability, as well as the systems needed to support the ongoing advances. Curation requires:
meaningful selection,
enrichment, and
sharing combining sources and
creation of new synnthesis
Curators have to create a new perspective or idea on top of the existing media which supports the content in the original. The curator has to select from the myriad upon myriad options available, to re-share and critically view the work. A search can be overwhelming in size of the output, but the curator has to successfully pluck the best material straight out of that noise.
Part 1 is a highly important treatment that is not technological, but about the system now outdated to support our healthcare system, the most technolog-ically advanced in the world, with major problems in the availability of care related to economic disparities. It is not about technology, per se, but about how we allocate healthcare resources, about individuals’ roles in a not full list of lifestyle maintenance options for self-care, and about the important advances emerging out of the Affordable Care Act (ACA), impacting enormously on Medicaid, which depends on state-level acceptance, on community hospital, ambulatory, and home-care or hospice restructuring, which includes the reduction of management overhead by the formation of regional healthcare alliances, the incorporation of physicians into hospital-based practices (with the hospital collecting and distributing the Part B reimbursement to the physician, with “performance-based” targets for privileges and payment – essential to the success of an Accountable Care Organization (AC)). One problem that ACA has definitively address is the elimination of the exclusion of patients based on preconditions. One problem that has been left unresolved is the continuing existence of private policies that meet financial capabilities of the contract to provide, but which provide little value to the “purchaser” of care. This is a holdout that persists in for-profit managed care as an option. A physician response to the new system of care, largely fostered by a refusal to accept Medicaid, is the formation of direct physician-patient contracted care without an intermediary.
In this respect, the problem is not simple, but is resolvable. A proposal for improved economic stability has been prepared by Edward Ingram. A concern for American families and businesses is substantially addressed in a macroeconomic design concept, so that financial services like housing, government, and business finance, savings and pensions, boosting confidence at every level giving everyone a better chance of success in planning their personal savings and lifetime and business finances.
Part 2 is a collection of scientific articles on the current advances in cardiac care by the best trained physicians the world has known, with mastery of the most advanced vascular instrumentation for medical or surgical interventions, the latest diagnostic ultrasound and imaging tools that are becoming outdated before the useful lifetime of the capital investment has been completed. If we tie together Part 1 and Part 2, there is ample room for considering clinical outcomes based on individual and organizational factors for best performance. This can really only be realized with considerable improvement in information infrastructure, which has miles to go. Why should this be? Because for generations of IT support systems, they are historically focused on billing and have made insignificant inroads into the front-end needs of the clinical staff.
St. Jude’s CEO is still betting on EnligHTN IV Study Renal Denervation System, despite Medtronic’s setback related to SYMPLICITY Phase IV
Reporter: Aviva Lev-Ari, PhD, RN
Article ID #92: St. Jude’s CEO is still betting on EnligHTN IV Study Renal Denervation System, despite Medtronic’s setback related to SYMPLICITY Phase IV. Published on 12/10/2013
WordCloud Image Produced by Adam Tubman
UPDATED on 1/14/2014
This is in continuation to our 1/9/2014 article:
Market Impact on Global Suppliers of Renal Denervation Systems by Pivotal US Trial: Metronics’ Symplicity Renal Denervation System FAILURE at Efficacy Endpoint
In the short term, the company, St. Jude suspended enrollment in three other related trials and announced plans to gather an independent panel of experts to plot a future course.
St. Jude Medical won a CE mark for its next-gen EnligHTN IV renal denervation system over the summer, but halted its own U.S. trial in December. Minnesota-based St. Jude said it had struggled to recruit viable candidates for the 590-patient trial, and was concerned that Medtronic’s Symplicity might siphon off viable patients needed for its own study. At the time, St. Jude said it would work to develop a new protocol to address trial enrollment challenges.
According to Mark Hollmer:
Symplicity’s setbacks may make that job much easier for St. Jude. They also create new opportunities for other rivals focused on developing similar technology, such as Boston Scientific ($BSX) and Covidien ($COV).
Curator of this article has expressed a different view in
St. Jude’s CEO is still betting on renal denervation, despite Medtronic’s setback
By Mark Hollmer
Medtronic’s Symplicity renal denervation device
If Medtronic’s ($MDT) recent U.S. clinical trial failure for its Symplicity renal denervation device throws the door wide open for its competitors, St. Jude Medical ($STJ) will likely waste no time walking through.
As MassDevice reported, St. Jude CEO Daniel Starks told an audience at the JPMorgan Healthcare conference in San Francisco that the company plans to keep plowing ahead with the development of its own technology.
“The fact that we had and that there have been favorable early clinical results in numerous other experiences is still valid,” MassDevice quoted Starks as saying. “There is open surgical data dating back several decades that was favorable to the impact of surgical renal denervation to treat hypertension.
That said, he also expressed genuine surprise about Medtronic’s trial setback.
“This was unexpected for us, to have a negative result from Medtronic’s trial, and it’s too soon for us to know what to make of that,” Starks said in the story.
Medtronic’s Symplicity device, which has a CE mark and is a market leader, had done well in previous trials in patients with different forms of hypertension and was on track to win FDA approval in 2015–potentially the first renal denervation device to reach that point.
The Minnesota device giant announced a few days ago that Symplicity proved safe in a 535-patient trial but failed to significantly lower blood pressure for drug-resistant hypertension.
This was a trial that mattered, designed to help fuel FDA approval.
Related Articles:
Medtronic’s flunked trial throws its hypertension program into doubt
St. Jude Medical will try again another day for a U.S. renal denervation study
St. Jude bags EU approval for next-gen renal denervation
SOURCE
From: FierceMedicalDevices <editors@fiercemedicaldevices.com> Date: Tue, 14 Jan 2014 18:14:06 +0000 (GMT) To: <avivalev-ari@alum.berkeley.edu>
Renal Denervation: EnligHTN IV Study Called Off and Potential Novel Indications – Diastolic Heart Failure
Reporter: Aviva Lev-Ari, PhD, RN
This Open Access Scientific Journal has covered all the major developments reported on Renal Denervation since its inception
ST PAUL, MN – The EnligHTN IVstudy (St Jude Medical, St Paul, MN), testing the multielectrode renal-denervation system in patients with resistant hypertension, has been stopped almost before it even began. The trial, which was announced in June and began enrolling a small number of patients this fall, was canceled because of concerns about slow enrollment.
Denise Perkins-Landry, a spokesperson for St Jude Medical, said the decision to discontinue the study was based on “anticipated recruitment challenges” and is not the result of any safety or efficacy issues with the device. “A US clinical trial for EnligHTN remains a very high priority for St Jude Medical, and we will be working with the FDA to develop a new protocol that will address anticipated enrollment challenges,” she stated in an email.
The full results of the SYMPLICITY HTN-3trial, a study similar to the EnligHTN IV study, which is sponsored by Medtronic (Minneapolis, MN), are expected in early 2014. While neither device is approved for clinical use in the US, it is expected that the Medtronic renal-denervation system will be first. As a result, it might be difficult to enroll patients to a sham procedure if there is another commercially available system for treating resistant hypertension, according to St Jude.
EnligHTN IV was to be a randomized, single-blind, controlled study with patients randomized from as many as 80 clinical centers in the US and Canada. It was intended to show the safety and effectiveness of the renal-denervation system in the reduction of systolic blood pressure in 590 patients with an office blood pressure >160 mm Hg despite taking three or more antihypertensive medications, including a diuretic.
Abrupt Decision to Stop the Study
Dr William White (University of Connecticut Medical Center, Farmington), one of the cochairs of the EnligHTN IV steering committee, told heartwirethe decision to cancel the study was made just last week. In fact, there were clinical centers already up and running in terms of enrollment, although these were pilot centers where any “bugs could be worked out.” The meeting for training investigators participating in the trial was scheduled for Saturday in Chicago, IL, although that is now off.
“In the grander scheme of things, I can tell you that the decision was not made because of any problem with the catheter or any safety issues,” said White. “Outside the US, the development is continuing as planned, but the biggest concern is that it might be very difficult, if not impossible, to continue doing a sham-controlled study a year from now if there were a commercially available renal-denervation catheter in the US, which there very well could be with Medtronic.”
Still, White said that it’s not even known if the SYMPLICITY HTN-3 study is positive or if the FDA will be satisfied with the trial and its outcomes. He said a lot of assumptions are being made by St Jude Medical in stopping the trial, and it could turn out to be a bad decision. In addition, reimbursement remains an open question.
“Commercially available doesn’t mean there’s going to be a payer,” White told heartwire . “If that happens, it will be doubly unfortunate for the patients that are out there because they might be willing and able to go into a clinical trial but they won’t have that opportunity.”
As a scientist, White said that he would have preferred the trial be pursued, regardless of what happens with Medtronic. He believes the EnligHTN catheter is “outstanding,” as it has multiple electrodes to enable physicians to thoroughly ablate the renal arteries within a couple of minutes. “The clinical scientist in me would have preferred that we go ahead as planned,” he said. “I think we would have gained a great deal of knowledge. And just because one study shows a p value of 0.05 doesn’t mean a second study will.”
The Medtronic SYMPLICITY renal-denervation system was launched in 2010 and is available in parts of Europe, Asia, Africa, and South America. The first-generation EnligHTN device has had CE Mark approval in Europe since 2012 while the updated second-generation system with multiple electrodes received European approval this past summer.
News of the halting of EnligHTN IV was first reported by Wells Fargo analyst Larry Biegelsen.
On December 06, 2013 Marlene Busko reported to Heartwire on
Renal Denervation’s Structural, Functional Heart Benefits May Be Independent of BP
HAMBURG, GERMANY — In a small study of patients undergoing renal denervation for resistant hypertension, left-ventricular hypertrophy and diastolic function improved independently of changes in blood pressure and heart rate [1].
“The novelty of our findings is the independence of morphologic improvements [regression of LV hypertrophy] from hemodynamic changes (reduction of blood pressure and heart rate),” Dr Stephan H Schirmer (University of Saarland, Hamburg, Germany) told heartwirein an email. “If this is confirmed in larger trials, it might open up novel indications for the use of renal denervation, for example, in [diastolic] heart-failure patients, independent of blood pressure.”
Dr Deepak L Bhatt (Harvard Medical School, Boston, MA) told heartwirethat the study observations are “provocative” and “exciting” but stressed that they need to be confirmed in a blinded, larger, multicenter study before they could be accepted into clinical practice. Bhatt and Dr George Bakris (University of Chicago, IL) are co–principal investigators for the ongoing SYMPLICITY HTN-3trial of bilateral renal denervation in patients with uncontrolled hypertension.
The study was published online December 4, 2013 in the Journal of the American College of Cardiology.
Are Renal Denervation Effects Always Tied to BP Change?
Renal denervation reduces heart rate and blood pressure in patients with resistant hypertension, and as reported by heartwire, a recent small study suggested that the procedure also reduces left-ventricular mass and improves diastolic function in such patients, Schirmer and colleagues write.
They hypothesized that renal denervation might affect cardiac structure and function, independent of the effect on blood pressure.
They enrolled 66 consecutive patients who underwent renal denervation using the Flex catheter system (Medtronic) at their center during 2010 and 2011 for treatment of resistant hypertension (office systolic blood pressure >140 mm Hg). Patients had a mean age of 64 years, and 55% were men. They were on a mean of 4.3 antihypertensive drugs. All were taking a diuretic, 89% were taking a beta-blocker, and 55% were taking an angiotensin-receptor blocker.
Six months after renal denervation,
Mean blood pressure decreased from 172.9/92.5 to 151.3/85.5 mm Hg, confirmed by 24-hour ambulatory monitoring, if available (n=50).
Mean heart rate decreased from 67.7 to 60.5 bpm.
Mean left-ventricular mass index decreased from 61.5 to 53.4 g/m2.
Measures of diastolic function also improved.
The changes in cardiac function and ventricular size were not tied to the magnitude of the blood-pressure reduction, which “suggest[s] a direct effect of the sympathetic nervous system on myocardial morphology and function,” Schirmer and colleagues write. They call for further research to investigate functional cardiovascular benefits of renal denervation beyond blood-pressure reduction.
Promising Early Benefit, Needs Confirmation
In an accompanying editorial [2], Bakris and Dr Sandeep Nathan (University of Chicago) commend Schirmer and colleagues “for providing promising early benefit of catheter-based renal denervation and for highlighting a possible blood-pressure–independent facet of this technique.” However, they caution that although the findings are “intriguing,” the study’s limitations include that it was
relatively small,
conducted at a single center,
lacked a sham control, and
relied on echocardiography rather than magnetic resonance imaging.
Therefore, “these observations need confirmation before acceptance in clinical practice . . . and can only be applied to those with inclusion criteria used in their study,” the editorialists conclude.
“It’s an exciting, provocative result, and there’s a good chance that it will stand the test of time, but I still think in general, it’s best to be cautious about new technologies and relatively small studies, because time typically shows that they provide an overestimate of what the true effects will be,” Bhatt commented when interviewed.
“Whether the reduction in left-ventricular mass is beyond what would be anticipated with blood-pressure and heart-rate reduction—certainly this analysis suggests that is a possibility—needs to be confirmed in larger studies,” he added, echoing the authors and editorialists.
Potentially referring physicians, in the United States where the procedure is investigational, and even in Europe where it’s approved, appear to be waiting for the results of SYMPLICITY HTN-3, Bhatt said. This blinded, randomized, multicenter trial will provide a clearer picture of what sort of blood-pressure reductions are achievable in patients with resistant hypertension who undergo renal denervation. Results are expected by mid-2014.
