transcatheter mv repair for functional mr: why we should not … · 2019-11-04 · transcatheter mv...

Transcatheter MV Repair for Functional MR: Why We Should Not Get Carried Away?

Controversies and Advances in the Treatment of Cardiovascular Disease, The 18th in the Series

November 14 & 15, 2019, Montage, Beverly Hills

Sanjay Kaul, MD, FACC, FAHA Department of Cardiology

Cedars-Sinai Medical Center Los Angeles, California, USA

The Laws of Diminishing Objectivity in the Interpretation of Evidence

• vehemence α evidence -1

Peter McCulloch The Lancet, 2004;363;9004

• vehemence α eminence 2

• Questionable biological plausibility - Why should reducing MR in a diseased myocardium & depressed LV function improve outcome?

• Low pre-test likelihood for benefit - Disappointing results with surgical experience - Clear and convincing inferiority of MitraClip device c/w surgery in DMR in EVEREST-II (null results in FMR subgroup in EVEREST-II driven by poor surgical outcome)

• Discordant results generated from two pivotal trials, MITRA-FR and COAPT - Which trial results are credible or reliable for regulatory and clinical decision making?

- Unconvincing explanations to reconcile differences in outcomes among the two trials

• Implausibly large treatment effects are seldom replicated (eg, perioperative beta blockade) - Need for a tie breaker: absent any cogent explanations, the logical thing to do is to collect more data to resolve the uncertainties (RESHAPE-HF 2 currently enrolling)

• Maintenance of equipoise - Cross over to device Rx not allowed in MITRA-FR until >5 yrs of f/u - Only 38% of surviving patients enrolled in COAPT crossed-over to device Rx after 2 yrs

- Is use of surgery as control vs TMVR (APOLLO) or sham control (CARILLON) ethically justified?

Why We Should Not Get Carried Away with TMVR for FMR? Top Five Reasons

Effectiveness* in EVEREST II Trial Exploratory Subgroup Analysis

0 1 2 3 4 5 6 LV EF>60% LV EF<60%

Degenerative MR Functional MR

<70 yrs >70 yrs

Female Male

All patients

Pinteraction

0.06

0.02

0.009

0.97

MitraClip better

Surgery better

Risk ratio (95% CI)

11/61 (18) 13/28 (46)

12/65 (18) 12/24 (50)

9/51 (18) 15/38 (39)

8/30 (27) 16/59 (27)

24/89 (27)

Surgery n/N (%)

MitraClip n/N (%)

47/111 (42) 33/68 (49)

59/133 (44) 22/48 (46)

47/95 (49) 34/86 (40)

30/67 (45) 51/114 (45)

81/181 (45)

MitraClip might have a role in high-risk patients such as >70 yr, functional MR, and EF<60%

Feldman T et al. NEJM 2011;364:1395-406

* death, MV surgery, or 3+/4+ MR

Effectiveness* in EVEREST II Trial Exploratory Subgroup Analysis

0 1 2 3 4 5 6 LV EF>60% LV EF<60%

Degenerative MR Functional MR

<70 yrs >70 yrs

Female Male

All patients

Pinteraction

0.06

0.02

0.009

0.97

MitraClip better

Surgery better

Risk ratio (95% CI)

11/61 (18) 13/28 (46)

12/65 (18) 12/24 (50)

9/51 (18) 15/38 (39)

8/30 (27) 16/59 (27)

24/89 (27)

Surgery n/N (%)

MitraClip n/N (%)

47/111 (42) 33/68 (49)

59/133 (44) 22/48 (46)

47/95 (49) 34/86 (40)

30/67 (45) 51/114 (45)

81/181 (45)

Null results in FMR driven by poor surgical outcome, not favorable MitraClip device outcome!

Feldman T et al. NEJM 2011;364:1395-406

* death, MV surgery, or 3+/4+ MR

Why are the COAPT Results so Different from MITRA-FR? Possible Reasons

Attribute MITRA-FR (n=304) COAPT (n=614) Key difference

Trial design and protocol

• 70% of screened enrolled • PEP: Death or HHF • F/U: 1yr • Analytical approach:

conventional (time to first event)

• 39% of screened enrolled • PEP: HHF (recurrent events) • F/U: 2yrs • Analytical approach:

unconventional (repeat events analysis)

More selective higher risk pts, unconventional

PEP & statistical analysis, longer

f/u, sponsor actively involved

Severe MR entry criteria Severe FMR by EU guidelines:

EROA >20 mm2 or RV >30 mL/beat

Severe FMR by US guidelines: EROA >30 mm2 or RV >45

mL/beat More MR Smaller LV

EROA (mean ± SD) 31 ± 10 mm2 41 ± 15 mm2 LVEDV (mean ± SD) 135 ± 35 mL/m2 101 ± 34 mL/m2

GDMT at baseline and FU

Receiving HF meds at baseline – allowed variable adjustment in each group during follow-up per

