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Thursday, September 5, 2019

Lilly into FDA pilot program to modernize drug development

The FDA has accepted Eli Lilly’s (LLY +1.3%) application to enter the Complex Innovative Trial Designs (CID) Pilot Meeting Program aimed at modernizing drug development.
The company’s proposed program involves a master protocol for developing novel approaches to treat multiple type of chronic pain that includes statistical advances and operational efficiencies that, it says, should facilitate faster evaluations of solutions.
The CID program is an initiative under the 21st Century Cures Act and a performance goal under the Prescription Drug User Fee Act VI.

Endo settles Ohio opioid case for $10M

Endo International (ENDP -8.6%) subsidiaries Endo Pharmaceuticals, Endo Health Solutions, Par Pharmaceutical and Par Pharmaceutical Companies have inked an agreement with two Ohio counties and certain related parties to settle their opioid epidemic-related litigation.
Under the terms of the settlement, Endo will pay $10M in cash to the plaintiffs and provide up to $1M of Vasostrict and/or Adrenalin to the counties at no charge without an admission of wrongdoing.
The company announced the settlement in principle on August 20.

Rise in Colorectal Cancer in Young Adults in Many High-Income Countries

The dramatic increase in colorectal cancer (CRC) in younger adults that was reported in the United States is also seen in many other high-income countries, according to a new analysis that included data from 43 countries on six continents.
This study is the first high-quality, global analysis of trends in early onset CRC, according to the authors. It was published online on September 5 in Gut.
The findings are in sharp contrast to the trend among older adults, where CRC rates are declining or stabilizing, most likely in response to preventive screening programs.
“These patterns potentially signal changes in early-age exposures conducive to large bowel carcinogenesis and highlight an urgent need for research to explore the potentially unique etiology of young-onset CRC,” author Rebecca Siegel, MPH, of the American Cancer Society in Atlanta, Georgia, said in a press release.
Disease trends in young age groups are a key indicator of recent changes in risk factor exposures. Rebecca Siegel, MPH
“Although the absolute risk of CRC in adults younger than 50 years is low relative to older adults, disease trends in young age groups are a key indicator of recent changes in risk factor exposures and often foreshadow the future cancer burden,” she continued.
CRC represents the third most common cancer worldwide, with about 1.8 million new cases in 2018, according to background information in the article.
Rates of CRC have been increasing in low- and middle-income countries, most likely related to adoption of western lifestyles.
In contrast, CRC incidence has been stabilizing in higher income countries, especially in the countries that have CRC screening programs. However, the exception is the increase in CRC seen in younger age groups, for which the cause remains unknown.
Siegel and colleagues reported in 2017 on the dramatic increase in CRC among young adults in the United States.
At that time, Siegel told Medscape Medical News: “We think that the increase we’re now seeing is likely related to the obesity epidemic.”
But the picture is more complicated than that, because rates of CRC have increased in parallel with the obesity epidemic. If only obesity caused the trend, rates of CRC would be expected to increase 10 or 20 years after the obesity epidemic started, not at the same time. Most likely, other factors related to excess weight, such as a sedentary lifestyle and unhealthy diets, are independently affecting CRC, Siegel explained.

New Global Analysis

For the new study, Siegel and colleagues analyzed long-term data from high-quality, population-based cancer registries. The analysis compared CRC incidence among individuals aged 20 to 49 years and those aged 50 years and older. These individuals were diagnosed with CRC through 2012 and later for some of the countries with available data.
Over the past decade, the team found that CRC incidence among adults under age 50 increased in 19 countries of 36 countries that had enough CRC cases to be included in the analysis.
In nine of the countries that showed an increase in early onset CRC, the incidence of CRC among older individuals was either stable or decreased (Australia, Canada, Denmark, Germany, New Zealand, Slovenia, Sweden, United Kingdom, and United States).
South Korea had the fastest increase in the incidence of early onset CRC (average annual percent change [AAPC], 4.2; 95% confidence interval [CI], 3.4 – 5.0).
In most countries, the increase in early onset CRC began in the mid-1990s.
In Cyprus, Netherlands, and Norway, the rate of increase of early onset CRC was twice as fast as that seen in older individuals. For example, Norway had an AAPC of 1.9 (95% CI, 1.4 – 2.5) in the younger age group, compared with 0.5 (95% CI, 0.3 – 0.7) among those over age 50.
However, not all the countries included in the analysis showed this increase in early onset CRC. The incidence was stable in 14 countries, and it showed a decrease in three countries (Austria, Italy, and Lithuania).
The authors mention several potential limitations. The analysis lumped cancer of the appendix into CRC cases. Doing so may have affected the accuracy of results, because cancer of the appendix may have different characteristics than other types of CRC, they point out.
Also, the study did not have long-term data on CRC incidence for most countries, and it lacked high-quality data for many low- and middle-income countries.
Nevertheless, the authors conclude: “Improving awareness of the marked increases in young-onset CRC incidence could facilitate more diligent assessment of cancer family history by primary care clinicians, as well as follow-up of symptoms in young individuals, many of whom are diagnosed at a late stage.”
Indeed, a recently reported survey of patients and survivors of young-onset CRC revealed that the disease is often initially misdiagnosed in these patients, which may explain why the disease is often advanced when it is eventually diagnosed.
The authors have disclosed no relevant financial relationships.
Gut. Published online September 5, 2019. Abstract

