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Meeting unmet needs in aortic valve disease

The Lotus™ Valve System represents a major and cost-beneficial advance in the treatment of cardiac valve stenosis
Dr Theresa Saklatvala
Hospital Healthcare Europe
Aortic valve stenosis results in an abnormal narrowing of the aortic valve opening, restricting the passage of oxygenated blood out of the left ventricle and into the aorta, causing the heart to work harder to pump a sufficient volume of blood. Symptoms of this condition include dyspnea, angina and syncope.
It affects 3% of people over the age of 65 years(1) and 5% of people over the age of 75 years,(2) an incidence of escalating proportions in an ageing population.
It can be the result of congenital abnormality or of infections, such as rheumatic fever or endocarditis,(3) but the most common cause in Europe is the build-up of calcium on the valve cusps that one sees with increasing age.(4)
In Europe, there are 1.2 million patients with severe, symptomatic aortic stenosis.(5,6) Once symptoms have been picked up, the average survival rate is 50% at two years(7) and 20% at five years.(8)
Unmet clinical need
Whereas the most common treatment is valve replacement during open heart surgery involving cardiopulmonary bypass, approximately 30% of patients are at too high a risk to undergo surgery, due to advanced age, advanced left ventricular dysfunction or various comorbidities.(9)
Major advances have been made through the development of Transcatheter Aortic Valve Implantation (TAVI) technology, in which the procedure is carried out by mounting the prosthetic valve on a catheter inserted through a small incision in the leg (femoral artery), and is tracked up the artery until it reaches and displaces the native aortic valve leaflets. The first randomised TAVI clinical trial, the PARTNER Trial, showed that this technique results in a significant improvement in all-case death rates at one year with 30.7% with TAVI compared to 50.7% with standard therapy.(10)
But early TAVI devices are limited by the occurrence of stroke, difficulties with precise positioning and paravalvular leakage (PVL).
PVL defines the unmet clinical need in TAVI. This leakage refers to the blood that backflows into the ventricle through gaps between the outer surface of the prosthetic valve and the abnormal native valve, and occurs due to either undersizing of the valve and/or valve malpositioning and/or irregular annulus.(11,12) The mortality risk following TAVI increases between 2.4 and 4.3-fold with moderate-to-severe PVL,(13–18) and it is PVL that is the strongest predictor of post-procedural mortality.(14,17,19) Some form of PVL is seen in the majority of patients receiving TAVI, with moderate-to-severe PVL seen in 9–21% of TAVI patients post procedurally with CoreValve™ and 6–13.9% of cases with Sapien XT™. 
In addition to raising the mortality rate by almost three-fold, a Canadian cost-effectiveness study has estimated the cost of PVL following TAVI to be €5587.(20)
In summary, the unmet needs have been around valve repositioning and a new-generation device should be able to reduce PVL, permit a simple, precise and atraumatic aortic/ventricular repositioning and allow full atraumatic retrieval.
The new Lotus™ Valve System is the first device of its kind with an Adaptive Seal™ technology, designed to promote annular sealing and prevent paravalvular leakage.
Controlled, accurate, predictable positioning
It is designed to be fully retrieved, redeployed or repositioned, including after full deployment and prior to release. Complete control of positioning during deployment is especially important where challenging anatomy is an issue. Deployment of the valve is via controlled mechanical expansion, and is neither self-expanding nor balloon expandable. It expands radially as it shortens, and accuracy of positioning is aided by a central radiopaque marker.
Clinical programme
The clinical programme supporting the Lotus™ Valve System is called REPRISE (REpositionable Percutaneous Replacement of Stenotic Aortic Valves though Implantation of Lotus Valve SystEm™) (see Table 1). It consists of three parts: REPRISE I (to demonstrate acute safety and successful deployment in symptomatic patients with calcified stenotic aortic valves); REPRISE II (to demonstrate safety and performance); and REPRISE III (a pivotal investigational device exemption trial, to support FDA approval in the US).
REPRISE I involved 11 high-risk patients with severe aortic valve disease, at three sites in Australia, in a prospective, single-arm feasibility study, examining the 23mm Lotus valve. Data proved successful deployment, with no moderate or severe PVL either after valve placement or at discharge. No major adverse cardiovascular or cerebrovascular events were seen in 91% of patients. Safety and efficacy were shown for up to 180 days.
