COREVALVE RCT 3YR Outcomes Josephine Mak Waikato Cardiothoracic Unit Journal Club

Aortic Stenosis Aortic stenosis is a debilitating disease in elderly people Causes LVOT obstruction Classical manifestations - heart failure, syncope, angina Poor prognosis after symptom onset – on medical treatment, mortality from the onset of symptoms is approximately 25% at 1 year and 50% at 2 years Add photo of stenotic vavle

http://blog.medillsb.com/anatomy-works-from-certified-medical-illustrator-alison-burke/

https://www. uptodate. com/contents/image https://www.uptodate.com/contents/image?imageKey=CARD%2F81124&topicKey=CARD%2F8165&rank=1~150&source=see_link&search=aortic%2 0stenosis%20prognosis

SURGICAL avr Vs tavi Current standard of treatment is surgical AVR for severe AS Often patients unsuitable for surgical AVR – HIGH RISK of death Transcatheter aortic valve implantation / replacement (TAVR) Valve loaded in a specialised delivery catheter, advanced via wire either through femoral artery (retrograde) or chest incision (transapical) Currently a number of trials beginning to compare outcomes in SAVR vs TAVI – CoreValve, PARTNER study

http://www. nature. com/nrcardio/journal/v13/n6/fig_tab/nrcardio. 2016 http://www.nature.com/nrcardio/journal/v13/n6/fig_tab/nrcardio.2016.43_F1.html http://www.medtronic.com/us-en/about/news/media-resources/media-kits/medtronic-corevalve-system.html

1yr Outcomes 795 patients underwent randomization at 45 centres in the United States. Powered to look for non inferiority in TAVR group as compared to SAVR noninferiority margin of 7.5%, assuming a 1:1 ratio in the treatment assignments and rate of death at 1 year of 20% in each group - 355 patients required in each group for power of 80% at a one-sided alpha level of 0.05. Enrol 790 patients to account for 10% loss to follow up In as-treated analysis, rate of death from any cause at 1 year was significantly lower in the TAVR than SAVR (14.2% vs. 19.1%) absolute reduction in risk of 4.9 percentage points (upper boundary of the 95% confidence interval, −0.4; P<0.001 for noninferiority; P = 0.04 for superiority). TAVR non-inferior with respect to echo indexes of valve stenosis, functional status, and quality of life. Suggestion of a reduction in the rate of major adverse cardiovascular and cerebrovascular events and no increase in the risk of stroke

Hypothesis “There is sustained 3-year clinical benefit of self-expanding TAVR over SAVR in patients with aortic stenosis at increased risk for surgery” Primary Outcome All cause mortality

Hypothesis Secondary Outcomes all stroke major stroke all-cause mortality or major stroke pacemaker implantation, life-threatening or disabling bleeding valve thrombosis valve endocarditis major adverse cardiovascular and cerebrovascular events (MACCE) (death, myocardial infarction, stroke, or reintervention). NYHA functional class ECHO findings estimations of AVA, mean aortic valve gradient, and aortic regurgitation were used for this analysis.

Methodology

Methods – Entry Criteria Multi-centre, prospective, randomised, non-inferiority trial 45 sites in USA, February 2011 through September 2012 995 patients were screened Eligible for randomisation severe AS and NYHA class II or higher (AVA of < 0.8 or an AV index of <0.5 cm2/m2 per square meter either a mean AV gradient of more than 40 mmHg or a peak aortic-jet velocity of <4.0m/s) increased risk for undergoing SAVR – as judged by two cardiac surgeons and one interventional cardiologist at the investigative site - risk of death within 30 days after surgery >15% and irreversible complications < 50% using STS scoring system independent Clinical Events Committee adjudicated all major clinical events independent data safety monitoring board provided study oversight Institutional review board at each site

Methods – Exclusion Criteria Recent active gastrointestinal bleed (<3 months), stroke (<6 months), or myocardial infarction (≤30 days) Any interventional procedure with bare-metal stents (<30 days) and drug-eluting stents (<6 months) Creatinine clearance <20 ml/min Significant untreated coronary artery disease Left ventricular ejection fraction <20% Life expectancy <1 year due to comorbidities

Methods – Study Protocol Randomly assigned to TAVR or SAVR in 1:1manner Stratified by study site and intended access site (iliofemoral or non iliofemoral) to ensure proportional assignment TAVR: Bio-prosthetic valve size chosen according to perimeter based diameter of the screening multidetector CT DAPT (Aspirin and clopidogrel) recommended before and for 3 months post TAVR SAVR: Site-specific standard surgical techniques Valve type & size selected by individual surgeon by direct anatomic measurement Aspirin prescribed indefinitely in all patients (“including those on warfarin”)