References
Schirmer SH, Sayed M, Reil J-C, et al. Improvements of left-ventricular hypertrophy and diastolic function following renal denervation – Effects beyond blood pressure and heart rate reduction. J Am Coll Cardiol 2013; DOI:10.1016/j.jacc.2013.10.073. Abstract
Bakris G, Nathan S. Renal denervation and left ventricular mass regression: A benefit beyond blood pressure reduction? J Am Coll Cardiol 2013; DOI:10.1016/j.jacc.2013.11.015. Editorial
The amount of success in stem cell research and recent successes is notable.
GEN News Dec 5, 2013
Stem Cell Leaders Call for Human Embryome Project
Just as an international consortium was formed to map and sequence the human genome, now a group of stem cell and regenerative medicine scientists say it’s critical that such an effort be ramped up to do a similar project focused on the human embryome.
This was the key message of a panel discussion, “From Mapping the Genome to Mapping the Embryome: The Urgent Need for an International Initiative,” moderated by Michael West, Ph.D., CEO of Biotime. It took place at the World Stem Cell Summit, which is taking place this week in San Diego.
“It is becoming increasingly clear in regenerative medicine that pluripotent stem cells, embryonic stem cells, and IPs cells will be as fundamentally important to medicine as was DNA. Maybe even bigger because you can genetically engineer these cells,” said Dr. West.
Dr. West and his colleagues adamantly believe that there needs to be a large international effort aimed at mapping the cellular and molecular basis of all human life starting with the fertilized egg and working its way up to the body of the adult. This is what it is termed the embryome.
“The opportunity presented by pluripotent stem cells to manufacture for the first time in the history of medicine all of the cellular components of the human body on an industrial scale is at once both an opportunity and a challenge,” said Dr. West. “The opportunity is to build a new field we call regenerative medicine in which many currently incurable diseases are treated with cells capable of regenerating tissues afflicted with disease. The challenge relates to the complexity of the cell types in the body and our ability to manufacture products with precisely defined compositions for human clinical use.”
Dr. West went on to say that to get these different types of stem cells into the clinic, and approved by the FDA, researchers will fully need to understand all aspects of the biology of these cells. An identification and understanding of any contaminating cells will also be essential to success in this field. The question to ask is “What is in the syringe?”
Unlike recombinant DNA, continued Dr. West, the contaminants in pluripotent stem cells are alive and may make things that are undesirable at the intended point of therapy. For example, you might have a bioreactor full of cells that are making heart muscle to regenerate heart function in a patient. But you have to be careful that your cells are not contaminated with neural crest cells from the head area which could generate a tooth along with the heart muscle.
“These contaminants, if you do not remove them, can lead to years of delay in filing an IND and a runup in costs as you try to identify these cells,” explained Dr. West.
The major problem in identifying them, according to Dr. West, is that no one has ever mapped the molecular markers or even a rudimentary cell ontology tree, i.e., mapped out the tree from the fertilized egg to the cells of the human body.
“If [there were] a detailed map of all the cellular and molecular components of life from the fertilized egg to adulthood, and then databased in a manner to the information in the human genome, medicine would be the true beneficiary,” added Dr. West. “That’s why we have made this call for an international initiative.”
Also, watch our video “A Brief History of Stem Cells” to see a timeline spanning over 60 years of stem cell research.
Mary Ann Liebert Wins Stem Cell Education Award
Mary Ann Liebert, president and CEO of Mary Ann Liebert Inc., and publisher of GEN, was presented with the Stem Cell Education Award by the Genetics Policy Institute. The award was given during a ceremony at dinner which took place at the World Stem Cell Summit, which is being held in San Diego this week.
Liebert was cited for her outstanding “work in educating patients, researchers, and the broader stem cell community, and in raising the standard in medical research journalism.” Among the seventy journals the Liebert company publishes is the peer-reviewed Stem Cells and Development.
In her acceptance speech Liebert told the audience that she was extremely gratified in being so recognized and thanked the entire staff at her company for their dedication in helping to promote excellence in medical publishing.
In his introductory remarks during the award ceremony GEN’s long-time editor in chief John Sterling noted that Mary Ann always encourages her editors and writers “to inform, enlighten when they can, and educate as much as possible.”
Sterling added that while she started her company 33 years ago her vision for her publications remains the same: “to help advance our knowledge of science and medicine in the best ways possible.”
Neural Precursors “Cure MS” in Mice
During a session at the this week’s World Stem Cell Summit in San Diego, an international research team described an “astonishing” experiment in which a mouse model of multiple sclerosis was able to virtually totally recover and move normally after being transplanted with human neural precursor cells (hNPC). The scientists were able to show almost full recovery in the mice up to six months later.
The investigators, led by Jeanne Loring, Ph.D., from the Scripps Research Institute, included scientists from the University of California, Irvine and a group from Australia.
“Our goal was to demonstrate cell therapy for MS,” Dr. Loring told the audience.
According to Ronald Coleman, a graduate student working with Dr. Loring and who is at UC-Irvine, the team used mice infected with a neurotropic JHM variant of mouse hepatitis virus (JHMV) as a model for MS. They injected hNPCs derived from human pluripotent stem cells (hPSC) into the mice to explore treatment options for the disease.
The results were indeed astonishing, said Dr. Loring. Non-control mice were able to move about in a manner that can be described as consistent and long lasting. T-cell proliferation was reduced and T regulatory cell induction took place. The spinal cords of the mice not only did not undergo further demyelination but actually exhibited remyelination. The control mice dragged their legs around when they tried to move.
“The only problem was that the hNPCs themselves are not directly responsible for the cure. They are not even there when the mice start walking,” explained Dr. Loring. “Those cells are rejected after seven days and we start to see a therapeutic response in three weeks.”
Both Dr. Loring and Coleman believe that the hNPCs are secreting proteins, like cytokines, that do the actual repair work in the CNS of the mice.
“We identified a set of candidate proteins secreted by hNPCs and not by undifferentiated pluripotent stem cells,” continued Dr. Loring, who said the team plans to continue building on this initial research.
World Stem Cell Summit: December 4, 2013 Update
GEN is on the scene at the World Stem Cell Summit in San Diego. Here are some highlights from the conference so far:
Bernard Siegel, J.D., founder and co-chair of the World Stem Cell Summit (WSCS) and executive director of Genetics Policy Institute, today welcomed attendees of WSCS 2013, being held December 4–6, in San Diego, CA.
“Stem cell science represents, to those afflicted with chronic disease, a vehicle for modeling disease and therapeutic development,” states Siegel in World Stem Cell Report 2013, a supplement to Stem Cells and Development (2013;22;Suppl1). “The field is a true scientific revolution and reflects the transformative power of hope, a powerful engine for progress.”
“The future is here now,” says Mahendra Rao, M.D., Ph.D., director, NIH Center for Regenerative Medicine, who delivered a plenary keynote and moderated the plenary panel discussion, “How Stem Cells are Transforming Medicine.” Cell therapies have been used to treat people safely and effectively; the technical barriers have been addressed. The challenge now is to reduce the cost of manufacturing. To drive routine adoption of cell therapy it must be cost effective and must demonstrate more than incremental benefit, according to Dr. Rao.
Professor Teruo Okano, Ph.D., Tokyo Women’s Medical University, described his group’s Cell Sheet Tissue Engineering strategy that involves enzymatic membrane disruption during cell harvesting and growth of an autologous cell sheet for transplantation on an “intelligent surface” that reversibly changes properties from hydrophobic to hydrophilic with a reversible in temperature from 37°C to 20°C. Dr. Okano further described the development of an automatic tissue factory and thick tissue evaluation system for fully automated, industrialized GMP cell processing.
Andre Terzic, M.D., Ph.D., Center for Regenerative Medicine, Mayo Clinic, noted during the opening session of the WSCS that “the Mayo Clinic has embraced regenerative medicine as a strategy for the future of medicine,” and he described their blueprint for moving from knowledge to delivery of treatments and procedures. Education is a critical dimension of this process. Another important component, according to Dr. Terzic, is the Regenerative Medicine Biotrust, in which “the patient is the center of the solution” to develop combinations of diagnostics and therapeutics and conduct clinical trials.
Regardless of the outcomes of current or future clinical trials, “I would argue that we have already seen breakthroughs,” said Evan Snyder, Ph.D., Sanford-Burnham Medical Research Institute, as stem cells “have completely changed the way medicine thinks about disease and development.” They have led to new views on plasticity and regeneration and the development of different types of drug targets.
WSCS 2013 is organized by the Genetics Policy Institute (GPI), California Institute for Regenerative Medicine (CIRM), Institute for Integrated Cell-Material Sciences at Kyoto University (iCeMS), Mayo Clinic, Sanford-Burnham Medical Research Institute, and The Scripps Research Institute. Mary Ann Liebert, Inc. publishers and Genetic Engineering & Biotechnology News (GEN) are sponsors of the summit.
Drug Testing Should Be with Human iPS Cells
Fri, 12/06/2013 – drug discovery & development (DDD)
Once established such neural stem cells can be used to continuously generate neurons for drug testing and disease modeling. Depicted is an immunofluorescence staining where proteins characteristic of neural stem cells are labeled with fluorescing antibodies (Nestin in green, Dach1 in red). (Source: Jerome Mertens / Uni Bonn)Once established such neural stem cells can be used to continuously generate neurons for drug testing and disease modeling. Depicted is an immunofluorescence staining where proteins characteristic of neural stem cells are labeled with fluorescing antibodies (Nestin in green, Dach1 in red). (Source: Jerome Mertens / Uni Bonn)Why do certain Alzheimer medications work in animal models but not in clinical trials in humans? A research team from the University of Bonn and the biomedical enterprise Life & Brain GmbH has been able to show that results of established test methods with animal models and cell lines used up until now can hardly be translated to the processes in the human brain. Drug testing should therefore be conducted with human nerve cells, conclude the scientists. The results are published by Cell Press in the journal Stem Cell Reports.
In the brains of Alzheimer’s patients, deposits form that consist essentially of beta-amyloid and are harmful to nerve cells. Scientists are therefore searching for pharmaceutical compounds that prevent the formation of these dangerous aggregates. In animal models, certain non-steroidal anti-inflammatory drugs (NSAIDs) were found to a reduced formation of harmful beta-amyloid variants. Yet, in subsequent clinical studies, these NSAIDs failed to elicit any beneficial effects.
“The reasons for these negative results have remained unclear for a long time”, said Oliver Brüstle, director of the Institute for Reconstructive Neurobiology of the University of Bonn and CEO of Life & Brain GmbH. “Remarkably, these compounds were never tested directly on the actual target cells—the human neuron”, added lead author Jerome Mertens of Brüstle’s team, who now works at the Laboratory of Genetics in La Jolla (USA). This is because, so far, living human neurons have been extremely difficult to obtain. However, with the recent advances in stem cell research it has become possible to derive limitless numbers of brain cells from a small skin biopsy or other adult cell types.
Scientists transform skin cells into nerve cells
Now a research team from the Institute for Reconstructive Neurobiology and the Department of Neurology of the Bonn University Medical Center together with colleagues from the Life & Brain GmbH and the University of Leuven (Belgium) has obtained such nerve cells from humans. The researchers used skin cells from two patients with a familial form of Alzheimer’s Disease to produce so-called induced pluripotent stem cells (iPS cells), by reprogramming the body’s cells into a quasi-embryonic stage. They then transformed the resulting iPS cells into nerve cells.
Using these human neurons, the scientists tested several compounds in the group of NSAIDs. As control, the researchers used nerve cells they had obtained from iPS cells of donors who did not have the disease. Both in the nerve cells obtained from the Alzheimer’s patients and in the control cells, the NSAIDs that had previously tested positive in the animal models and cell lines typically used for drug screening had practically no effect: The values for the harmful beta-amyloid variants that form the feared aggregates in the brain remained unaffected when the cells were treated with clinically relevant dosages of these compounds.
Metabolic processes in animal models differ from humans
“In order to predict the efficacy of Alzheimer drugs, such tests have to be performed directly on the affected human nerve cells”, concluded Brüstle’s colleague Philipp Koch, who led the study. Why do NSAIDs decrease the risk of aggregate formation in animal experiments and cell lines but not in human neurons? The scientists explain this with differences in metabolic processes between these different cell types. “The results are simply not transferable”, says Koch.
The scientists now hope that in the future, testing of potential drugs for the treatment of Alzheimer’s disease will be increasingly conducted using neurons obtained from iPS cells of patients. “The development of a single drug takes an average of ten years”, said Brüstle. “By using patient-specific nerve cells as a test system, investments by pharmaceutical companies and the tedious search for urgently needed Alzheimer medications could be greatly streamlined”.
Large part of the time and cost for developing a new medical device or a new drug is allocated for achieving regulatory compliance. While quality and safety are desired, having to continually spend additional time and money throughout the product’s life cycle just on the proof of its quality and safety is painful to all, especially for the health systems which eventually have to pay for it.
It has almost become routine: under narratives of increased patient safety and improved efficiency new regulatory requirements are developed, resulting in increased requirements on the industry. The new European pharmacovigilance legislation and the upcoming European medical device regulatory updates are only two examples. Being part of the industry you have very limited impact on the regulations but have to comply with them anyway. That is – if you were to continue marketing your device or drug. Under certain circumstances the cost of meeting legal requirements is so great it may bring into question the viability of continuing certain business activities. This is especially the case for smaller companies or niche products.
It is clear, thus, that you have a huge incentive to try to achieve compliance with minimal effort. If we take a bird’s eye view on the challenge of reaching compliance, two major elements become evident:
The quality system is, in itself, a high maintenance object which consumes ongoing resources:
It needs to be revisited often due to changes in the regulatory system or in the business environment.