‘Snack Tax’ Can Have Much Greater Impact Than Levy on Soft Drinks

Taxing sugary snacks like cookies and cakes may have a substantially larger impact in fighting obesity than levies on sweetened drinks, suggests a new study.
Using economic modeling, UK researchers found that increasing sugary snack prices by 20% had an effect on annual calorie intake, body mass index (BMI), and obesity prevalence much greater than that of a similar price increase in sweetened beverages.
Taxing sugary snacks would be linked to an estimated 2.7% decrease in the prevalence of obesity in the UK in the first year, they estimate.
“This analysis provides policymakers with estimates of the relative magnitude of plausible impacts if a scenario of price increase in high sugar snacks were to be implemented and suggests that this option is worthy of further research and consideration as part of an integrated approach to tackling obesity,” write Pauline Scheelbeek, MPH, PhD, of the London School of Hygiene and Tropical Medicine, and colleagues in their article published online in BMJ.
In an accompanying editorial, J. Bernadette Moore, PhD, University of Leeds, UK, and Barbara A. Fielding, PhD, University of Surrey, UK, write: “The novelty in Scheelbeek and colleagues’ data is the suggestion that increasing the price of sugary snacks might be more effective at reducing BMI than increasing the price of sugar sweetened beverages.”
The results are likely relevant to other countries where consumption of sugar sweetened beverages has decreased in response to research, policy, and advocacy activities, they note.

Additional Interventions Needed to Reduce Sugar Intake

Between 1975 and 2016, rates of obesity tripled worldwide. In the UK, obesity is estimated to affect around one in four adults and one in five children aged 10 to 11 years, with higher rates among those living in more deprived areas.
The use of taxes to lower sugar and energy intake have mainly focused on sugar sweetened drinks and there is currently a “sugar” tax on such beverages in the UK, introduced in 2018.
But high sugar snacks, such as cakes, chocolates, and sweets, make up more free sugar and energy intake than soft drinks in the UK, so reducing these purchases has the potential to make a greater impact on population health, the researchers point out.
They add that several countries, including Mexico, Finland, and Hungary, have introduced taxes on unhealthy foods, including high sugar snacks. “Early evaluations show a major reduction in the purchase of such foods,” they note.
Encouraged by the large reformulation efforts of the food industry after the soft drink industry levy was introduced, Public Health England developed a voluntary sugar reduction and reformulation program for snacks, “but the initiative has been only modestly successful…highlighting the need for additional interventions to reduce sugar intake,” say Scheelbeek and coauthors.

Average Weight of UK Adult Would Drop by 1.3 kg a Year

Their analysis included nationally representative data from 36,324 households and 2544 adults in the UK. Researchers separated analyses by income group and BMI (overweight: BMI ≥ 25 and < 30 kg/m2; obesity: BMI ≥ 30 kg/m2).
Results for all income groups combined showed that increasing the price of sugary snacks by 20% would result in an average annual decrease in consumption of 8900 calories, an average decrease in weight of 1.3 kg (2.2 lb), and an average drop in BMI of 0.53 kg/m2, in the first year
These changes would lead to a drop in the prevalence of obesity of 2.68% in the first year, the researchers estimate.
Furthermore, the impact of taxing sugary snacks was much greater than a similar price increase for sugary drinks, which was linked to weight loss of only 0.2 kg (0.4 lb) in the first year.
They also found that the impact of taxing sugary snacks would be largest in low income groups. Among low income households, the prevalence of obesity would drop by 3.1%, compared with 2.5% in middle income households and 2.3% in high income households.
The authors note that these findings may also be applicable to countries with similar eating habits to the UK, such as Australia — where sugary snacks are a greater culprit in the contribution to obesity than soft drinks — but might not apply to countries where people drink a lot of sugary beverages, like Mexico.