REPRISE II involved 120 symptomatic high-risk patients aged 70 years or older in 14 sites in Australia, France, Germany and the UK in a prospective, single-arm, multicentre trial, with follow-up at discharge/seven days, three months, six months, one year and annually for five years. Valves of 23 and 27mm were implanted. Device performance primary endpoint was measured by mean aortic valve pressure gradient at 30 days, while safety primary endpoint was all-cause mortality at 30 days.
The Lotus™ Valve System translated into 100% implantation success in its 120 patients, with no procedural complications(21) and the lowest incidence of major vascular complications, such as perforation, dissection and haematoma, when compared to Sapien™ (Edwards), Sapien XT™ (Edwards) and CoreValve™ (Medtronic). Zero procedural complication was reported for TAV-in-TAV, aborted procedure, aortic rupture, aortic dissection, cardiopulmonary bypass, valve embolisation, ectopic valve placement, valve migration, non-study valve implantation and repeat procedures for valve dysfunction. 
Lotus™ Valve was associated with moderate PVL among 1.0% (1/103) of patients after 30 days, and 0% (0/52) had moderate or severe PVL after six months.(22) PVL was 92–96% lower than that seen in comparable trials. Although not directly comparable with Lotus™ Valve (no head to head trials), the PARTNER II trial (severe inoperable aortic stenosis patients randomised to transfemoral TAVI with Sapien™ (n=276) or Sapien XT™ (n=284)) reported moderate-to-severe PVL of 16.9% (Sapien™) and 24.2% (Sapien XT™) after 30 days.(23) The PARTNER trial reported moderate-to-severe PVL of 11.3% after six months and 8.1% after one year for pooled Sapien™ Cohorts (inoperable and high risk).(10,24) In the CoreValve™ US pivotal trial, 30-day moderate-to-severe PVL included 11.5% of patients.(25) Given that moderate-to-severe PVL raises mortality risk by almost 200%,(13) the observed reduction of PVL is likely related to the observed lower mortality compared to some other TAVI devices.(9,26–29)
Although not directly comparable, available data show that it was associated with lower mortality rates at six months(30) and disabling stroke rates at 30 days than Sapien™, Sapien XT™(23,24) or CoreValve™.(25)
The Lotus™ Valve System is associated with the lowest all-cause six-month mortality among currently available TAVI systems (6.8% versus ≥14.0%) and the lowest 30-day disabling stroke rate (1.7% versus ≥2.40%). 
It received its CE Mark in October 2013, and signifies a unique and effective alternative treatment for patients with severe aortic stenosis at high risk with surgical valve replacement.
Potential for cost reduction
Speaking at the 2013 PCR London Valves Congress, Dr Dan Blackman, Consultant Cardiologist at Spire Leeds Hospital in the UK, postulated ‘since the valve is fully repositionable, there should not be (and has not been in the REPRISE studies) any need for the use of more than one valve in the same procedure. Since with both CoreValve™ and Sapien™ there is a small incidence of two valves (2–3%), this will be a cost saving’.
Additionally, ‘the absence of any patients with moderate or severe aortic regurgitation (AR)/PVL should save money through: reduction in AR/PVL-related mortality; reduction in need for re-intervention for moderate or severe AR/PVL (post-dilation/valve in valve/conversion to aortic valve replacement; improvement in quality of life due to absence of moderate or severe AR; savings in drugs/clinics/re-hospitalisation related to AR/PVL’.
The Lotus™s Valve System has unique design features that contribute to its value in the treatment of severe aortic stenosis. 
It is the first device that, while optimising clinical outcomes, may also contribute to economic benefits for hospitals. Further economic modelling and analysis are needed to determine the cost-saving potential.
Key points
  • Severe aortic stenosis is expensive and challenging to treat, representing a high unmet need
  • The Lotus™ Valve System has unique design features
  • REPRISE II patient experience few complications
  • The Lotus™ Valve System is associated with low mortality rates at six months, and a lower incidence of PVL
  • Patients experience improved functional capacity at six months
  • Economic modelling indicates that the Lotus™ Valve System may lower costs
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  2. Lester SJ et al. The natural history and rate progression of aortic stenosis. Chest 1998;113:1109–14.
  3. World Health Organization (WHO).
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  5. Bordoni B et al. Prevalence of degenerative aortic valve stenosis in the elderly; results of a large community-based epidemiological study. G Ital Cardiol 2013;14:262–8.