Each change may affect many components of the system and a quick modification may cause inconsistency.
Each modification needs to be accepted, signed-off formally by several people and be disseminated via formally recorded training.
The organization should withstand audits and inspections in regards to the quality system.
Living with the quality system: Each SOP and work instruction has to be followed, and typically forms need to be filled, signed and filed.
Young companies which are just embarking on the regulatory path often do not realize these two characteristics of the quality system. Quick fixes in the form of SOP texts copied from other organizations or generic templates are being used to get the initial certification. However, as the organization evolves it realizes that a quality system is not a one-time effort and cannot be glued on from external sources. It has to be streamlined and become part of the way that the organization lives and does business. Companies are enjoying the benefits of improved process design and automation on a large scale every day, in many areas. When recently did you see a delivery person arriving to a pickup without a Barcode reader, so that he does not need to fill any form manually? When was the last time that a software package was released without an automatic consistency check? So too your quality system and related processes may be dramatically engineered to serve you better.
Better efficiency in quality compliance should thus be achieved through careful analysis and optimization of two types of processes:
How do we better maintain the quality system? How do we make it easier to change the system, keep it consistent, train in it, etc.
The SOPs and work instructions: SOPs cannot be just imported from outside or suggested by a QA/RA consultant who does not know the organization very well. SOPs should be a true marriage between the legal and business requirements and should be the result of a careful consideration by all stakeholders. From my experience, the best SOPs are written by the process owner, with the guidance of the regulatory expert. For example: the R&D manager should be the one drafting the design control SOP, with input of the regulatory expert. Such a SOP is much more likely to fit the business needs, and also more likely to be followed by the process owner.
Yes, I realize that thinking this way is very often not what companies do when they rush compliance. I insist that this is what has to be done to achieve sustainable compliance. The good news is that, when companies do look at their quality system in this way, they see many opportunities for significant improvement. Some of those improvements are achieved through use of better IT tools. These tools would typically be in the area of document management and versioning, workflow automation, improved collaboration and electronic signatures. Like any other change, this also requires a vision and a certain effort. However, the long term business impact may be as significant as the difference between business success or failure.
Don’t Ignore the Many Lessons of the MitraClip Failure
John M. Mandrola, MD
August 30, 2018
Comments
It would be wrong to say that use of this device for this indication provided no benefit to patients. The more accurate conclusion is that the MitraClip caused net harm. That’s because in addition to no benefit in the efficacy endpoints, patients in the device group endured a procedural complication rate of more than 10%, including a sevenfold higher rate of stroke.
Once again, we can learn both specific lessons about the treatment of people with heart failure and more general lessons on the acceptance of untested therapeutics.
Other comments
Dr. MIGUEL QUINTANA| Cardiology, General
A bad day for interventional cardiology. I do believe that interventional cardiologist are aware about the mechanisms of severe MR in dilated hearts, however when a point of no return in those ventricles is reached, something has to be done.
I do agree with Dr. Mandrola regarding the behaviour of the industry to drive new devices in medical practice without performing RCT. However the main responsible are the institutions approving the devices (FDA and European Commission for drugs and devices).
I wish to hear some comments of Dr. Mandrola regarding the new trends in performing RCT using just the non-inferiority criteria and the growing trends of using the “big data” of mega data registries to establish guidelines for clinical treatments and not only to test new hypothesis.
Dr. James Rittelmeyer| Cardiology, Interventional
When the point of no return has been reached palliative care is a great plan. It causes no harm and is relatively inexpensive.
Dr. Johannes Schaar| Cardiology, General
Right!!!!!! We should stay away from interventional cardiologists, who have know idea what they do and are on the payroll of the industry
This link suggests that the only FDA approved device may have a more limited indication, but is still helping the very sickest patients, with the ‘negative’ outcome for the quoted study. Functional Mitral Regurgitation (6 M patients in the US) still has no approved viable transcatheter therapy, and the interpretations of the latest study results suggest a more restricted patient selection for the MitraClip®device.
Edward Hlozek, Chairman and CEO, ValveCure, LLC, on 8/30/2018
BarrelEye portends to be available to all classes of patients with Functional MR and significantly improve quality of life and extend lives, offering future non-invasive repeatability of the therapy, without an implant.
Earlier Intervention for Mitral Valve Disease May Lead to Improved Outcomes
Slow progression of disease may mask symptoms until damage cannot be fully repaired
In this study, the data showed that the overall repair rate was 65.6 percent (57,244) and the replacement rate was 34.4 percent (29,970). Overall operative mortality was 2 percent (1,762).
“We found that the number of operations performed for mitral valve disease is growing faster than any other category of heart operation and that the results were excellent with low risks of death and complications,” said Gammie.
The researchers also revealed that while the prevalence of mitral valve disease and the number of mitral valve operations performed per year are increasing, overall aortic valve operations were performed 1.6 times more commonly than mitral valve operations during the study period.
“This may suggest important under-referral and under-treatment of mitral valve disease, which may be related to the slower progression of signs and symptoms of mitral compared to aortic disease, as well as potential lack of adherence to guidelines for intervention,” said Gammie. “So although contemporary outcomes are excellent, there remains an important and substantial opportunity to improve results for patients with mitral valve disease by following established guidelines and encouraging earlier referral for operation.”
Percutaneous repair or replacement for mitral regurgitation?
by Ted E. Feldman, MD
by Nicole Lou
Contributing Writer, MedPage TodayApril 04, 2017
Mitral repair is still a relatively youthful field at 14 years, but now operators are taking it further and developing methods for mitral valve replacement, says Ted E. Feldman, MD, of Evanston Hospital in Illinois, where mitral repair first got its start.
In this exclusive MedPage Today video, the interventionist shares his insight into the limitations of the device synonymous with mitral repair, the MitraClip, and discusses the current challenges of outright percutaneous replacement of the valve.
“100 patients underwent Mitral valve repair vs 1000s of Aortic valve the TAVR.”
MV repair via transcatheter valve implant (TMVR) will be extremely difficult to get right because of the complex nature of the anatomy versus the simple circle that is the aortic valve (TAVR)…and MitraClip is limited because leaflets sometime cannot be caught right for the device to be implanted. Think of ValveCure’s platform device that is not an implant and tightens up the valve biologically.
Aortic and Pulmonic are basically planar circular shapes. The shape of the Mitral and Tricuspid are parabolic ellipsoidal. This unique shape makes designing a transcatheter mitral valve implant challenging, especially considering that most are of a unique shape and dimension. And the aortic is more calcified, which lends to a better attachment of a transcatheter implant because it is more rigid and planar.
MitraClip Issues, Outcomes Come to Fore in US Registry Experience
by Nicole Lou
Reporter, MedPage Today/CRTonline.org
10.03.2016
Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner
Cardioband is a product of Valtech acquired by Heartware in 2015. Medtronic completed acquisition of Heartware in August 2016. See Updates, below
A novel surgical-style transcatheter device showed promise for the treatment of functional mitral regurgitation, investigators reported.
The Cardioband direct annuloplasty device was associated with no periprocedural deaths and had a 1-month mortality rate of 5%, according to Georg Nickenig, MD, of Heart Center Bonn in Germany, and colleagues in their study published online in JACC: Cardiovascular Interventions. By 6 months, the death rate had climbed to 9.6%.
Annular septolateral dimensions fell from 3.7 cm at baseline to 2.5 cm at 1 month and 2.4 cm after 6 months (P<0.001) with the device, which is implanted in a transvenous, transseptal procedure to encircle the valve annulus and, secured with small anchors, cinch it until the valve closes fully again.
In addition, the proportion of patients with grade 3 or worse mitral regurgitation also dropped from 77.4% to 10.7% at 1 month (P<0.001) and was recorded at 13.6% after 6 months (P<0.001). The proportion still categorized as being in New York Heart Association functional class III or IV dropped from 95.5% at baseline to 18.2% (P<0.001).
Over the 6-month follow-up in the study, exercise capacity generally improved (332 m in a 6-minute walking test versus 250 m at baseline, P<0.001), as did patients’ quality of life (Minnesota Living With Heart Failure Questionnaire score 18.1 versus 38.2 at baseline,P<0.001).
Medtronic Completes Acquisition of HeartWare International
Broadens Heart Failure Leadership Into Growing Circulatory Support Sector
DUBLIN – Aug. 23, 2016 – Medtronic plc (NYSE: MDT), the global leader in medical technology, has completed its acquisition of HeartWare International, Inc., a leading innovator of less-invasive, miniaturized, mechanical circulatory support technologies (MCS) for treating patients with advanced heart failure. HeartWare will become part of the Heart Failure business within the Medtronic Cardiac Rhythm and Heart Failure division. Under the terms of the transaction, each outstanding share of HeartWare common stock has been converted into the right to receive $58.00 in cash, without interest, subject to any required withholding of taxes.
HeartWare develops and manufactures miniaturized implantable heart pumps, or ventricular assist devices (VAD), to treat patients around the world suffering from advanced heart failure. Its flagship product, the HVAD® System, features the world’s smallest full-support VAD and is indicated for refractory end-stage left-ventricular heart failure patients in the U.S. who are awaiting a heart transplant, as well as approved in Europe for long-term use in patients at risk of death from refractory, end-stage heart failure.
Medtronic estimates that the global VAD market is approximately $800 million currently, and worldwide is expected to grow in the mid-to-high single digits for calendar years 2016-17, and accelerate to high-single/low-double digits beyond calendar year 2017.
“Not only does the current HeartWare portfolio expand Medtronic leadership across the heart failure continuum, its product pipeline – when married with our expertise – can result in progressively less-invasive heart pumps that have the potential to benefit even more patients,” said David Steinhaus, M.D., vice president and general manager of the Heart Failure business, and medical director for the Cardiac Rhythm and Heart Failure division at Medtronic. “Today, Medtronic offers the industry’s leading cardiac resynchronization therapy devices, including MR-conditional CRT-defibrillators; MCS therapy for advanced heart failure patients; heart failure diagnostics; and meaningful expert analysis through Medtronic Care Management Services, including the recently launched Beacon Heart Failure Management Service.”
The acquisition of HeartWare broadens the Medtronic portfolio of therapies, diagnostic tools and services for patients suffering from heart failure, aligning with Medtronic’s Mission of alleviating pain, restoring health and extending life. The acquisition is part of the Company’s therapy innovation strategy to surround the physician with innovative products while focusing on patients and disease states.
“This is an exciting moment, as more than 600 HeartWare employees are now part of the broader Medtronic organization,” said Doug Godshall, who served as president and chief executive of HeartWare for the past decade. “HeartWare has delivered incredible advancements for patients suffering from heart failure, through the commercialization of the HVAD system and pipeline development, and I am convinced that being part of Medtronic will allow us to accelerate meaningful innovations even more quickly.”
Heart failure, also known as congestive heart failure, is a condition in which the heart isn’t pumping enough blood to meet the body’s needs. Heart failure usually develops slowly after an injury to the heart. Some injuries may include a progressive deterioration of the heart muscle, heart attack, untreated high blood pressure, or heart valve disease. Heart failure remains a leading cause of hospitalization and death in the United States, and its prevalence continues to increase, affecting more than 5 million people in the U.S. alone. The cost of heart failure is high. Healthcare expenditures in the U.S. on heart failure are estimated to be approximately $39 billion per year, making it one of the largest expenses to the healthcare system. With the aging of the population, Medtronic estimates that the number of patients with heart failure could exceed 8 million by 2030.
This transaction is expected to meet Medtronic’s long-term financial metrics for acquisitions. Medtronic does not intend to modify its fiscal year 2017 revenue outlook or earnings per share (EPS) guidance as a result of this transaction, although it is expected to provide increased confidence in the company’s ability to deliver on its FY17 revenue growth outlook. In addition, Medtronic expects minimal to no net EPS dilution from this transaction for the first two years as the company intends to offset the expected dilutive impact. The acquisition is expected to be earnings accretive in year three.
In collaboration with leading clinicians, researchers and scientists worldwide, Medtronic offers the broadest range of innovative medical technology for the interventional and surgical treatment of cardiovascular disease and cardiac arrhythmias. The company strives to offer products and services of the highest quality that deliver clinical and economic value to healthcare consumers and providers around the world.
The Tender Offer and Merger The tender offer for all of the outstanding shares of HeartWare common stock expired as scheduled immediately after 11:59 p.m. Eastern time on August 22, 2016. Computershare Trust Company, N.A., the depositary and paying agent for the tender offer, has advised Medtronic that 14,952,817 shares of HeartWare common stock were validly tendered and not properly withdrawn in the tender offer, representing approximately 85.15% of the outstanding shares. All of the conditions to the tender offer have been satisfied, and on August 23, 2016, Medtronic Acquisition Corp., a subsidiary of Medtronic, accepted for payment and will promptly pay for all shares validly tendered and not properly withdrawn in the tender offer.
Following acceptance of the tendered shares, Medtronic completed its acquisition of HeartWare through the merger of Medtronic Acquisition Corp. with and into HeartWare without a vote of HeartWare’s stockholders pursuant to Section 251(h) of the Delaware General Corporation Law. As a result of the merger, HeartWare became a wholly-owned subsidiary of Medtronic. In connection with the merger, all HeartWare shares not validly tendered into the tender offer (other than shares (i) owned by HeartWare as treasury stock or owned by Medtronic, Inc. or Medtronic Acquisition Corp., which shares were cancelled and retired and cease to exist or (ii) held by any person who was entitled to and has properly demanded statutory appraisal of his or her shares) have been cancelled and converted into the right to receive the same $58.00 per share in cash, without interest, subject to any required withholding of taxes, as will be paid for all shares that were validly tendered and not properly withdrawn in the tender offer. HeartWare common stock will cease to be traded on The NASDAQ Stock Market LLC.