Taxing Sweet Snacks Doesn’t up Consumption of Healthy Foods

In their editorial, however, Moore and Fielding also urge caution when interpreting the results.
“The reformulation of products in response to consumer demand can…have unintended consequences, such as substituting one unhealthy ingredient for another,” they observe.
And while fiscal policies aimed at reducing consumption of sugar, salt, and saturated fat “might be useful,” they “fail to incentivize the consumption of healthy foods.”
Ultimately, tackling obesity- and diet-related diseases requires close scrutiny of the social determinants of food environments and “a systemic, sustained group of initiatives aimed at reducing health inequalities,” they conclude.
England’s former chief medical officer, Professor Dame Sally Davies, has previously said the UK government should be prepared to impose higher taxes on unhealthy foods and use the proceeds to make fruit and vegetables more affordable.
One or more authors have reported receiving support from the National Institute for Health Research Policy Research Programme. Moore and Fielding have reported no relevant financial relationships.
BMJ 2019;366:l4786, l5298. Full textEditorial

PainWeek: Forget Detox for Substance Use Disorder

There’s a lot more to substance abuse disorder than physical dependence, which means that acute detox treatment by itself isn’t an effective therapy, a researcher said here.
The real key, said Debra Gordon RN, DNP, of the University of Washington in Seattle, in a talk here at the annual PAINWeek conference, is establishing a relationship with patients so that behavioral changes can be implemented.
Withholding opioids from patients with substance use disorder will not cure their addiction, she said. Moreover, providing them with opioids will not necessarily worsen their addiction and may help them accept behavioral therapies.
“There is no evidence that detoxing someone in an acute situation or hospital setting is going to impact that disease,” Gordon said in a presentation. “In fact, the evidence seems to be they will be more at risk for using at their discharge and having an overdose, some of that being in the prison system, but you see that in hospitals too.”
Patients with substance use disorder continue to use drugs despite recurrent problems in their social, workplace, or familial spheres that occur because of their use. Many take multiple substances and have underlying mental health disorders, both of which need to be screened for, Gordon said.
These patients have a higher pain threshold and the prevalence of chronic pain is also much higher in patients with drug abuse disorder. As such, using the Numeric Rating Scale (NRS-11) to define their pain will be insufficient, and providers should determine whether the source of pain is acute, chronic, or related to the patient’s addiction.
Clinicians should also anticipate that patients with substance abuse disorder may have had negative experiences with the healthcare system previously, Gordon said, and asking open-ended questions without judgment may mitigate feelings of shame or fear that prompt them to withhold information.
Seemingly obvious physical comforts, like turning off the lights or keeping a room quiet, also go a long way as well, Gordon said. Cognitive behavioral therapy can also help patients change their perception of pain and help with sleep, mood, and anxiety issues co-occurring with substance use disorder.
Still, some patients may not be willing to change, and others may try to use within the hospital. When encountering patients who deny having a problem, or who recognize the disorder but are unwilling to change, providers should focus on helping them transition out of the hospital when the time comes and providing naloxone emergency overdose kits to patients who may return to illicit drug use.
“Failure to engage in treatment is not a failure,” Gordon said. “It’s part of the process and it’s part of the disease.”
But despite the treatment options available for patients with substance abuse, some providers may be unaware they exist, or may be unsure of what they are authorized to provide, Gordon said.
“There are barriers in the healthcare system in terms of the way we’ve traditionally been trained and traditionally work in silos, and to care for this population we have to really have a team approach,” Gordon told MedPage Today. “It’s one thing to say stuff on paper and another to try and find out how it works in the real world.”
Gordon did not report any disclosures.