“real-world” practice

CEC confirmed pts were failing maximally-tolerated GDMT at baseline – few major changes

during follow-up

Optimal medication

Acute results: No clip / ≥3+ MR 9% / 9% 5% / 5%

Better technique or procedural

success Procedural complications 14.6% 8.5%

12-mo MitraClip ≥3+ MR 17% 5%

Characteristic Cohort ? Cohort ? Rx A Rx B Rx A Rx B

Age (yr) 71.7± 11.8 72.8 ± 10.5 70.1 ± 10.1 70.6 ± 9.9 Male sex - % 66.6 61.5 78.9 70.4 BMI 27.0 ± 5.8 27.1 ± 5.9 NR NR DM - % 35.1 39.4 32.9 25.7 Previous MI - % 51.7 51.3 49.3 34.2

Prior CABG - % 40.1 40.4 46.7 42.4 Prior PCI - % 43.0 49.0 NR NR Prior Atrial fib - % 57.3 53.2 34.5 32.7

Cerebrovascular dz, % 18.5 15.7 NR NR PVD, % 17.2 18.3 30.3 25.1 Any COPD, % 23.5 23.1 41.3 52.5 Prior CRT, % 38.1 34.9 30.5 23.0 Prior ICD, % 30.1 32.4 31.8 37.5 HF hosp. within 1 yr, % 58.3 56.1 NR NR Anemia (WHO) 59.8 62.7 NR NR Cr Cl, mL/min 50.9 ± 28.5 47.8 ± 25.0 48.8± 19.7 50.2 ± 20.1

Secondary MR Trials Patient Demographics (1)

Can we tell the 2 cohorts (North American vs. European) apart?

Characteristic Cohort ? Cohort ?

Rx A Rx B Rx A Rx B HF etiology - Ischemic, % - Non-ischemic, %

60.9 39.1

60.6 39.4

62.5 37.5

56.3 43.7

NYHA - II, % - III-IV, %

42.7 57.0

35.4 64.6

36.8 63.1

28.9 71.1

Medical therapy - beta blocker, % - RAAS inhibitors, % - MRA, % - Diuretic, % - OAC, %

91.1 71.5 50.7 89.4 46.4

89.7 62.8 49.7 88.8 40.1

88.2 83.0 56.6 99.3 61.2

90.8 86.4 53.0 98.0 61.2

Secondary MR Trials Patient Demographics (2)

Can we tell the 2 cohorts (North American vs. European) apart?

MITRA-FR vs COAPT MR, LV Volume & Function

Variable MITRA-FR

(n=304) COAPT (n=614)

EROA, mm2 (mean + SD) - <30 mm2 - 30-40 mm2

- >40 mm2

31 + 10 52% 32% 16%

41 + 15 14% 46% 41%

LVEDV, mL/m2 (mean + SD) 135 + 35 101 + 34

LVEF, % (mean + SD) 33 + 7 31 + 9

LVEDD >65mm (70%) <70mm

COAPT ECHO Substudy (Asch FM et al, JACC 2019): The beneficial effect of TMVR over GDMT alone was consistent in all echocardiographic subgroups, independent of the severity of LV dysfunction, LV dilatation, pulmonary HTN, severity of TR or individual MR characteristics

Variable Cohort ? Cohort ?

Device + OMT OMT Device + OMT OMT

One-Year Outcomes Death or HHF 51.3% 46.5%

All-cause death 22.4% 23.2%

MITRA-FR vs COAPT Outcomes (ITT, TTFE Analysis, KM Estimates)

Can we tell which cohort is at higher risk for outcomes?

Variable Cohort ? Cohort ?

Device + OMT OMT Device + OMT OMT



Two-Year Outcomes Death or HHF 67.1% 67.9%

HHF 61.8% 56.7%


Can we tell which cohort is at higher risk for outcomes?

Variable MITRA-FR (n=304) COAPT (n=614)

Device + OMT (n=151)

OMT (n=152)


OMT (n=312)



Two-Year Outcomes Death or HHF 67.1% 67.9%

HHF 61.8% 56.7%

CV death 21.1% 38.2%



Higher risk of mortality but not HHF or death/HHF in MT in COAPT



OMT (n=152)


OMT (n=312)

Death or HHF 54.6% 51.3% 33.9% 46.5%

1.16 (0.73, 1.84), p=0.53 0.63 (0.49, 0.82), p<0.001

CV death 21.7% 20.4% 1.09 (0.67, 1.78)

HHF 48.7% 47.4% 1.13 (0.81, 1.56)

All-cause death 24.3% 22.4% 19.1% 23.2% 1.11 (0.69, 1.77) 0.81 (0.57, 1.15)

MITRA-FR vs COAPT One-Year Outcomes (ITT Analysis)

No benefit with MitraClip seen in MITRA-FR at 1-yr follow-up



OMT (n=152)


OMT (n=312)