About Medtronic Medtronic plc (www.medtronic.com), headquartered in Dublin, Ireland, is among the world’s largest medical technology, services and solutions companies – alleviating pain, restoring health and extending life for millions of people around the world. Medtronic employs more than 85,000 people worldwide, serving physicians, hospitals and patients in approximately 160 countries. The company is focused on collaborating with stakeholders around the world to take healthcare Further, Together.
Two-year outcomes from the National Institutes of Health (NIH)–sponsored Cardiac Surgery Clinical Research Network (CTSN) trial suggest that patients with severe ischemic mitral regurgitation (MR) fare just as well when the valve is repaired or replaced, at least when it comes to measures of left ventricular reverse remodeling and survival, but that replacing the mitral valve provides a more durable correction of MR[1].
Presenting the results of the CTSN trial here at the American Heart Association (AHA) 2015 Scientific Sessions, the researchers reported no significant difference in the mean left ventricular end-systolic volume index (LVESVI) among 251 patients randomized to mitral-valve repair or chordal-sparing mitral-valve replacement.
In addition, there was no mortality advantage with either approach. The 2-year mortality rate was 19.0% in the repair arm and 23.2% in the replacement group, a difference that was not statistically significant (hazard ratio 0.79; 95% CI 0.46–1.35).
Despite the equivocal results, investigators, including lead researcher Dr Daniel Goldstein (Montefiore Medical Center/Albert Einstein College of Medicine, New York), did observe significantly higher recurrence rates among patients who underwent surgical repair. At 2 years, 59% of patients in the repair arm and 3.8% in the replacement arm were diagnosed with moderate or severe MR (P<0.001).
“Recurrence was rather striking,” said Goldstein during a press conference announcing the results. “Interestingly, most of the recurrences were moderate, were not severe.”
This difference in MR translated into a significantly increased risk of heart failure at 2 years among patients undergoing mitral-valve repair (24.0% vs 15.2% in the repair and replacement arms, respectively; P=0.05) as well as an increased readmission rate to hospital for cardiovascular causes (48.3% vs 32.2%, respectively;P=0.01).
Dr Daniel Goldstein
“There was no difference in the total readmissions to the hospital between groups,” said Goldstein. “However, if you look at just cardiovascular readmissions, there was a striking difference, with repair patients requiring many more heart-failure readmissions than replacement patients. What were those heart-failure readmissions for? They were for true heart failure or for the placement of an ICD or biventricular pacers, which in essence are also heart-failure readmissions because the people who are getting those technologies are people with advanced heart failure.”
The bottom line, say investigators, is that the 2-year data reveal a divergence in clinical outcomes not evident at 1 year. The deficiency in the durability of correction of MR with surgical repair is “disconcerting,” they add, noting that MR recurrence predisposes patients to heart failure, atrial fibrillation, increased hospitalizations, and other adverse outcomes.
The 2-year results are published November 9, 2015 in the New England Journal of Medicine to coincide with the late-breaking clinical-trials presentation. One-year outcomes presented at the AHA 2013 meeting and reported by heartwirefrom Medscape at that time.
Who Should Get Repair? Who Replacement?
Dr Alain Carpentier (Descartes University, Paris, France), one of the world leaders in mitral-valve repair, said the findings are particularly important for younger, less experienced surgeons. “If these results are confirmed, it means that the young surgeon with little experience in valve repair shouldn’t feel guilty for replacing a valve because he or she will be certain that the result will be as good.”
Valve repair, added Carpentier, is a “question of experience” and should be done only by surgeons with a large amount of clinical practice in the surgical technique. The present study is unique as the surgeons performing the procedure in BEAT-HF were experienced surgeons, a component of the trial that partially explains why repair and replace both fared as well in terms of the primary end point.
Speaking with the media, Goldstein said physicians who support valve repair believe it is associated with lower morbidity and mortality, noting that it results in the preservation of the entire mitral subvalvular apparatus. MR recurrence is a known problem, however, and this can lead to functional mitral stenosis if the ring is very small. Replacement, on the other hand, is associated with higher perioperative morbidity and mortality, but it does provide a more durable correction of MR.
Goldstein said that even though there was no difference in LVESVI at 2 years or in mortality either, recurrence is a factor that will weigh in a decision over whether or not to repair or replace the mitral valve. Right now, he is comfortable performing a mitral-valve replacement as first-line treatment in a majority of patients. “I think we still need to follow these patients a little longer, because you have to remember you have a prosthesis in there,” he said. “The prosthesis can give you problems. There’s thromboembolic complications, it can get infected, it can deteriorate and need rereplacement, so the balance of those issues awaits more time.”
That said, in the absence of reliable predictors of a successful mitral-valve repair, surgical replacement of the mitral valve is a viable option. “Based on experience, I think a lot of people want to start thinking a little more liberally about replacing the valve in general just because of these data,” he said. Optimal valve-replacement candidates would include individuals with a basal aneurysm or basal dyskinesia, he noted.
Goldstein reports grant support from the National Institutes of Health and consulting fees from Medtronic. Disclosures for the coauthors are listed on the journal website.
UPDATED Sept. 10, 2015, with details on MVAD trial pause, expanded field action and Valtech acquisition.
HeartWare International (NSDQ:HTWR) today said it’s pausing enrollment in a clinical trial of its next-generation MVAD heart pump while it looks to fix an issue with the manufacturing process for the left ventricular assist device’s controller.
“There was a feeding frenzy starting to develop around Valtech. We agreed with them that we would put in a 2nd investment earlier this year that would buy us an exclusivity period that expired mid-September. It was quite clear from the communications we were getting from the company that they were having to fend off interest from others. It was also quite clear from the company that they are an R&D powerhouse that doesn’t really want to build a commercial organization,” he said. “Frankly if we couldn’t do Valtech, we weren’t going to do mitral because we believe we need the ability to repair surgically and repair interventionally and we believe we need a portfolio.”
Implications of this M&A on the Global EcoSystem for Carviovascular Repair Tools Segment
September 6, 2015
It is my strong belief that HeartWare inked $929m deal for Valtech Cardio’s mitral and tricuspid valves Is creating a new constellation of concentration among players, thus M&A could be the optimal solution as a fallout from the new reality of $1Billion investment in Israeli Valtech, for many Early stage Start Ups in the Mitral Valve Repair and Replacement Segment.
What implications this deal has on the Mitral Valve Repair Technology Start Ups vs Mitral Valve Replacement OEM of Artificial Valves?
Percutaneous Annuloplasty May Offer Safe, Effective Alternative to Surgery for HF Patients With MR
What are the Market implications of this announcement on
Medtronic
Edwards LifeSciences
St. Jude (new announcement)
Abbot
In addition,
Lev-Ari, A. 6/22/2012Competition in the Ecosystem of Medical Devices in Cardiac and Vascular Repair: Heart Valves, Stents, Catheterization Tools and Kits for Open Heart and Minimally Invasive Surgery (MIS)
Lev-Ari, A. 6/19/2012Executive Compensation and Comparator Group Definition in the Cardiac and Vascular Medical Devices Sector: A Bright Future for Edwards Lifesciences Corporation in the Transcatheter Heart Valve Replacement Market
Lev-Ari, A. 6/22/2012Global Supplier Strategy for Market Penetration & Partnership Options (Niche Suppliers vs. National Leaders)in the Massachusetts Cardiology & Vascular Surgery Tools and Devices Market for Cardiac Operating Rooms and Angioplasty Suites
Medtronic (NYSE:MDT) said today that it agreed to pony up as much as $458 million for Twelve Inc. and its transcatheter mitral valve implant, as the race to get a TMVI device to market heats up.
Twelve, a spinout from the Foundry incubator that’s based in Redwood City, Calif., is backed by Domain Associates, Versant Ventures, Morgenthaler Ventures, Longitude Capital, Emergent Medical Partners, Vertex Venture Management, and Capital Group, Fridley, Minn.-based Medtronic said.
The deal calls for a $408 million payment once the deal closes, expected in October, and another $50 million pegged to CE Mark approval in the European Union for the Twelve TMVI device.
“Upon close, this acquisition will strategically augment our existing capabilities in the transcatheter mitral space, which represents an important growth opportunity for Medtronic,” coronary & structural heart president Sean Salmon said in prepared remarks. “We have followed the transcatheter mitral valve space closely and firmly believe that Twelve has the most novel technology along with a strong, proven team. The combined strengths of our organizations will significantly accelerate our ability to deliver an exciting and differentiated therapy to patients, physicians and healthcare systems around the world.”
Edwards Lifesciences (NYSE:EW) last week said it agreed to pay $400 million for CardiAQ Valve Technologies and its transcatheter mitral valve implant, saying it also reached a deal to revise the protocol for restarting a trial of its own Fortis mitral valve.
The deal for CardiAQ Valve, which like Edwards is based in Irvine, Calif., calls for an up-front payment of $350 million in cash and another $50 million pegged to “achievement of a European regulatory milestone,” Edwards said. The deal is expected to be “slightly dilutive” to 2015 earnings, the company said.
“Edwards’ primary strategy is to create valuable therapies that transform patient care. We believe the acquisition and integration of CardiAQ will advance our development of a transformational therapy for patients with mitral valve disease who aren’t well-served today,” chairman & CEO Michael Mussallem said in prepared remarks. “While still early in the development of this therapy, the progress of the team of employees and clinicians working on our Fortis mitral replacement system has reinforced our confidence in a catheter-based approach. We believe the experiences and technologies of Fortis and CardiAQ are complementary and that this combination will enable important advancements for patients.”
“CardiAQ is proud of our pioneering efforts in the early development of this transcatheter mitral valve therapy conceived by cardiac surgeon Dr. Arshad Quadri. We believe our technology, which incorporates multiple delivery approaches with a single valve, shows great promise for patients,” added CardiAQ CEO Rob Michiels.
In April, CardiAQ won an investigational device exemption from the FDA for a 20-patient feasibility trial of its as-yet-unnamed TMVI candidate, with a protocol calling for 10 subjects to be treated transfemorally and another 10 treated via the transapical approach.
“We look forward to joining Edwards, whose experience and leadership as a developer of breakthrough therapies for heart valve disease will advance our work,” co-founder, president & COO Brent Ratz said in a statement.
Edwards also said it reached a deal with the investigators in its Fortis trial for changes to study’s protocol, after blood clots in some of the 20 patients implanted with the device prompted a temporary halt for the trial.
Abbott’s percutaneous MitraClip mitral valve repair device SUPERIOR to Pacemaker or Implantable Cardioverter Defibrillator (ICD) for reduction of Ventricular Tachyarrhythmia (VT) episodes
Harpoon Medical is a development stage medical device company commercializing a minimally invasive, image guided surgical tool for beating heart mitral valve repair. The technology was developed in the Division of Cardiac Surgery at The University of Maryland School of Medicine. With the Harpoon device, surgeons can access and repair the mitral valve in a beating heart via a small incision between the ribs without the need for cardiac arrest or cardiopulmonary bypass. The tool enters the left ventricle transapically and inserts “bulky knot” neochords in the leaflet to eliminate mitral valve regurgitation. When introduced to the market, the Harpoon device should transform the traditional open heart mitral valve surgical procedure from a complex 3-6 hour operation to a 60-minute procedure and reduce the recovery period from weeks to days.
Mitral-Valve Repair versus Replacement for Severe Ischemic Mitral Regurgitation
Michael A. Acker, M.D., Michael K. Parides, Ph.D., Louis P. Perrault, M.D., Alan J. Moskowitz, M.D., Annetine C. Gelijns, Ph.D., Pierre Voisine, M.D., Peter K. Smith, M.D., Judy W. Hung, M.D., Eugene H. Blackstone, M.D., John D. Puskas, M.D., Michael Argenziano, M.D., James S. Gammie, M.D., Michael Mack, M.D., Deborah D. Ascheim, M.D., Emilia Bagiella, Ph.D., Ellen G. Moquete, R.N., T. Bruce Ferguson, M.D., Keith A. Horvath, M.D., Nancy L. Geller, Ph.D., Marissa A. Miller, D.V.M., Y. Joseph Woo, M.D., David A. D’Alessandro, M.D., Gorav Ailawadi, M.D., Francois Dagenais, M.D., Timothy J. Gardner, M.D., Patrick T. O’Gara, M.D., Robert E. Michler, M.D., and Irving L. Kron, M.D. for the CTSN
Ischemic mitral regurgitation is associated with a substantial risk of death. Practice guidelines recommend surgery for patients with a severe form of this condition but acknowledge that the supporting evidence for repair or replacement is limited.
METHODS
We randomly assigned 251 patients with severe ischemic mitral regurgitation to undergo either mitral-valve repair or chordal-sparing replacement in order to evaluate efficacy and safety. The primary end point was the left ventricular end-systolic volume index (LVESVI) at 12 months, as assessed with the use of a Wilcoxon rank-sum test in which deaths were categorized below the lowest LVESVI rank.