Fairly Modest Health Reform May Create More Value Than ‘Medicare for All’

Twelve years ago, February, Barack Obama stood in front of a freezing crowd on the steps of the Old State Capitol in Springfield, Illinois, and launched his campaign for the presidency. A major theme of his campaign was the need to provide health coverage for then estimated 50 million Americans who lacked it. Fulfilling this promise in the face of a serious financial crisis consumed the first third of his first presidential term and brought us the 2010 Affordable Care Act (ACA).
Obama expended every dime of his political capital on arresting the country’s slide into a depression and on his health policy agenda. His reward: loss of control over Congress in 2014, the rise of the Tea Party, and eventually a president named Donald Trump. Much of this was a reaction to what sadly became known as “ObamaCare.”
As we enter a new political cycle, like swallows returning to Capistrano, aspiring Democratic presidential candidates have returned to universal coverage through the strategy of “Medicare for All,” as a rallying point. If anything, true Medicare for All is a far more ambitious policy goal than either Obama or President Bill Clinton and First Lady Hillary Clinton advocated: It abolishes private insurance (which covers about half of Americans) and places health spending (and provider incomes) firmly under the control of the federal government.
Although it is still early days, it seems likely that a successful Democratic president in 2020 would need Johnsonian majorities in Congress to sunset a one trillion dollar industry and dramatically reduce the income of another. Paul Krugman, no conservative, has recently written:
“And there’s one big fact on the ground that any realistic health strategy has to deal with: 156 million Americans—almost half the population—currently receive health insurance through their employers. And most of these people are fairly satisfied with their coverage. A Medicare for All plan would in effect say to these people: ‘We’re going to take away your current plan, but trust us, the replacement will be better. And we’re going to impose a bunch of new taxes to pay for all this, but trust us, it will be less than you and your employer currently pay in premiums.’
The thing is, both claims might well be true! A simple, single-payer system would probably have lower overall costs than a hybrid system that preserves some forms of private coverage. But even if optimistic claims about Medicare for All are true, will people believe them?”
In other words, will voters have enough faith in the power and competence of the federal government to believe that the benefits of Medicare for All will be worth the price paid?

Is Universal Coverage The Most Effective Solution To The Nation’s Health Problems?

What is concerning about the emerging 2020 policy debate is the thus far unchallenged assumption that closing the remaining insurance coverage gap is the only valid health policy goal. The ACA brought the percentage of uninsured Americans down into the high single digits for the first time in our political lifetimes and got us far closer to “universal” coverage than most people realize.
Of the estimated 27.4 million uninsured Americans in 2017, roughly 19 million were eligible for either Medicaid or publicly subsidized coverage on the ACA exchanges (state or federally facilitated) or else declined coverage offered by their employers, mainly for reasons of cost. In the absence of a stronger individual mandate or more generous subsidies, that is as close as we get. Another four million uninsured are undocumented immigrants. That is, 83 percent of the remaining uninsured Americans either declined proffered coverage or were not citizens.

What Are We Trying To Maximize?

It might be helpful for health policy advocates to ask: Are we right in assuming that Americans’ health is best improved by getting from 90 percent to 100 percent of the population covered? This question takes on greater poignancy given that:
  • 2020 may mark the first four-year-long decline in US life expectancy since the US Civil War, and that US life expectancy is only four months longer than Albania’s. According to the Economist, a 15-year-old American has less of a chance to reach age 50 than a citizen of Bangladesh!
  • In 2017, 117,000 Americans, roughly the population of Odessa, Texas, either committed suicide or died of drug overdoses.
  • African American women have a five-fold higher likelihood of dying in or after childbirth than Americans of other ethnicities, and the overall US maternal death rate has risen by a sickening 56 percent since 1990, while other major countries have cut it by half or more.
Is the most effective solution to these problems “universal” health coverage or somehow addressing the gaps in a crumbling society through which more and more people are tumbling to the pavement? Put another way, are there more achievable alternatives to universal health coverage that more directly address those challenges that give rise to illness, at a smaller total price tag in dollars and disruption?
There is ample circumstantial evidence that the fraying of the social and economic fabric of the country might be the real source of the declines in health status in the US. The rise in what Angus Deaton and Anne Case called “death of despair,” or indeed the rise in overall deaths in mid-life, are not randomly distributed geographically (see p. 414, figure 9). Areas that have been struggling economically for decades—what one might term “greater Appalachia,” the deep South, and much of the “desert Southwest” (which contain many of the nation’s Native American reservations)—seem to have been the worst hit. While it is entirely possible that a broader-based expansion of Medicaid might have alleviated some of this trend (for example, by bringing more generous funding of drug treatment to addiction hot spots), an alternative approach might have addressed the social causes of poor health more directly.

