william bowden, do, facc january 22, 2020 · partner 3 trial safety and effectiveness of the...

William Bowden, DO, FACC

January 22, 2020

Topics in 2019 TAVR for low risk patients

ISCHEMIA Trial

Statins and Cognitive Function

Aspirin Trials for Primary Prevention

CABANA Trial for Ablation in Atrial Fibrillation

Apple Watch Study

Drug Safety Resource


ISCHEMIA Trial

Statin Update



Apple Watch Study


Transcatheter Aortic Valve Replacement

Sapien vs Core

Replacement: TAVR or SAVR?

Evolution of Sapien Valves & FDA Approvals

2018

Sapien 3 Ultra

Sapien Device Evolution

PARTNER 2 2032 Intermediate risk Pts were randomized

1021 Surgical

994 (76.3%)TAVR (Sapien XT valve)

236 (23.7%) Transthoracic

174 Transapical,

62 Transaortic)

Mean STS score was 5.8% (83% had a score 4.0-8.0%)

NEJM 2016; 374:1609-1620

TAVR vs SAVR Mortality: Intermediate Risk Patients

TAVR In 2016, the FDA cleared the way for the PARTNER

III trial, which examined the use of TAVR in low surgical risk patients with symptomatic severe aortic stenosis.

TVT Registry: “Risk Creep: for TAVR before FDA approval

Partner 3 Trial Safety and effectiveness of the Edwards 3 Sapien valve in

TAVR versus SAVR in low (<2%) operative risk patients at discharge, 30 days, 6 months, annually through 10 years

1000 pts, randomized to SAVR vs TAVR

Start Date: March 2016, Estimated Enrollment completion date: January 2020, [Enrollment was complete March 21, 2018]

Study Completion Date: March 2027

Results: ACC in 2019

Low-risk TAVR Trials: Studies presented at the ACC Scientific Sessions in

New Orleans, March 2019

PARTNER 3 Trial (Edwards)

1,000 Pts (mean age 73), severe AS, STS risk score 1.9% randomized to TAVR with Sapien 3 or surgical AVR (NEJM, March 16, 2019)

Evolut Low Risk trial (Medtronic)

1,468 Pts (mean age 74), severe AS, low risk assigned TAVR with CoreValve, Evolut R or Evolut Pro) vs SAVR (NEJM March 16, 2019)

PARTNERS Outcomes 1 Year:OUTCOME TAVR Group Surgery Group Results

Death/CVA/rehos 8.5% 15.1% P<.001 for noninferiority; P=.02 for superiority

Mortality 1% 2.5% HR=.41; 95% CI; .14-1.17

All stroke 1.2% 3.1% HR=.38; 95% CI; .15-1

Death or disabling stroke

1% 2.9% HR=.34; 95% CI; .12-.97

Rehospitalization 7.3% 11% HR=.65; 95% CI; .42-1

Mack M. et al. NEJM 2019;doi:10:1056

Evolut Low Risk Trial OutcomesOutcome TAVR Surgery Results

All cause mortality or disabling stroke at 2 yrs

5.3% 6.7% Prob of noninferiority > 0.999

Disabling stroke at 30 days 0.5% 1.7% 95% BCI, -2.4 to -0.2

Life-threatening or disabling bleed at 30 days

2.4% 7.5% 95% BCI, -7.5 to -2.9

Acute renal injury at 30 days 0.9% 2.8% 95% BCI, -3.4 to -.5

AF at 30 days 7.7% 34.5% 95% BCI, -31.8 to -23.6

All cause mortality or disabling stroke at 1 year

2.9% 4.6% 95% BCI, -4 to .4

HF hosp at 1 year 3.1% 6.4% 95% BCI, -5.9 to -1

Popma JJ, et al NEJM 2019;dol:10.1056

Low-risk TAVR Trials:TAVR (PARTNERS) TAVR (Evolut)

Age 67.5 – 79.1 years old (73.3) Mean age 74

Excluded Bicuspid AV or other anatomical features

Low-risk TAVR Trials: August, 2019 the FDA approved the Sapien 3 and

Sapien Ultra valves (Edwards) and the Evolut series valves (Medtronic) for TAVR in low risk patients

TAVR is not suitable for all patients

“It is true, though, that if we see 20 patients in a day, 19 of them are asking for TAVR.” – Tamin Nazif, MD Columbia University Irving Medical Center, NY, NY