RESULTS
At 12 months, the mean LVESVI among surviving patients was 54.6±25.0 ml per square meter of body-surface area in the repair group and 60.7±31.5 ml per square meter in the replacement group (mean change from baseline, −6.6 and −6.8 ml per square meter, respectively). The rate of death was 14.3% in the repair group and 17.6% in the replacement group (hazard ratio with repair, 0.79; 95% confidence interval, 0.42 to 1.47; P=0.45 by the log-rank test). There was no significant between-group difference in LVESVI after adjustment for death (z score, 1.33; P=0.18). The rate of moderate or severe recurrence of mitral regurgitation at 12 months was higher in the repair group than in the replacement group (32.6% vs. 2.3%, P<0.001). There were no significant between-group differences in the rate of a composite of major adverse cardiac or cerebrovascular events, in functional status, or in quality of life at 12 months.
CONCLUSIONS
We observed no significant difference in left ventricular reverse remodeling or survival at 12 months between patients who underwent mitral-valve repair and those who underwent mitral-valve replacement. Replacement provided a more durable correction of mitral regurgitation, but there was no significant between-group difference in clinical outcomes.
(Funded by the National Institutes of Health and the Canadian Institutes of Health; ClinicalTrials.gov number, NCT00807040.)
Verna Hoy knew something wasn’t right; she was coughing a lot and running out of breath. Both her mother and a sister had heart murmurs — which doctors heard in Hoy’s chest, too — so she wasn’t surprised to be referred to a cardiologist.What cardiologists found would not be so simple to fix, however. At least, it didn’t use to be. Hoy had two problems: a leaky mitral valve in her heart, which caused blood to back up into her left atria, and something called hypertrophic cardiomyopathy (HCM) that obstructed blood flow in her heart. And the only way to fix it, before, was risky and invasive open heart surgery. But doctors didn’t want to do that to the 87-year-old from Richfield.Instead, her cardiologist turned to a just-approved device called a MitraClip that could be deployed via a catheter snaked up to her heart through a vein in her leg.On Dec. 11, Hoy became the first patient in Minnesota to receive the MitraClip to repair a leaky mitral valve. Turns out, Hoy also is the first person in the world to also have her HCM treated with the same device.“They decided they would try this procedure to see if it would work,” Hoy said recently. Its seems to be working just fine. A week after her procedure, Hoy was washing clothes, running errands to the grocery store and drugstore and heading out to lunch.”We’re all very excited about it,” said Dr. Paul ?Sorajja, an interventional cardiologist at the Minneapolis Heart Institute Foundation and Abbott Northwestern Hospital. “This is a new advance in the management of patients with HCM.”The combination of HCM and a faulty mitral valve affects 400,000 Americans. The MitraClip, developed by Abbott Laboratories, won approval from the Food and Drug Administration in October. It has been available in Europe for several years.
The MitraClip is the only commercially available mitral valve repair device that can be placed into the heart through a blood vessel, a much less-invasive process that speeds patient healing.
Sorajja and Dr. Wes Pedersen, director of the Transcatheter Valve Therapy Program at the Minneapolis Heart Institute, were investigators into the safety and effectiveness of the procedure during clinical trials.
“The device has proved its effectiveness in research studies and we are excited to see this device commercially available and improving and extending the lives of thousands of people,” Sorajja said. “When we looked at how this device can be used to treat mitral regurgitation, we felt that it could also be used to simultaneously treat obstruction due to HCM.”
HCM is a condition in which the walls of the heart thicken, interfering with the heart’s activities. In Hoy’s case, a thick wall in her left ventricle slowed the flow of blood out of the ventricle. At the same time, the thickening caused the mitral valve in her heart to leak blood into her left atrium — called mitral regurgitation. That combination was hurting Hoy.
For patients with HCM, doctors usually open the chest to remove part of the thickened heart wall. In some cases, they inject alcohol into the tissue to kill it, causing a small heart attack. But the MitraClip, which essentially clips the middle of the leaky mitral valve, also keeps that valve from further obstructing blood flow, Sorajja said. One device, two problems solved.
According to the FDA, repairing the valve during open heart surgery still is the preferred method. But MitraClip is now acceptable for patients who are not considered healthy enough for the surgery.
Sorajja, who came to Abbott Northwestern from the Mayo Clinic, said, “We had our suspicions that this would work. It was a great day. It was a really great day for us. We are so happy.”
Hoy, who was discharged from the hospital just two days after the procedure, said she still gets a little breathless.
“I seem to be OK,” she said. “I was told not to lift anything over 10 pounds and I watch it.”
She said trying a new device didn’t worry her. Besides, she likes the idea of maybe helping others with what doctors learn from her.
“There are a lot of people on this Earth,” she said. “If it is my time, so be it. But I thought if it would help other people, I would take a shot.” ___
A. Who is a Patient Candidate for a Non-Ablative Fully Non-Invasive Procedure?
A.1 Patient Segments by Medical Diagnosis
If a patient is disqualified for CABG then the patient is likely to be disqualified for Open Heart Surgery for Mitral Valve Repair and Replacement.
For all cases that a percutaneous Transcatheter for Mitral Valve Repair is deemed to be non indicated – the patient’s SOLE choice is the proposed Non-Ablative Fully Non-Invasive Procedure – a novel technology under development by Dr. Pearlman.
Special Patient Subsets
A. Elderly Patients
Elderly patients being considered for CABG have a higher average risk for mortality and morbidity in a direct relation to age, LV function, extent of coronary disease, and comorbid conditions and whether the procedure is urgent, emergent, or a reoperation. Nonetheless, functional recovery and sustained improvement in the quality of life can be achieved in the majority of such patients. The patient and physician together must explore the potential benefits of improved quality of life with the attendant risks of surgery versus alternative therapies that take into account baseline functional capacities and patient preferences. Age alone should not be a contraindication to CABG if it is thought that long-term benefits outweigh the procedural risk.
B. Women
A number of earlier reports had suggested that female sex was an independent risk factor for mortality and morbidity after CABG. More recent studies have suggested that women on average have a disadvantageous, preoperative clinical profile that accounts for much of this perceived difference. Thus, the issue is not necessarily sex itself but the comorbid conditions that are particularly associated with the later age at which women present for coronary surgery. Thus, CABG should not be delayed in or denied to women who have appropriate indications.
ACC/AHA Practice Guidelines, ACC/AHA Guidelines for Coronary Artery Bypass Graft Surgery: Executive Summary and Recommendations. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1991 Guidelines for Coronary Artery Bypass Graft Surgery)
Current existing guidelines do not recommend surgery for asymptomatic or mildy symptomatic patients1, there is a large cohort of patients with significant mitral regurgitation that do not undergo surgery, thus allowing for observational studies of outcomes in non-surgically treated patients.
Before expanded application of mitral valve repair in the 1990s, cohorts of symptomatic patients with mitral valve prolapse were followed on medical therapy allowing determination of natural history of mitral regurgitation.
Mitral valve prolapse with severe regurgitation reduces long-term survival irrespective of medical therapy. It appears that the prolapse itself is not the cause of mortality or morbidity (cardiac event rates are extremely low for the entire population with prolapse), but it is
severe regurgitation and consequent left ventricular dilatation that results in morbidity2, 3. Heart failure, arrhythmia, endocarditis and stroke are the leading causes of death.
Enriquez-Sarano and colleagues have performed analyses to define which group of patients with mitral regurgitation are at greatest risk of cardiac events4, 5, 6.
Notably, when considering asymptomatic patients, the greater the severity of mitral regurgitation (preferably determined by quantitative echocardiography), the higher the frequency of cardiac events irrespective of a normal ventricular function (Figure 1).
Other risk factors for cardiovascular morbidity include
Presence of these factors implies a reduced life expectancy if mitral regurgitation is uncorrected. Current evidence from surgical cohorts, suggests that mitral valve repair (assuming an operative mortality below 1%) yields a better outcome (survival and freedom from cardiac events) compared to the outcomes observed in non-surgically treated patients with severe regurgitation. For example
Mitral valve repair in patients with good ventricular function has a long term survival similar to expected survival in age matched cohorts5, 8, 9, whereas long term follow-up of patients with mitral valve prolapse treated medically shows a reduced survival compared to expected survival10 (Figure 2).
In the U.S. over 5 million patients are estimated to suffer from moderate to severe mitral regurgitation with an additional 300,000+ new patients diagnosed annually. In Western Europe the number is comparable and other medically advanced countries around the world add to this addressable patient population. The rest of the world market has been assumed to be equal to twice the size of the US market.
Of these over 5 million patients in the US, about 130,000 have annuloplasty surgeries every year (about 65% repair and 35% replacement). Another 700,000 are deemed high risk. These high risk patients represent a non-served market because there is no non-implantable device/simpler surgical procedure available.
Due to the surgical probe and lateral device’s inherent simplicity of application compared to current implantable techniques, ValveCure forecasts that in addition to capturing some of the current annuloplasty procedures, a large number of currently unserved mitral regurgitation patients will avail themselves of this new technology.
Surgical treatment of mitral regurgitation (MR) has evolved from mitral valve replacement (MVR) to repair (MVRe), because MVRe produces superior long-term outcomes. In addition, MVRe can be achieved through minimally invasive approaches. This desire for less invasive approaches coupled with the fact that a significant proportion of patients—especially elderly persons or those with significant comorbidities or severe left ventricular (LV) dysfunction, are not referred for surgery, has driven the field of percutaneous MVRe. Various technologies have emerged and are at different stages of investigation. A classification of percutaneous MVRe technologies on the basis of functional anatomy is proposed that groups the devices into those targeting the leaflets (percutaneous leaflet plication, percutaneous leaflet coaptation, percutaneous leaflet ablation), the annulus (indirect: coronary sinus approach or an asymmetrical approach; direct: true percutaneous or a hybrid approach), the chordae (percutaneous chordal implantation), or the LV (percutaneous LV remodeling). The percutaneous edge-to-edge repair technology has been shown to be noninferior to open repair in a randomized clinical trial (EVEREST II [Endovascular Valve Edge-to-Edge REpair Study]). Several other technologies employing the concepts of direct and indirect annuloplasty and LV remodeling have achieved first-in-man results. Most likely a combination of these technologies will be required for satisfactory MVRe. However, MVRe is not possible for many patients, and MVR will be required. Surgical MVR is the standard of care in such patients, although percutaneous options are under development.
“LPBI Proposals for Precision Mitral Annuloplasty: Extensions to RF Solutions and MRI Methods and Devices”
Inventor and Author:Justin D Pearlman, MD, PhD, FACC
The primary goal for therapy of mitral regurgitation is reduction in the leakage without causing stenosis (excessive flow resistance), prior to the development of fibrosis of heart muscle secondary to abnormal workload. The specific treatment can be adapted to the specific mechanism of the valve leakage. Mechanisms of mitral regurgitation include prolapse (leaflet inversion) due to a large excessively flexible leaflet and/or excessive length of chordae, malcoaptation/incomplete valve closure assocated with relatively large or dilated annular support, or rarely, perforation of a leaflet. Shrinkage of excessive tissue can be achieved surgically or non-surgically. Under non-disclosure we can elaborate on proprietary methods that can achieve these goals surgically or non-surgically, either with direct contact (invasive) but without requiring cardiac bypass, robotic catheter (minimally invasive) or with no skin breach at all (completely non-invasive).
C.1 Three extensions of ValveCure Non-Hardware Surgical Mitral Annuloplasty
C.2 Three non-Surgical Alternatives to RF Mitral Annuloplasty: Response Modulated Excitation – MRi Methods and Devices
C.3 Features of Novel Technology: MRI Methods and Devices
Three extensions of Current Non-Hardware Surgical Mitral Annuloplasty
Three Less Invasive methods
For the full presentation go to the link, below and request access for the PASSWORD PROTECTED Article by e-mailing to the inventor
Dr. David H. Adams is the Marie-Josée and Henry R. Kravis Professor and Chairman of the Department of Cardiothoracic Surgery at The Mount Sinai Medical Center. Dr. Adams is a leader in the field of mitral valve reconstruction and heart valve surgery. As Program Director of Mount Sinai’s Mitral Valve Repair Reference Center, he has set national benchmarks for the specialty with a repair success rate of more than 99 percent in patients with degenerative mitral valve disease, while running one of the largest and most respected valve programs in the United States.
Dr. Adams’ impact extends far beyond his own operating room. As the holder of multiple patents, he carries out a prodigious research agenda to develop new techniques and tools to push frontiers in complex valve surgeries and make procedures safer for patients. He is the co-inventor of two mitral valve annuloplasty repair rings (the Carpentier-Edwards Physio II Annuloplasty Ring and the Carpentier-McCarthy-Adams IMR ETlogix Ring), and inventor of a new tricuspid annuloplasty ring (Medtronic Tri-Ad Tricuspid Annuloplasty Ring) and has royalty agreements with Edwards Lifesciences andMedtronic. Dr. Adams has performed the first successful implantations of the IMR ETlogix, Physio II, and Tri-Ad Rings in the United States. All of these rings are now used extensively throughout the world.
Dr. Adams is a much sought after speaker both nationally and internationally and has given over 300 invited lectures and operated on patients in multiple teaching courses throughout the world. His desire to share knowledge and collaborate with other cardiac surgeons led him to develop one of the world’s largest video libraries of techniques in valve reconstruction. He is the author of over 200 publications, and is recognized as a leading surgeon scientist and medical expert, serving on the Editorial Boards of several medical journals, including Cardiology and The Annals of Thoracic Surgery. He is currently the Co-Editor of Seminars in Thoracic and Cardiovascular Surgery. Dr. Adams has served in an advisory capacity to essentially all industry leaders in cardiovascular surgery. He also serves as the National Co-Principal Investigator of the United States FDA pivotal trial of the Medtronic CoreValve Transcatheter Aortic Valve replacement device.