A Better Way Forward

Below, I advocate a three-fold approach: block grants for community-based efforts to address social determinants of health, expanded public health funding targeted at strengthening primary care and social care, and a limited expansion of Medicare targeted at the oldest and sickest uninsured.

Increase Social Funding Targeted At Social Determinants Of Health, Including Homelessness, Drug Dependency, Suicide Risk, Food Insecurity, And Domestic Violence

While poverty may be the root cause of a lot of the socially driven causes of premature death and disparities, a new “war on poverty” is probably not the most efficacious solution. Repair of the social safety net in economically troubled areas might have a more immediate and tangible effect. Some examples: drug intervention, detox and sober supports including employment, housing-first homeless initiatives with organized mental health follow-on, tighter links of emergency services to drug rehabilitation, and mental health services for those who have attempted or are contemplating suicide.
A cookie-cutter “federal” initiative here won’t work. The approach taken in Grand Junction, Colorado, is going to look much different than the one taken in Hardwick, Vermont, or Pine Bluff, Arkansas. Moreover, neither businesses nor faith-based organizations should be excluded from funding; the funding model should be flexible enough to encompass both for for-profit and not-for-profit organizational models. The federal agency that provides matching funding should help foster local “incubation” of bright ideas and help scale-up the ones that show measurable health status improvement. The key is broad-based community participation, underwriting compelling business/care models, and the potential to employ many of those at risk in helping others.

Guarantee Universal Access To Primary Care Services Through Public Health Expansion

By international standards, the United States grossly underinvests in public health. At $85 billion a year, public health spending was less than 2.5 percent of total US health outlays in 2017. Strengthening the primary care end of this public system is a high-leverage, cost-effective way to reach the remaining uncovered, as well as those loosely connected to a regular source of care. (Almost 17 percent of the US adult population does not have a regular source of care.
If we cannot, for political reasons, guarantee every citizen comprehensive health coverage, we can guarantee that every person who wants a primary care physician or regular source of primary care can have one. This approach proposes increasing the capacity of the federally qualified health centers (FQHCs) and public hospital systems’ community care networks in the near suburbs where the poor and near poor have been pushed by gentrification.
Care in the FQHCs is provided not just by physicians but also advanced practitioners, social workers, and rehabilitation specialists. FQHCs are an excellent resource for providing the prenatal care minority populations need to identify and close maternal death risks. There is clear evidence that FQHCs reduce health spending and service demand.
FQHC funding was significantly increased (nearly doubled) under the ACA, then reduced along with other public health funding in the out years, both by appropriations cuts and the 2012 sequester. But expanding the FQHCs is far less expensive than funding more “Insurance” coverage for a meaningful percentage of those who remain uninsured. Assuring access to primary care through public provision might cost merely single-digit billions per year, rather than the $21 trillion 10-year price tag for Medicare for All.
Concerns about controlling the total cost of care could be alleviated by agreeing that public programs (Medicaid, Medicare, and the Veterans Health Administration) would capitate both the FQHCs and organized primary care groups for managing the total cost of their expanded patients base. Emphasis would be given to capitating those dually eligible for Medicare and Medicaid. One of the only definitive pieces of good news from the now nearly 15-year experiment with accountable care organizations (the physician group practice demo began in 2005) is that organized physician groups including the FQHCs can succeed in managing population health at risk! 