Transcatheter Valve in Valve Historically, mechanical valves were used in younger

pts (price of increased bleeding from long-term anticoagulation)

STS database: Bioprosthetic valve use has increased

1997: 43.6% Bioprosthetic valves implanted

2006: 78.4%

Shift to bioprosthetic valves fueled in part by TAVR valve in Valve (VIV) replacement

FDA cleared CoreValve and Sapien 3 for VIV in “high risk surgical candidates” despite no controlled studies

Transcatheter Valve in Valve Bioprosthetic valves can have an ideal landing zone for

TAVR but the frame (as opposed to the native annulus) is nonelastic and prevents complete expansion of the TAVR valve (esp in smaller bioprosthetic valves)

VIV residual gradients >20mmHg are common, esp if bioprostheses is <23mm size and are associated with increased mortality

Pibarot et al. reported data from the VIVID registry

1,168 Pts with pre-existing patient-prosthesis mismatch (PPM) on outcomes in TAVR VIV

Pibarot et al. JACC 2018;11:133-141

Transcatheter Valve in Valve Pibarot et al. found Pts with pre-existing severe PPM

were more likely to have a surgical prosthesis <21 mm compared to Pts without severe PPM (77.5% vs 26.6%)

The severe PPM group had a higher number of Pts with residual gradient >20mmHg post VIV and had a 2-4 fold higher mortality at 30 days and significantly higher adjusted mortality at 1 year.

TAVR cannot correct PPM since most surgical valve frames are not expandable

Pibarot et al. JACC 2018;11:133-141

Transcatheter Valve in Valve Surgical bioprosthetic valves should be > 23 mm

except in rare circumstance

Surgeons must take measures to reduce PPM such as choosing surgical valves with better hemodynamics or performing root enlargements

If it is not possible to use a larger prosthesis then consideration should be given to doing a TAVR upfront (TAVR results is larger AV area than surgery)

TAVR Valve Longevity Damage to AV bioprosthesis: oversizing,

manipulation, delivery, positioning and deployment can injure the leaflets and increase leaflet mechanical stress

NOTION trial: (Sondergaard et. al. (2019) JACC (5):546-555 looked at structural valve deterioration (SVD) in randomized pts: 139 TAVR or 135 SAVR

SVD described as mean gradient >20 mmHg, increase mean gradient >10mmHg from 3 mths post procedure, > mild AI, new or worsening 3 months post procedure

NOTION TRIAL Nonstructural valve deterioration (NSVD) – moderate to

severe patient-prosthesis mismatch at 3 mths or mod/severe paravalvular VI (AI)

Bioprosthetic valve failure (BVF): valve-related death, AV reintervention or severe hemodynamic SVD

At 6 years: all-cause morality was similar: TAVR(42.5%) vs SAVR (37.7%)

SVD was higher for SAVR than TAVR (24.0% vs 4.8%; p<.001)

No difference in NSVD (57.8% vs 54.0%; p=.52) or endocarditis; BVF were similar

NOTION Conclusion: Through 6 years, SVD was significantly greater for SAVR

than TAVR

BVF was low and similar for both groups

TAVR had significantly higher rates of moderate para-valvular leaks

Problems:• Barely 50% of participants were followed up at 6 years Long term follow up is needed for both

No adjudication of echo data by a core laboratory

TAVR durability was only reported in one type of valve (CoreValve - Medtronic) and may not apply to others

Low Risk TAVR Conclusions: TAVR in low risk Pts (<2% STS score) over the age of 65 is

indicated

Studies have included Pts over 65 y.o. (mean age in Partners III, 73 in Evolut 74)

Longevity of valves with TAVR is still pending

VIV and SVF, PPM are a concern especially in younger Pts

Almost everyone wants TAVR over SAVR


ISCHEMIA Trial (November AHA meeting)




Apple Watch Study


ISCHEMIA Trial The International Study of Comparative Health Effectiveness With

Medical and Invasive Approaches (ISCHEMIA) trial was presented at the AHA Nov, 2019 in Philadelphia [5,179 Pts, median age 64; 23% women)

Main ISCHEMIA trial excluded Pts with renal disease and ISCHEMIA-CKD included only Pts with GFR < 30 mL/min)

Pts (recent MI, EF <35% or unacceptable angina at baseline) were randomized to:

2,588 to Invasive ( cath followed by PCI or CABG)

2,591 to Conservative (cath only if optimal medical therapy failed)

All Pts received secondary prevention (lifestyle and drugs as needed)