Dr. Adams’ clinical interests include all aspects of heart valve surgery, with a special emphasis on mitral valve reconstruction and multiple valve surgery. His major research interests include outcomes related to mitral valve repair, novel mitral valve repair strategies, and percutaneous valve replacement. Past research honors include the Alton Ochsner Research Scholarship from the American Association for Thoracic Surgery and the Paul Dudley White Research Fellowship from the American Heart Association. He has also received honorary Professorships from Capital University in Beijing and Keio University in Tokyo. In 2009, he received the New York American Heart Association Award for Achievement in Cardiovascular Science and Medicine.
Dr. Adams received his undergraduate and medical education at Duke University and completed his internship and residency in general and cardiothoracic surgery at Brigham and Women’s Hospital and at Harvard Medical School. Dr. Adams followed that with a fellowship in London under Professor Sir Magdi Yacoub. In addition, he completed a two-year research fellowship under Professor Morris Karnovsky in the Department of Pathology at Harvard Medical School. He later served at Brigham and Women’s Hospital as the Associate Chief of Cardiac Surgery. He has been Chairman of the Department of Cardiothoracic Surgery at The Mount Sinai Medical Center since 2002.
David H. Adams, MD
Marie-Josée and Henry R. Kravis
Professor and Chairman
Department of Cardiothoracic Surgery
The Mount Sinai Medical Center
New York, NY 10029
212-659-6820
Essentially, all degenerative mitral valves are repairable. By matching echocardiographic findings to the appropriate surgical skill level required to consistently deliver a repair, valve replacement for degenerative mitral valve disease should be infrequent.
Most patients with mitral regurgitation remain asymptomatic for long periods of time. The most common presenting signs and symptoms include fatigue, decreased exercise capacity, shortness of breath, and palpitations or supra-ventricular arrhythmias such as atrial fibrillation. Auscultatory examination usually reveals a high-pitched systolic murmur radiating from the apex to the axilla. A holosytolic murmur suggests prolapse simultaneous with ejection typical of chordal rupture, whereas a murmur beginning in mid- or late systole favors billowing or chordal elongation. Radiographic findings may include left atrial and ventricular dilatation and prominent pulmonary vasculature in patients with long standing severe mitral regurgitation. The electrocardiogram may be normal, or show evidence of left atrial enlargement or atrial fibrillation.
Table 1: Selected ranges for grading severity of mitral regurgitation. Rvol, regurgitation volume, ERO, effective regurgitant orifice1, 2.
Two dimensional echocardiography with doppler is essential to determine the mechanism (dysfunction) and severity of mitral regurgitation. Semi-quantitative assessment of regurgitant flow using maximal jet length, area, and ratio of jet to left atrial area is recommended to assess the severity of mitral regurgitation1. Regurgitant jet geometry and area are assessed in multiple views and mitral regurgitation severity is graded typically as a rank order variable (e.g. 1+ trace, 2+ mild, 3+ moderate and 4+ severe mitral regurgitation). The direction of the jet provides evidence of segmental involvement as it is typically opposite to the prolapsing segment. Quantitative doppler grading of mitral regurgitation is gaining in popularity and is based on the calculation of regurgitant volume (the difference between the mitral and aortic stroke volumes) and effective regurgitant orifice (ratio of regurgitant volume to regurgitant time velocity integral). Table 1 shows the correlation between the semi-quantitative and quantitative grading of mitral regurgitation in degenerative mitral disease. Transesophageal echocardiography (TEE) is a useful adjunct to confirm the diagnosis and understand the mechanism of degenerative valve disease in the case of a non-definitive transthoracic examination. Experience is also gaining with three dimensional echocardiography in the assessment of annular geometry and leaflet dysfunction in the setting of mitral regurgitation, and can be predicted to have a more significant role in planning reparative procedures in the future.
(1) Zoghbi WA, Enriquez-Sarano M, Foster E et al. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003 July;16(7):777-802.
(2) Dujardin KS, Enriquez-Sarano M, Bailey KR, et al: Grading of mitral regurgitation by quantitative Doppler echocardiography: calibration by left ventricular angiography in routine clinical practice. Circulation 96(10):3409-15 1997.
In the hands of reference mitral valve-repair surgeons, 95–100% of degenerative valves are repairable, regardless of etiology; however, in the general cardiac surgical community, the repair rates are around 50%. In contrast to fibroelastic deficiency, Barlow’s valves have more complex pathology and require advanced techniques to effect a repair.
Mitral valve regurgitation is present when the valve does not close completely, causing blood to leak back into the left atrium. Mitral valve stenosis is present when the valve does not open completely, causing a relative obstruction to blood flow. Both of these conditions increase the workload on the heart and are very serious conditions. If left untreated, they can lead to debilitating symptoms including cardiac arrhythmia, congestive heart failure, and irreversible heart damage.
Figure 1: Carpentier’s functional classification. Type I, normal leaflet motion; Type II, increased leaflet motion (leaflet prolapse); Type IIIa restricted leaflet motion during diastole and systole; Type IIIb restricted leaflet motion predominantly during systole.*
Carpentier refers to the confusion surrounding classification and description of mitral valve disease as “the Babel Syndrome,” in reference to the Biblical story of what happens when workers do not speak the same language1. Degenerative mitral valve disease is the best example of this phenomenon, where terms such as prolapse, flail, partial flail, billowing, Barlow’s disease, floppy valve, and myxomatous valve disease are often used inter-changeably by different specialists, blurring the distinction between valve dysfunction and disease. Carpentier’s pathophysiologic triad1describes the inter-relationship between etiology (the cause of the disease), lesions (the result of the disease) and leaflet motion dysfunction (which results from the lesions). Carpentier’s classification of dysfunction is based on the opening and closing motions of the mitral leaflets in relation to the annular plane (Figure 1). It is in this context that degenerative mitral valve disease is best understood.
The most common leaflet dysfunction in degenerative valve disease is Type II, excess motion of the margin of the leaflet in relation to the annular plane. The lesions in degenerative valve disease that result in the Type II dysfunction are usually chordae elongation or rupture. Annular dilatation is almost always an associated finding. The most common diseases that cause degenerative mitral valve disease are Barlow’s disease and fibroelastic deficiency (Figure 2). Barlow’s disease, first described in the 1960s2, is characterized by several distinguishing features. Excess leaflet tissue with large billowing and thickened leaflets is a hallmark of Barlow’s disease, and the annular size is quite large. The chordae tendinae tend to be thickened and have a mesh type appearance in their insertion in the body of the leaflets. Chordal elongation is the most common cause of prolapse, and multiple leaflet segments are usually involved. It generally occurs in younger patients (aged
In contrast, fibroelastic deficiency is a degenerative disease of older individuals (usually >60 years of age), with a shorter history of valve regurgitation3. Rupture, often of a single chord, is the most common cause of leaflet dysfunction in fibroelastic deficiency, and in most cases the only abnormal leaflet tissue is found in the prolapsing segment. The other leaflet segments are often thin and translucent, and of normal height. The posterior annulus may be dilated, but the size of the anterior leaflet and valve are most often normal.
Type I dysfunction with normal leaflet motion and pure annular dilatation is a less common form of degenerative valve disease. It may be associated with conditions that result in significant atrial dilatation such as long-standing atrial fibrillation, or may occur in patients with connective tissue disorders.
(*) Modified from Carpentier A, Adams DH, Filsoufi F. Carpentier’s Reconstructive Valve Surgery. From Valve Analysis to Valve Reconstruction. 2010 Saunders Elsevier.
(1) Carpentier A. Cardiac valve surgery–the “French correction”. J Thorac Cardiovasc Surg1983 September;86(3):323-37.
(2) Barlow JB, Pocock WA. The significance of late systolic murmurs and mid-late systolic clicks. Md State Med J1963 February;12:76-7.
(3) Carpentier A, Chauvaud S, Fabiani JN et al. Reconstructive surgery of mitral valve incompetence: ten-year appraisal. J Thorac Cardiovasc Surg1980 March;79(3):338-48.
Portions excerpted, with permission, Adams DH, Anyanwu AC. The cardiologist’s role in increasing the rate of mitral valve repair in degenerative disease. Current Opinion in Cardiology 2008, 23:105–110.
A.2 Barlow Mitral Valve Disease
The syndrome of mid-systolic click accompanying a systolic murmur was first described in the late 1800s, but it was in the early 1960s that its association with mitral regurgitation was demonstrated by Barlow and colleagues using cine-ventriculography1. Criley et al.2 correctly identified the mechanism of the regurgitation as posterior leaflet prolapse due to excess leaflet motion, coining the phrase ‘mitral valve prolapse’. Carpentier and co-workers later characterized the surgical lesions resulting from the myxoid degeneration present in Barlow’s disease, which included leaflet thickening, large redundant leaflets, chordal elongation or rupture, and annular dilatation. As the myxoid degenerative process often affects the entire valve, patients with Barlow’s disease generally have complex valve pathology and dysfunction, which is most often multisegmental (i.e. involves more than one segment of the posterior or anterior leaflet).
Clinical Presentation
Figure 1: ((a) Transesophageal echocardiography 4 chamber view showing bileaflet billowing with prolapse, large valve size, and thickened leaflet, all hallmarks of Barlow’s disease. (b) Surgical view of the same valve shows thickened tall prolapsing leaflets with excess tissue. (c) Valve has been successfully repaired after ‘complex’ bi-leaflet plasty. Repairs of this nature can only be reproducibly undertaken by reference mitral surgeons – in nonreference settings this valve would generally be replaced.
Patients with Barlow mitral-valve disease are generally adults around the age of 50 years who have known for a long period of time, often decades, that they ‘have a murmur’. Often asymptomatic, patients may have been followed by an internist for years, and referral to a cardiologist and subsequently to a cardiac surgeon is usually triggered by the development of symptoms or signs such as atrial fibrillation, shortness of breath and fatigue, or echocardiographic documentation of ventricular or atrial enlargement, or a decline in ventricular function, often accompanied by varying degrees of pulmonary hypertension. Physical examination most often reveals the presence of a mid-systolic click and a mid to late systolic murmur, which reflects the timing of prolapse in the setting of excess tissue and chordal elongation without chordal rupture (i.e. flail leaflet)2.
Echocardiographic Findings
Echocardiography is a sensitive tool in the differentiation of degenerative mitral valve disease. A striking feature of the patient with Barlow’s disease is the size of the valve apparatus – the leaflets are usually thick, bulky, elongated, and distended; the chords thickened and elongated, often mesh-like in nature; and the annulus dilated and enlarged, often times greater than 36mm in the intercommissural distance (Figure 1). The prolapse is often multisegmental, and involves both leaflets in up to 40% of patients3. The insertion of the posterior leaflet is often displaced toward the left atrium away from its normal insertion in the atrio-ventricular groove, creating a cul-de-sac at the base of the leaflet. The bodies of distended leaflet segments often billow above the plane of the annulus, and the margin of the leaflet segments prolapse in mid-systole in the setting of chordal elongation, or in early systole if chordal rupture has occurred. Calcification of the annulus and papillary muscles may be present. Real time three-dimensional echocardiography is allowing additional clarity of the segmental nature of the billowing, as well as prolapse, in Barlow’s disease4,5,6 and may play a critical role in the preoperative work up of these patients in the future.
Surgical Considerations
The complexity of surgical lesions in Barlow mitral-valve disease is consistent with the echocardiographic findings (Figure 1). Lesions include excessively thick and billowing leaflet segments, chordal elongation and chordal rupture, calcification of the papillary muscles and/or annulus with chordae restriction, and severe annular dilatation with giant valve size. It is important that the cardiologist as well as the surgeon has an appreciation for these lesions, as the complexity of techniques required to achieve a successful repair then becomes obvious in this subset of degenerative mitral-disease patients. Dealing with excess tissue height is an important consideration to reduce the likelihood of postoperative systolic anterior motion. Repair of Barlow valves is thus more complicated and, in our experience, often requires multiple different techniques and 2–3 hours to remove all of the diseased tissue, and reconstruct the leaflets to a normal configuration3.
Table 1: Targeting referral pattern to optimize repair rates.
To achieve a Barlow repair, the surgeon therefore needs to be well versed with various advanced mitral repair techniques, such as extensive leaflet resection, sliding leaflet plasty, chordal transfer, neochordoplasty, commissuroplasty, annular decalcification and use of large annuloplasty rings. Patients with advanced forms of Barlow’s disease will therefore likely have a high probability of successful valve repair only if done in reference centers by mitral subspecialists (Table 1).
Excerpted, with permission, Adams DH, Anyanwu AC. The cardiologist’s role in increasing the rate of mitral valve repair in degenerative disease. Current Opinion in Cardiology 2008, 23:105–110.
(1) Barlow JB, Pocock WA, Marchand P, Denny M. The significance of late systolic murmurs. Am Heart J 1963; 66:443–452.
(2) Criley JM, Lewis KB, Humphries JO, Ross RS. Prolapse of the mitral valve: clinical and cine-angiocardiographic findings. Br Heart J 1966; 28:488–496.
(3) Adams DH, Anyanwu AC, Rahmanian PB, et al. Large annuloplasty rings facilitate mitral valve repair in Barlow’s disease. Ann Thorac Surg 2006; 82:2096–2100.
(4) Sharma R, Mann J, Drummond L, et al. The evaluation of real-time 3-dimensional transthoracic echocardiography for the preoperative functional assessment of patients with mitral valve prolapse: a comparison with 2-dimensional transesophageal echocardiography. J Am Soc Echocardiogr 2007; 20:934– 940.