Medicare Expansion Targeted At Older Uninsured Americans

It is one thing to be 26 years old, immortal, and uninsured. It is quite another to be 52 years old, diabetic, and uninsured. Nearly nine million, or more than 30 percent, of the uninsured are older than age 45. These, the sickest of the uninsured, are much sicker yet when they become eligible for Medicare at age 65, and they stay more expensive for seven years after enrollment. Expanding Medicare coverage to those stranded in midlife without coverage would directly address the bulge in midlife death rates Deaton and Case identified in their troubling 2015 paper.
As Paul Starr, an advocate of breaking the age 65 barrier for Medicare enrollment, has pointed out, most of the newly eligible have already been contributing to Medicare for decades, and even with income-related subsidies, enrolling them would be less expensive per capita than the current Medicare population.
If current enrollment trends were replicated, half of the newly covered under age 65 folks would choose Medicare Advantage, which controls rates for out-of-network services and is much cheaper than coverage under the ACA exchanges. These newly enrolled folks would be ideal candidates for enhanced Medicare models that incorporate chronic care management and some long-term care services, such as CareMore and SCAN have developed in Southern California.
Blurring the lines between acute “sick care” and chronic care is the key to reducing long-term health cost trends for Medicare. The newly enrolled would join roughly nine million younger than age 65 folks who are already on Medicare because they are receiving Supplemental Security Income (SSI) benefits from Social Security. However, the two-year waiting period faced by SSI folks for Medicare eligibility, a relic of a prior age, has limited enrollment of the many chronically ill mid-lifers, many of whom are unwilling to run the gauntlet to get Social Security disability coverage.
Creating a Medicare buy-in option for uninsured folks under the age of 65 who are not disabled would be politically complex. Hospital opposition effectively prevented adding Medicare expansion for people younger than age 65 to the ACA. If it creates the potential for corporate employers to terminate coverage of older workers, the downstream effect of voluntary Medicare buy-in after age 50 would be to damage hospital earnings by accelerating the erosion of their privately insured patient base. Navigant discovered that the difference between a “leak-proof” Medicare buy-in, which prevented employers from dumping older workers, and a leaky one that permitted this cost a hypothetical $1.4 billion health system $90 million dollars in lost earnings. Solving the leakage problem would neutralize hospital opposition and add the sickest of the uninsured to coverage by the most cost-effective method.

Summing Up

There is ample room for improvement in US health outcomes by reducing disparities between population groups and addressing the spike in mortality in mid-life. We should redouble efforts to close gaps in states that have not expanded Medicaid coverage under the ACA. But elimination of private insurance and installation of a single government-run universal health plan is a bridge too far in the likely political environment of the 2020s and frankly does not make as much policy sense as the ideas outlined above.
Thus, political leaders should close gaps in social care, expand the public-health primary care infrastructure, and execute limited coverage expansion for mid-life Americans. Costing out this alternative pathway is beyond the scope of this conceptual essay.

Abbott in 1st Pivotal Trial of New Repair of Leaky Tricuspid Heart Valves

Abbott (NYSE: ABT) today announced the launch of the company’s TRILUMINATE Pivotal trial to evaluate the safety and effectiveness of the company’s TriClip transcatheter tricuspid valve repair system for the treatment of severe tricuspid regurgitation (TR). This is the first pivotal Investigational Device Exemption (IDE) trial in the U.S. to evaluate a catheter-based, non-surgical treatment for patients with severe TR – a condition in which the valve doesn’t close properly, allowing blood to flow backward into the heart, which forces the heart to work harder. In severe cases, this condition can potentially lead to heart failure if left untreated.i.ii.iii
In the U.S. alone, approximately one in 30 people over the age of 65 have moderate to severe TRiv. Despite the prevalence of tricuspid valve disease, the tricuspid valve is often referred to as the “forgotten heart valve” as treatment options are limited. There are currently no approved non-surgical, minimally invasive treatments for people with severe TR.
The first enrollments in the TRILUMINATE IDE study occurred at Abbott Northwestern hospital in Minneapolis, Minn., led by Paul Sorajja, M.D., and his cardiac team. Dr. Sorajja also serves as the trial co-primary investigator.
“Patients with symptomatic tricuspid regurgitation are often at an increased risk for conventional surgery. As a result, many are not referred for intervention,” said David Adams, M.D., Chairman of the Department of Cardiovascular Surgery at the Icahn School of Medicine at Mount Sinai and the Cardiac Surgeon-in-Chief of the Mount Sinai Health System and co-primary investigator in the trial. “The opportunity to assess how we can better treat these patients with a minimally invasive approach is critical and  we’re excited about the potential for this therapy in improving the quality of life for these patients.”
The TRILUMINATE Pivotal study is a prospective, multi-center, randomized, controlled global study of approximately 700 patients expected to enroll in the United StatesCanada, and Europe. Patients will be randomized to receive either the TriClip device or medical therapy and followed for a total of five years. The study will also have a single arm for the treatment of subjects with more complex tricuspid valve disease.