  6. Iung B et al. Valvular heart disease in the community: a European experience. Curr Probl Cardiol 2007;32:609–61.
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  9. Iung B et al. Decision-making in elderly patents with sever aortic stenosis: why are so many denied surgery? Eur Heart J 2005;26:2714–20.
  10. Leon MB et al. Aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597–1607.
  11. Martinez CA et al. Management of paravalvular regurgitation after Edwards SAPIEN transcatheter aortic valve replacement: Management of paravalvular regurgitation after TAVR. Catheter Cardiovasc Interv 2013;82(2):300–11.
  12. Genereux P et al. Paravalvular leak after transcatheter aortic valve replacement: the new Achilles’ heel? A comprehensive review of the literature. J Am Coll Cardiol 2013;61(11):1125–36. 
  13. Toggweiler S et al.  5-year outcome after transcatheter aortic valve implantation. J Am Coll Cardiol 2013;61(4):413–9.
  14. Abdel-Wahab M et al. Aortic regurgitation after transcatheter aortic valve implantation: incidence and early outcome. Results from the German transcatheter aortic valve interventions registry. Heart 2011;97(11):899–906. 
  15. Gotzmann M, et al. Transcatheter aortic valve implantation in patients with severe symptomatic aortic valve stenosis-predictors of mortality and poor treatment response. Am Heart J 2011;162(2):238–45. 
  16. Sinning JMet al.  Aortic regurgitation index defines severity of peri-prosthetic regurgitation and predicts outcome in patients after transcatheter aortic valve implantation. J Am Coll Cardiol 2012;59(13):1134–41. 
  17. Tamburino C et al. Incidence and predictors of early and late mortality after transcatheter aortic valve implantation in 663 patients with severe aortic stenosis. Circulation 2011;123(3):299–308.
  18. Van Belle E. et al Procedural predictors of Post-TAVR Aortic Regurgitation for Balloon-expendable and Self-expendable devices? Insights from the France 2 registry. Presented at ESC 2013 Amsterdam; 2013. 
  19. Kodali SK et al. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012;366:1686–95.
  20. Hancock-Howard RL et al. Cost effectiveness of transcatheter aortic valve replacement compared to medical management in inoperable patients with severe aortic stenosis: Canadian analysis based on the PARTNER Trial Cohort B findings. J Med Econ 2013;16(4):566–74. 
  21. Shakour P et al. Lotus™ valve system clinical experience summary;2013. 
  22. Meredith IT. Six-month outcomes for the first 60 patients in a clinical study of a repositionable second generation device for transcatheter aortic valve implantation. Presented at the 4th PCR London Valves. London: 2013. 
  23. Leon MB. A Randomized evaluation of the SAPIEN XT Transcatheter Valve System in patients with aortic stenosis who are not candidates for surgery: PARTNER II, Inoperable Cohort. Presented at the 62nd Annual American College of Cardiology Scientific Session & Expo;2013.
  24. Smith CR et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 2011;364(23):2187–98.
  25. Popma JJ. CoreValve US Pivotal Trial Extreme Risk Iliofemoral Study Results. Presented at the 2013 TCT Conference, San Francisco. 
  26. Vaes B et al. The prevalence of cardiac dysfunction and the correlation with poor functioning among the very elderly. Int J Cardiol 2012;155(1):134–43. 
  27. Buellesfeld L et al. 2-year follow-up of patients undergoing transcatheter aortic valve implantation using a self-expanding valve prosthesis. J Am Coll Cardiol 2011;57(16):1650–7. 
  28. Grube E et al. Percutaneous aortic valve replacement for severe aortic stenosis in high-risk patients using the second- and current third-generation self-expanding CoreValve prosthesis: device success and 30-day clinical outcome. J Am Coll Cardiol 2007;50(1):69–76. 
  29. Petronio AS et al. Safety and efficacy of the subclavian approach for transcatheter aortic valve implantation with the CoreValve revalving system. Circ Cardiovasc Interv 2010;3(4):359–66. 
  30. Meredith I et al. REPRISE II: A prospective registry study of transcatheter aortic valve replacement with a repositionable transcatheter heart valve in patients with severe aortic stenosis. Presented at the 2013 TCT Conference, San Francisco.