(5) Patel V, Hsiung MC, Nanda NC, et al. Usefulness of live/real time threedimensional transthoracic echocardiography in the identification of individual segment/scallop prolapse of the mitral valve. Echocardiography2006; 23:513–518. (6) Muller S, Muller L, Laufer G, et al. Comparison of three-dimensional imaging to transesophageal echocardiography for preoperative evaluation in mitral valve prolapse. Am J Cardiol 2006; 98:243–248.
A.3 Fibroelastic Deficiency
In contrast to Barlow’s disease, patients with mitral regurgitation due to fibroelastic deficiency have a lack of connective tissue as the pathological mechanism that triggers leaflet and chordal thinning and eventual chordal rupture1. Carpentier’s group characterized the typical findings in fibroelastic deficiency, noting that the chordal rupture resulting in mitral valve prolapse was often isolated, usually leading to prolapse of a single leaflet segment2.
Clinical Presentation
Figure 1: (a) Transesophageal echocardiography 4 chamber view shows single segment prolapse in a normal sized valve with isolated ruptured chord. The leaflets do not billow. (b) Valve analysis shows an otherwise normal-looking valve with a single chordal rupture to the P2 segment. (c) This valve was easily repaired with a limited triangular resection and ring annuloplasty, techniques that can be reproducibly performed by most experienced cardiac surgeons.
The typical patient with fibroelastic deficiency is over the age of 60 years, and does not have a long history of a heart murmur. Often asymptomatic until the time of chordal rupture, the patient often presents with palpitations or shortness of breath of limited duration. Patients may remain asymptomatic after chordal rupture, and present as a new-onset murmur or abnormal echocardiogram, but this is less frequent than in the setting of Barlow’s disease. Physical examination is remarkable for a holosystolic murmur, often harsh in nature.
Echocardiographic Findings
In contrast to Barlow’s disease, echocardiographic signatures of fibroelastic deficiency include normal or near-normal valve size, thin leaflets and chordae, and typically single segment prolapse, most commonly of the middle scallop of the posterior leaflet (P2) (Figure 1). The prolapsing segment may appear to be distended, thickened, and elongated, while the adjacent segments appear normal in height and consistency. Billowing of nonprolapsing segments is not observed, and bi-leaflet dysfunction is uncommon.
Surgical Considerations
In contradistinction to Barlow’s disease, patients with fibroelastic deficiency often present with minimal, as opposed to excess, tissue (Figure 1), so extensive leaflet resection or complex leaflet remodeling procedures are rarely indicated. In general, a limited quadrangular or triangular resection, or simple leaflet resuspension with a chordal transfer or artificial chord, is all that is required to correct leaflet prolapse. For posterior leaflet prolapse, although the prolapsing segment may look very abnormal, the remainder of the valve is relatively unaffected, so that the surgeon does not usually require advanced techniques to achieve a successful mitral valve reconstruction.
Table 1: Targeting referral pattern to optimize repair rates.
It should, however, be noted that ‘complex’ prolapse can occur in fibroelastic deficiency, usually involving an anterior leaflet segment or a commissural segment, and in this setting more advanced techniques and surgical skill are generally required to perform a successful reconstruction. Otherwise, simple fibroelastic deficiency with P2 prolapse is a condition associated with high repair rates in most experienced surgeons’ hands, and a virtually 100% repair rate within a reference center setting with a mitral repair subspecialist (Table 1).
Excerpted, with permission, Adams DH, Anyanwu AC. The cardiologist’s role in increasing the rate of mitral valve repair in degenerative disease. Current Opinion in Cardiology 2008, 23:105–110.
(1) Anyanwu AC, Adams DH. Etiologic Classification of Degenerative Mitral Valve Disease: Barlow’s Disease and Fibroelastic Deficiency. Semin Thorac Cardiovasc Surg 2007; 19:90–96.
(2) Carpentier A, Chauvaud S, Fabiani JN, et al. Reconstructive surgery of mitral valve incompetence: ten-year appraisal. J Thorac Cardiovasc Surg 1980; 79:338–348.
Numerous studies that have compared long term-survival of patients undergoing mitral valve repair or replacement have consistently shown a survival benefit with mitral valve repair. The ‘repair rate’ is thus an important variable. The ideal repair technique should be applicable to over 90% of cases. Repair rate statistics are not integral to the technique and vary from surgeon to surgeon. Unfortunately, most series do not include repair rates and prospective databases generally do not differentiate etiologies of mitral disease, such that it is not possible to accurately define repair rates for degenerative disease. We believe that the overall replacement rate in degenerative disease may be as high as 50%. In a review of United States practice in 1999 and 2000, 42.4% of patients having isolated mitral valve surgery for valve regurgitation had a valve repair (all etiologies of mitral disease)1. Similarly, in the United Kingdom, 35% of mitral procedures were repairs in 2000-20012. In the United Kingdom, more mechanical mitral valve replacements were performed than mitral repairs (ratio 6:5). We believe that as degenerative disease often occurs in young patients (who are the usual candidates for mechanical valves), and as the incidence of rheumatic disease has declined substantially in western countries, a considerable number of these mechanical mitral valve replacements are likely performed for degenerative disease. Indeed a review of contemporary mitral valve replacement literature shows substantial proportions of replacements for degenerative disease. For example, Bouchard and associates3 in a series examining outcomes of mitral valve replacement, include 213 replacements for degenerative disease over a ten-year period. In another recent study, Yun et al4 randomized 47 patients over two years to two forms of chordal sparing valve replacement; 31 of these patients had degenerative disease. Finally in a series of 154 bioprosthetic implants reported by Rizzoli et al, 34 were performed for degenerative disease5. Repair rates in large published series generally range from 85% to 90%, although most include historical patients from the 1980s. Our philosophy is that repair should be attempted in all degenerative valves. Using this approach we have achieved a 99.5% repair rate over a 4 year period. For mitral valve repair to be the standard of care for degenerative disease, it should be available and applicable to all patients. Certainly any surgeon performing surgery for asymptomatic degenerative disease should have > 95% repair rate for the lesion present, as mitral repair is the only therapy currently advisable in this group6. Current national repair rates, however, suggest that there remains a considerable body of surgical practice that has not embraced systematic repair of degenerative valves.
(1) Savage EB, Ferguson TB, Jr., DiSesa VJ. Use of mitral valve repair: analysis of contemporary United States experience reported to the Society of Thoracic Surgeons National Cardiac Database. Ann Thorac Surg 2003 March;75(3):820-5.
(2) Keogh BE, Kinsman R. Fifth National Adult Cardiac Surgical Database Report 2003. Henley-on-Thames: Dendrite; 2004.
(3) Bouchard D, Pellerin M, Carrier M et al. Results following valve replacement for ischemic mitral regurgitation.Can J Cardiol 2001 April;17(4):427-31.
(4) Yun KL, Sintek CF, Miller DC et al. Randomized trial comparing partial versus complete chordal-sparing mitral valve replacement: effects on left ventricular volume and function. J Thorac Cardiovasc Surg 2002 April;123(4):707-14.
(5) Rizzoli G, Bottio T, Vida V et al. Intermediate results of isolated mitral valve replacement with a Biocor porcine valve. J Thorac Cardiovasc Surg 2005 February;129(2):322-9.
(6) Hayek E, Gring CN, Griffin BP. Mitral valve prolapse. Lancet 2005 February 5;365(9458):507-18.
B.2 Long Term Survival
When interpreting data on long-term survival, it should be appreciated that available data refer to the outcomes of mitral repair and cardiac surgery as practiced 10 to 20 years previously1. Cardiac surgery has, however, since improved in several ways; for example, the widespread adoption of blood cardioplegia has likely reduced the ventricular damage during surgery which in turn will impact long-term survival (as left ventricular function is a major determinant of long-term survival). There is therefore no way of knowing the long-term survival outcomes of mitral valve surgery as currently practiced. Based on existing data, it appears that if surgery is undertaken before onset of symptoms and where left ventricular function is preserved, the life expectancy should be similar to that of the general population2, 3, 4. When significant symptoms of heart failure have developed (NYHA III – IV) before mitral valve surgery is undertaken, the long term survival is significantly reduced (Figure 1), regardless of the left ventricular function5. Similarly, patients with an impaired left ventricular ejection fraction at time of surgery have a reduced long-term survival (Figure 2).
Figure 1: Comparison of observed and expected survival after mitral valve surgery in patients in NYHA classes I-II (left) and classes III-IV (right). Numbers underneath indicate percentage of expected survival achieved.*
Figure 2: Survival after mitral valve surgery according to preoperative echocardiographic ejection fraction (EF). Numbers at bottom indicate patients at risk.**
(1) Adams DH, Anyanwu A. Pitfalls and limitations in measuring and interpreting the outcomes of mitral valve repair. J Thorac Cardiovasc Surg 2006 March;131(3):523-9.
(2) Enriquez-Sarano M. Timing of mitral valve surgery. Heart 2002 January;87(1):79-85.
(3) Mohty D, Orszulak TA, Schaff HV, Avierinos JF, Tajik JA, Enriquez-Sarano M. Very long-term survival and durability of mitral valve repair for mitral valve prolapse. Circulation 2001 September 18;104(12 Suppl 1):I1-I7.
(4) Braunberger E, Deloche A, Berrebi A et al. Very long-term results (more than 20 years) of valve repair with carpentier’s techniques in nonrheumatic mitral valve insufficiency. Circulation 2001 September 18;104(12 Suppl 1):I8-11.
(5) Tribouilloy CM, Enriquez-Sarano M, Schaff HV et al. Impact of preoperative symptoms on survival after surgical correction of organic mitral regurgitation: rationale for optimizing surgical indications. Circulation 1999 January 26;99(3):400-5.
(*) Modified from Tribouilloy CM, Enriquez-Sarano M, Schaff HV, et al: Impact of preoperative symptoms on survival after surgical correction of organic mitral regurgitation: rationale for optimizing surgical indications.Circulation 99 (3):400-5, 1999. Lippincott Williams & Wilkins
(**) Modified from Enriquez-Sarano M, Tajik AJ, Schaff HV, et al: Echocardiographic prediction of survival after surgical correction of organic mitral regurgitation. Circulation; 90(2):830-7, 1994. Lippincott Williams & Wilkins
B.3 Failures and Re-operations
Figure 1: Outcome after mitral valve repair. A,freedom from reoperation in patients with posterior, anterior and bileaflet prolapse. B,freedom from recurrent moderate (3+) or severe (4+) MR according to prolapsing leaflet. AL, anterior leaflet, PL, posterior leaflet, BL, bileaflet prolapse.*
Failure of repair, defined by recurrence of moderate or severe mitral regurgitation, or re-operation for mitral regurgitation are principal endpoints to evaluate the long-term outcomes of mitral valve repair. Failure rates of mitral valve repair are determined principally by the original dysfunction (posterior leaflet, anterior leaflet and bi leaflet) and by repair technique. The longest term follow-up available is for conventional ‘Carpentier’ techniques. Braunberger and colleagues1reported in 2001 on the long term outcomes of 162 non-rheumatic patients (of whom 90% were degenerative) who underwent a Carpentier repair between 1970 and 1984. They observed that 97% of patients with posterior leaflet, 86% with anterior leaflet and 83% of patients with bileaflet prolapse were free of re-operation at 20 years (Figure 1a). They also found 74% were free from cardiac events at 20 years. The difference between freedom from reoperation and freedom from cardiac event rates, however highlights the limitations of re-operation rate as an outcome measure for mitral repair. Because the decision to undergo reoperation is physician and patient dependent, at least some of those patients with cardiac symptoms had recurrent mitral regurgitation, but never underwent reoperation. In the absence of echocardiographic follow-up, there is no way of quantifying the true long-term failure rate. David and colleagues2 also presented 20 year follow-up for patients (operated between 1981 and 2001) using a variety of repair techniques, including conventional Carpentier techniques and gortex neochordoplasty, and found 96%, 88% and 94% freedom from re-operation rates at 12 years for posterior, anterior and bileaflet prolapse respectively. They also reported on freedom from moderate or severe mitral regurgitation – 80%, 65% and 67% respectively at 12 years (Figure 1b) – however, follow-up echocardiographic data was available for only half of the patients. The lack of systematic echocardiographic follow-up is the major limiting factor in determining the true durability of all mitral repair techniques3; most series have focused on survival and re-operation rates which may not necessarily be reflective of the durability of repair.
Figure 2: Freedom from recurrent mitral regurgitation after mitral valve repair. Kaplan-Meier estimates of freedom from non-trivial MR (MR>1/4) and failing repair (MR>2/4). A linearized recurrence rate per year of 8.3% is found for MR grade >1/4. The rate grade >2/4 is 3.4%.**
The most complete and elaborate follow-up for mitral repair in contemporary literature is probably the series of Flameng and associates4 who report a series of 242 consecutive mitral repairs with serial follow-up echocardiography done at 6 month intervals. They found a freedom from moderate or severe mitral regurgitation of 71% at 7 years and found that new recurrent mitral regurgitation appeared at a rate of 3.7% per year (Figure 2). The data of Flameng and colleagues4 suggest that durability of many mitral repairs is limited; the linear recurrence rate implies that recurrent mitral regurgitation is likely a reflection of progression of underlying valve disease. This hypothesis is supported by data from mitral re-operations after previous repair, as the previous repairs are found to be intact in two-thirds of patients, with recurrent regurgitation usually due to new valve lesions (chordal rupture, fibrosis, calcification, leaflet perforation)5. Technical failure can be a major cause of recurrence, particularly with early failures6, but should be minimal in experienced hands. Some surgical factors that predispose to recurrence of mitral regurgitation include the non-use of an annuloplasty ring, and the technique of chordal shortening.