Death or HHF 63.8% 67.1% 45.7% 67.9%

1.01 (0.77, 1.34), p=0.92 0.57 (0.45, 0.71), p<0.001

CV death 20.5% 21.1% 23.5% 38.2%

0.99 (0.66, 1.48) 0.59 (0.43, 0.81), p<0.001

HHF 55.9% 61.8% 35.7% 56.7%

0.97 (0.72, 1.30) 0.52 (0.40, 0.67), p<0.001

All-cause death 34.9% 34.2% 29.1% 46.1%

1.02 (0.70, 1.50) 0.62 (0.46, 0.82), p<0.001

MITRA-FR vs COAPT 2-Year Outcomes (ITT, TTFE Analysis, KM Estimates)

No benefit with MitraClip seen in MITRA-FR at 2-yr follow-up

MITRA-FR vs COAPT 2-Year Outcomes (Death or Hospitalization for HF)

MITRA-FR COAPT

Lung B et al. Eur J Heart Fail 2019:on-line Stone GW et al. NEJM. 2018;379:2307-18

51.3% 46.5% 54.6%

33.9%

No benefit in death/HHF with MitraClip in MITRA-FR at 2-yr follow-up

Cumulated Rate of Recurrent HHF at 2 Years MITRA-FR

Post hoc exploratory analysis shows numerical imbalance in recurrent HHF favoring the device arm in MITRA-FR using similar analysis as in COAPT

106.9/100PY

88.3/100PY

HHF HR (time-to-first-event): 0.97 (0.72, 1.30)

Severe MR Can Take Place in 1 of 2 Ways Proportionate vs Disproportionate MR

COAPT and MITRA-FR Trials Enrolled Two Populations with Different Types of FMR

Packer and Grayburn, Circulation 2019

EROA divided by LVEDV x 1000 >13 likely to benefit with device

Distinct Effects in COAPT Proportionate vs Disproportionate MR All-Cause Mortality or Hospitalization for HF

(Post hoc Subgroup Analysis)

• MITRA-FR-like cohort in COAPT did not experience clinically meaningful benefit in death or HHF at 1 year

• What about COAPT-like cohort in MITRA-FR?

Proportionate MR Disproportionate MR

https://www.accessdata.fda.gov/cdrh_docs/pdf10/P100009S028B.pdf


Functional Outcomes in COAPT Proportionate FMR (EROA <0.3 cm2 + LVEDVi >96mL/m2)

• Clinically meaningful benefit in 6MWD and KCCQ were observed in the ‘proportionate’ MR subgroup indicating effectiveness of the device in the MITRA-FR like cohort!

• These data are inconsistent with the conceptual framework of differential effect of MitraClip device in ‘proportionate’ vs ‘disproportionate’ FMR

6MWD (m) KCCQ Score



Was Medical Therapy Better in COAPT c/w MITRA-FR? Not Really!

• Centralized monitoring of optimal GDMT in COAPT was not reflected in greater intensity of GDMT at baseline

• Slightly greater use of beta blockers and MRA in the device group during the course of COAPT trial is not sufficient to account for treatment benefit

Was Procedural Success and Operator Experience Superior in COAPT?

Maybe and Maybe Not!

It is a stretch to link large mortality difference among the trials to small difference in procedural performance and durability of effectiveness!

MITRA-FR COAPT

Acute results: No clip / ≥3+ MR 9% / 9% 5% / 5%

Procedural complications* 14.6% 8.5%

12-mo MitraClip ≥3+ MR 17% 5%

Minimal patient experience during trial roll-in period 5 3

Mean number of enrolled patients per center 2.6 1.4

*none were fatal

MitraClip Device

FDA Approves MitraClip Device for FMR March 14, 2019

Label: The MitraClipTM NTR/XTR Clip Delivery System, when used with maximally tolerated guideline-directed medical therapy (GDMT), is indicated for the treatment of symptomatic (NYHA II-IVa), moderate-to-severe or severe secondary (or functional) mitral regurgitation (MR; MR ≥ Grade III per American Society of Echocardiography criteria) in patients with a left ventricular ejection fraction (LVEF) ≥ 20% and ≤ 50%, and a left ventricular end systolic dimension (LVESD) ≤ 70 mm whose symptoms and MR severity persist despite maximally tolerated GDMT as determined by a multidisciplinary heart team experienced in the evaluation and treatment of heart failure and mitral valve disease.

MitraClip-eligible patients with HF & FMR: 3.7% of 6.5 million = 240,500

• Questionable biological plausibility

• Low pre-test likelihood for benefit

• Discordant results generated from two pivotal trials, MITRA-FR and COAPT

• Implausibly large treatment effects are seldom replicated (eg, perioperative beta blockade)

• Maintenance of equipoise

• Difficult patient selection

• Long procedural ‘learning curve’ of up to 200 cases (bare minimum of 50 cases)

• High residual mortality risk (3-year mortality with MitraClip device in COAPT: 42.8%)

• Poor ability to predict responders vs non-responders (baseline demographics, echo, etc.)

• Lifetime ICER of $55,600 per QALY gained (‘acceptable’ economic value based on current

US thresholds)

• CMS reimbursement: NCA currently under way (expected completion date: 5/14/2020)

Why We Should Not Get Carried Away with TMVR for FMR? Top Five Reasons And Then Some More…

transcatheter mv repair for functional mr: why we should not … · 2019-11-04 · transcatheter mv...

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