Methods – Endpoints An independent Clinical Events Committee evaluated 3-year clinical events using the Valve Academic Research Consortium-1 criteria primary end point was also analysed in the intention-to-treat population, which included all the patients who had undergone randomization Clinical sites reported NYHA Class Clinical sites reported ECHO findings - Worsening aortic valve gradients were defined as a >50% increase in the aortic valve gradient from 1-month to 3-year follow-up

Methods – Statistical Analysis Statistical analysis evaluated the as-treated population Ie all patients who underwent an attempted implantation Categorical variables were compared using the Fisher’s exact test or chi-square test. Continuous variables are presented as the mean +/- SD, compared using the Student t test Kaplan-Meier estimates were used to construct the survival curves on the basis of all available follow-up data for the time-to-event analysis Differences in events rates between the TAVR and SAVR groups were evaluated using the log-rank test echo measurements were evaluated using a 2-sample Student t test or the Wilcoxon rank sum test for continuous variables and the Mantel-Haenszel test for categorical variables All testing used a 2-sided alpha level of 0.05

Results

Results Combined: average age = 83.2 +/- 6.7 years 53% men Generally highly symptomatic, with NYHA functional class III or IV symptoms in 86.1% of the patients The mean STS score was 7.4 +/- 3.2% Significant CAD – why not CABG? Definition of ‘CAD’? Significant pre-existing PPM numbers Significant CHF numbers

Results Significant MACCE High PPM rate - ?COREValve known to result in higher PPM rate

Results (Tables and Diagrams) TAVR: 20.1% relative reduction in the occurrence of all-cause mortality or stroke at 3 years in TAVR compared with SAVR (p <0.006) (with an absolute risk reduction of 9.4%) nonsignificant 15.9% relative risk reduction in all-cause mortality 33.7% relative risk reduction in all stroke 15.9% relative risk reduction in all-cause mortality or major stroke 16.1% relative risk reduction in MACCE

Results Life-threatening or major bleeding and aki more common in the SAVR group Vascular complications, reintervention, and the need for new permanent pacemakers were more common in the TAVR (most within first 30 days) 3YR AV gradients were lower in TAVI than sAVR (mean aortic valve gradient 7.62 +/- 3.57 mmHg vs. 11.40 +/- 6.81 mmHg in surgical patients; p < 0.001) moderate or severe AR was higher in TAVR (6.8%vs. 0.0% in surgical patients; p < 0.001) no evidence of clinical valve thrombosis or structural valve deterioration in either group rates of worsening aortic valve gradients, defined as a >50% increase from 1 month to 3 years, were similar (9.5% in TAVR,12.6% in the SAVR group; p = 0.38)

Results (Tables and Diagrams)

Author’s Conclusion Their findings support use of SAVR as treatment of choice in patients suboptimal for surgery - Sustained 3yr clinical benefit in self-expanding TAVR over SAVR Reductions in all-cause mortality and stroke Improved valve haemodynamics (lower 3-year mean aortic valve gradients and larger effective orifice areas ALTHOUGH more AR) No difference between TAVR and SAVR in structural valve deterioration over time “Additional studies are needed to validate outcomes of TAVR over even longer follow-up intervals and in lower-risk patients with severe aortic stenosis”

Discussion

Strengths of the study Follow up – status of 92%-93% of patients in both groups known Stratification of randomisation

Limitations “crimping–recrimping of the transcatheter valve” – will this have an impact on long- term bioprosthesis durability? Only a 3 year follow-up so far – no long term data on TAVR Where did they find the 3 extra patients? Are they going to publish a paper a year?

Limitations

limitations Medtronic… Funded the study Developed the protocol – in collaboration with a study steering committee Selected the 45 clinical sites Monitored the data Managed all source data Managed statistical analyses Statistical analyses “validated by Harvard Clinical Research Institute, with all major clinical events reviewed by independent board, and independent data and safety monitoring responsible for study oversight”

Impact of the study

How has the study impacted on practice Further trials on TAVR ongoing Expansion of their use in lower risk patients Surgical valves - ?sutureless valves Those with more experience – how have you picked the valve you use and why?

References Journal club paper – 3yr outcomes Original paper http://www.onlinejacc.org/content/67/22/2565 Original paper http://www.nejm.org/doi/10.1056/NEJMoa1400590 https://www.uptodate.com/contents/natural-history-epidemiology-and-prognosis-of- aortic-stenosis https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-aortic- stenosis-in-adults