The edge-to-edge technique is a relatively new repair strategy with limited follow-up compared to Carpentier techniques. One large published series from De Bonis and colleagues7 included 133 patients, followed for a median of 3 years, in whom anterior leaflet prolapse was treated with the edge-to-edge technique; they estimated a 10 year freedom from re-operation of 96.5%, but do not include data that allow computation of the freedom from mitral regurgitation rate.
(1) Braunberger E, Deloche A, Berrebi A et al. Very long-term results (more than 20 years) of valve repair with carpentier’s techniques in nonrheumatic mitral valve insufficiency. Circulation 2001 September 18;104(12 Suppl 1):I8-11.
(2) David TE, Ivanov J, Armstrong S, Christie D, Rakowski H. A comparison of outcomes of mitral valve repair for degenerative disease with posterior, anterior, and bileaflet prolapse. J Thorac Cardiovasc Surg 2005 November;130(5):1242-9.
(3) Adams DH, Anyanwu A. Pitfalls and limitations in measuring and interpreting the outcomes of mitral valve repair. J Thorac Cardiovasc Surg 2006 March;131(3):523-9.
(4) Flameng W, Herijgers P, Bogaerts K. Recurrence of mitral valve regurgitation after mitral valve repair in degenerative valve disease. Circulation 2003 April 1;107(12):1609-13.
(5) Cerfolio RJ, Orzulak TA, Pluth JR, Harmsen WS, Schaff HV. Reoperation after valve repair for mitral regurgitation: early and intermediate results. J Thorac Cardiovasc Surg 1996 June;111(6):1177-83.
(6) Shekar PS, Couper GS, Cohn LH. Mitral valve re-repair. J Heart Valve Dis 2005 September;14(5):583-7.
(7) De BM, Lorusso R, Lapenna E et al. Similar long-term results of mitral valve repair for anterior compared with posterior leaflet prolapse. J Thorac Cardiovasc Surg 2006 February;131(2):364-70.
(*) Modified from A, Braunberger E, Deloche A, Berrebi A, et al: Very long-term results (more than 20 years) of valve repair with carpentier’s techniques in nonrheumatic mitral valve insufficiency. Circulation 104(12 Suppl 1):I8-11 2001 Lippincott Williams & Wilkins and B, Reprinted from J Thorac Cardiovasc Surg 130(5), David TE, Ivanov J, Armstrong S, et al, A comparison of outcomes of mitral valve repair for degenerative disease with posterior, anterior, and bileaflet prolapse, 1242-9, Copyright 2005, with permission from the American Association for Thoracic Surgery.
(**) Modified from Flameng W, Herijgers P, Bogaerts K: Recurrence of mitral valve regurgitation after mitral valve repair in degenerative valve disease. Circulation 107(12):1609-13 2003. Lippincott Williams & Wilkins
B.4 Operative Mortality and Morbidity
The operative mortality rate for mitral valve surgery has steadily declined over the past decade, with the current mortality rates reported to the Society of Thoracic Surgery Database in the region of 1.5% for mitral valve repair and 5.5% for mitral valve replacement. There is a suggestion that centers doing large numbers of repairs for degenerative mitral valve disease deliver especially low mortality. For example, David and colleagues1 had only five operative deaths in a series of 701 repairs over 20 years, De Bonis and associates2 reported 2 deaths in a series of 738 repairs over 13 years, while Gillinov and colleagues reported 3 deaths in 1072 repairs for degenerative disease over a-12 year period3. Performing a tricuspid repair at time of mitral valve repair does not appear to increase mortality risk4, but mortality rises to above 3% with concomitant coronary artery bypass surgery5. Complications rates are low for elective mitral valve repair for degenerative valve disease. In our series of 67 consecutive Barlow patients we observed one patient with mediastinitis, one re-operation for bleeding and no strokes6. Major neurological complications should be uncommon in the 1% range, although there are recent data suggesting that patients having surgery via minimally invasive approaches may have a higher incidence of stroke7. Meticulous myocardial preservation is imperative to obtaining good results as the period of aortic clamping is lengthy for complex repairs (in our Barlow’s series we had a mean cardiopulmonary bypass time of 191 minutes)6.
(1) David TE, Ivanov J, Armstrong S, Christie D, Rakowski H. A comparison of outcomes of mitral valve repair for degenerative disease with posterior, anterior, and bileaflet prolapse. J Thorac Cardiovasc Surg 2005 November;130(5):1242-9.
(2) De BM, Lorusso R, Lapenna E et al. Similar long-term results of mitral valve repair for anterior compared with posterior leaflet prolapse. J Thorac Cardiovasc Surg 2006 February;131(2):364-70.
(3) Gillinov AM, Cosgrove DM, Blackstone EH et al. Durability of mitral valve repair for degenerative disease. J Thorac Cardiovasc Surg 1998 November;116(5):734-43.
(4) Dreyfus GD, Corbi PJ, Chan KM, Bahrami T. Secondary tricuspid regurgitation or dilatation: which should be the criteria for surgical repair? Ann Thorac Surg 2005 January;79(1):127-32.
(5) Gillinov AM, Blackstone EH, Rajeswaran J et al. Ischemic versus degenerative mitral regurgitation: does etiology affect survival? Ann Thorac Surg 2005 September;80(3):811-9.
(6) Adams DH, Anyanwu A, Rahmanian PB, Abascal V, Salzberg SP, Filsoufi F. Larger Annuloplasty Rings Facilitate Mitral Valve Repair in Barlow’s Syndrome. Ann Thorac Surg. 2006;82:2096-2101.
(7) Cheema FH, Martens TP, Duong JK et al. Comparison of Minimally Invasive Versus standard Approach to Mitral Valve Surgery: Results from an Audited State-Wide mandatory Database. Ann Thorac Surg. In press 2006.
Most complex mitral valve repair surgery can be performed through a 4 inch sternotomy.
Our Minimally Invasive Heart Surgery Center offers minimally invasive heart valve surgery to selected patients. Not all patients are suitable for minimally invasive surgery. Patients who require additional cardiac procedures like coronary artery bypass surgery, elderly patients, patients with very diseased arteries, and patients with a very weakly contracting heart will not be suitable for this approach. Our paramount objective is to ensure a good valve repair, with no residual leakage, at a low operative risk.Our surgeons will only perform a repair through a small incision when they believe they can do a good quality valve repair at a low risk to the patient; if the valve disease is complicated (as assessed by the echocardiogram) then we recommend a full incision as we believe a larger scar is preferable to an imperfect repair.
Ask the surgeon if this is an option for you.
Different Approaches to Minimally Invasive Heart Surgery
Dr. David Adams and Dr. Ani Anyanwu use special instruments to perform minimally invasive heart valve surgery.
The term “minimally invasive surgery” covers a spectrum of approaches. The goal is to perform surgery through a smaller incision without compromising the safety and long-term results of conventional mitral valve repair. The advantage of a small incision is mainly cosmetic (the scars are smaller and less visible). In some patients, the pain after surgery may be reduced and recovery from surgery is faster when surgery is done through a smaller incision. Operating through small incisions is however more technically demanding and in some cases could reduce the safety of the procedure. This page describes the various incisions, and you can read more about the associated benefits and disadvantages of each.
Lower Sternotomy
Dr. David Adams with Mary D., five weeks after surgery, whose minimally invasive valve repair was performed with a sternotomy.
In this approach the surgeon makes a 4 inch incision over the lower aspect of the midline of the chest and divides only the lower portion of the breast bone to gain access to the valve. This limits the actual amount of opening, and thus chest wall trauma. Through this incision we can easily access the heart and all the major vessels and can perform most complex mitral valve repairs along with aortic valve replacement or coronary artery bypass grafting. This incision has the advantage that if the surgeon encounters problems, he or she can easily extend the incision and divide the remaining breast-bone and convert to the standard approach. When fully healed the lower sternotomy scar is concealed by clothing, even when the patient wears low-necked clothing. In some women the scar is well concealed by their brassiere. It is the most flexible approach to the heart, and it is the approach we use in most patients.
Mini-Thoracotomy
Mitral valve surgery can be carried out through a 2-3 inch incision, usually under the right breast, which allows the surgical team to see and work on the mitral valve directly. The patient is placed on the heart-lung machine either through the same chest incision or through the vessels in the groin via a 1 inch incision. Durable, simple and more complex mitral repairs can be performed, eliminating mitral regurgitation in a wide range of patients.
Thoracotomy
Dr. David Adams shows a thoracotomy incision from a minimally invasive heart valve repair, eight days after surgery.
In this approach the surgeon makes a 4 to 6 inch incision in the right side (instead of middle) of the chest and gains access to the heart by going through the ribs. Some women prefer this incision because the scar may be placed underneath the breast crease and is therefore largely concealed. Access to the heart may be difficult in some cases making it more difficult to achieve a perfect repair.
Low Skin Incisions
Patients who are concerned about cosmesis, but who are not suitable for minimally invasive surgery, can request a low incision. The surgeon can make the standard skin incision start an inch lower and yet perform full division of the breastbone. The scar will therefore not be visible when wearing normal clothing. Patients who cannot have a minimally invasive operation, but who are concerned about the scar, can also request the services of our plastic surgeon to cosmetically close the incision.
Robotic Surgery and Endoscopic Surgery
In these approaches the surgeon performs the operation through several mini-incisions or “port sites”, the largest being about 2 inches. Robotic mitral valve repair is performed using the assistance of a ‘robot’ and specially designed instruments to perform the operation. The surgeon sits at a console and controls the instruments which are mounted on the arms of a robot by another surgeon. Endoscopic mitral valve repair is performed using long instruments placed through the port sites. The patient is placed on the heart-lung machine via blood vessels in the groin. In both cases, the surgeon uses video cameras to see inside the chest cavity.
Although cosmetically superior, these approaches limit the complexity of repair that can be undertaken by the surgeon, and in some cases may compromise on the quality of repair. For this reason, we do not offer these two approaches at Mount Sinai as we cannot guarantee the same high standards of mitral valve repair as we can with other approaches.
B. Non-surgical Management
Asymptomatic mitral regurgitation and
Medical management according to the effective regurgitant orifice (ERO)
Figure 1: Cardiac events among patients with asymptomatic mitral regurgitation and medical management according to the effective regurgitant orifice (ERO). Kaplan-Meier estimates of means ± standard deviation. Cardiac events were defined as death due cardiac causes, congestive heart failure, or new onset of atrial fibrillation.*
As current existing guidelines do not recommend surgery for asymptomatic or mildy symptomatic patients1, there is a large cohort of patients with significant mitral regurgitation that do not undergo surgery, thus allowing for observational studies of outcomes in non-surgically treated cohorts. Additionally, before expanded application of mitral valve repair in the 1990s, cohorts of symptomatic patients with mitral valve prolapse were followed on medical therapy allowing determination of natural history of mitral regurgitation. Mitral valve prolapse with severe regurgitation reduces long-term survival irrespective of medical therapy. It appears that the prolapse itself is not the cause of mortality or morbidity (cardiac event rates are extremely low for the entire population with prolapse), but it is severe regurgitation and consequent left ventricular dilatation that results in morbidity2, 3. Heart failure, arrhythmia, endocarditis and stroke are the leading causes of death. Enriquez-Sarano and colleagues have performed analyses to define which group of patients with mitral regurgitation are at greatest risk of cardiac events4, 5, 6. Notably, when considering asymptomatic patients, the greater the severity of mitral regurgitation (preferably determined by quantitative echocardiography), the higher the frequency of cardiac events irrespective of a normal ventricular function (Figure 1). Other risk factors for cardiovascular morbidity include atrial fibrillation, left atrial enlargement, age > 50 years and thickening of mitral leaflets7 – presence of these factors implies a reduced life expectancy if mitral regurgitation is uncorrected. Current evidence from surgical cohorts, suggests that mitral valve repair (assuming an operative mortality below 1%) yields a better outcome (survival and freedom from cardiac events) compared to the outcomes observed in non-surgically treated patients with severe regurgitation. For example mitral valve repair in patients with good ventricular function has a long term survival similar to expected survival in age matched cohorts5, 8, 9, whereas long term follow-up of patients with mitral valve prolapse treated medically shows a reduced survival compared to expected survival10 (Figure 2).
Figure 2: Long-term survival with medical treatment compared with expected durations of survival for patients with mitral regurgitation due to flailing leaflets. Kaplan-Meier curve of survival.**
It should be emphasized that the alternative to surgical therapy is, strictly speaking, not medical therapy, but observation, as there are no pharmacological options for treatment of severe mitral regurgitation. Data supporting the role of any medical treatment – particularly vasodilators – in the management of severe regurgitation due to degenerative mitral valve disease is scant11. Indeed it has been suggested that vasodilator therapy can lead to paradoxical worsening in mitral regurgitation by shifting the prolapse earlier in the cardiac cycle12. Vasodilator therapy can also mask left ventricular dysfunction and result in (potentially deleterious) delay to mitral valve surgery. According to current guidelines, there is little role for pharmacological treatment in the management of severe mitral regurgitation1.
Figure 1: Comparison of observed and expected survival after mitral valve surgery in patients in NYHA classes I-II (left) and classes III-IV (right). Numbers underneath indicate percentage of expected survival achieved.*
Figure 2: Survival after mitral valve surgery according to preoperative echocardiographic ejection fraction (EF). Numbers at bottom indicate patients at risk.**
Figure 2: Long-term survival with medical treatment compared with expected durations of survival for patients with mitral regurgitation due to flailing leaflets. Kaplan-Meier curve of survival.**
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