ISCHEMIA Trial Primary composite endpoint: CV death, MI resuscitated cardiac arrest or hospitalization for UA: initially occurred more frequently in the invasive group but at two years the curves crossed and primary outcome occurred more frequently in conservative group

Major secondary endpoints: CV death and MI (occurred in 11.7% in invasive group vs 13.7% in conservative group at 4 years): again more frequent in invasive group but curves crossed at approximately 2 years

ISCHEMIA Trial Results: median 3.3 years follow up:

NS difference for invasive and conservative groups (p=.34)

NS difference for secondary endpoints of CV death and MI (p=.21)

NS benefit for invasive vs conservative for CV death, MI UA, CHF resuscitated cardiac arrest or stroke (p=.50)

ISCHEMIA Trial Early procedural harm was offset by a small late benefit in reduction of MI (suggesting there are Pts that the invasive approach can prevent heart events)

Quality of life benefits (less angina) were improved in the invasive group (this quality of life benefit was not seen in ISCHMIA-CKD)

ISCHEMIA TrialConclusion:

PCI won’t necessarily make Pts live longer or improve their outcomes, but may improve their quality of life with less angina over the next few years.


ISCHEMIA Trial




Apple Watch Study


Statins Samaras et al reported in JACC (2019) 1,037 Pts 70-90

(average 79) studied in Australia

395 Never used statins

642 Users (including 99 who started statins during the study period) Average use was 9.1 years of statin Rx

Complete data for 573 participants

Followed over 6 years with neuropsychological testing every 2 years

Memory and global cognition scores were similar and NS difference on rate of decline

Samaras,K. et al. JACC 2019; DOI 10.1016/j.jacc.2019.09.041

Statins Bradley et al. (2019)looked at 5,693 Pts recommended

a statin in the PALM (Pt and Provider Assessment of Lipid Management) registry and found:

26.5% were not on a statin; of those 59.2% reported never being offered a statin, 10% declined, 30% D/C’ed

Women, black adults and Pts without insurance were more likely to never be offered a statin

Fear of side effects was the main reason to decline

67.7% never offered and 59.7% of D/C’ed Pts were willing to start or retry a statin

Bradley C.K. et al. JAHA 2019;8e011765, DOI 10,1161

Statins in 2019:Statins do not cause memory or

cognition problems

Statins are under prescribed to the appropriate Pts

Consideration for restarting a different statin if stopped


ISCHEMIA Trial




Apple Watch Study


ARRIVE Study Presented at the European Society of Cardiology

Congress and published simultaneously in The Lancet, August 2018

12,546 Pts randomized to ECASA (Bayer 100 mg) or placebo and followed for 5 years

Primary endpoint: time to CV death, MI, UA, TIA or CVA (4.3% of aspirin group, 4.5% placebo NS)

No difference in serious or overall adverse events but GI bleeds (mild) occurred twice as often in ASA group

Gaziano JM, et al. Lancet 2018;doi:10.1016/S0140-6736(18)31924-X

ARRIVE Study Goal was to address ASA for primary prevention in Pts

at moderate risk for CV disease based on risk factors but the study population ended up as a lower-risk population

Conclusion: ASA does not reduce initial vascular events in low-to-moderate risk population

Gaziano JM, et al. Lancet 2018;doi:10.1016/S0140-6736(18)31924-X

ASCEND Trial 15,480 Pts > 40 y.o with diabetes (type I or II) but no

evidence of CVD were randomized to 100 mg ASA vs Placebo and followed for 7.4 years {2x2 design with Omega-3 FFA sup}

Primary endpoints: MI, CVA, TIA, vascular death excluding IC hemorrhage

Results: Primary endpoints: ASA (8.5%), Placebo (9.6%) [p=.01]

Major bleeding: ASA (4.1%), Placebo (3.2%) [p=.003]

GI cancer: NS

All cancers: NS

Bowman L. et al. NEJM 2018, Oct 18;379(16); 1529-1539

ASCEND Trial Conclusion:

The use of low-dose ASA in diabetic Pts reduced the major adverse

vascular events but caused more major bleeding.

ASPREE Trial 19,114 Pts > 65 y.o. without CVD, dementia or disability

at baseline (NIH trial), ECASA (100 mg vs placebo) followed for 4.7 years

Primary endpoints: major hemorrhage and CVD (fatal CHD, nonfatal MI, fatal or nonfatal CVA or HF hosp.

CVD events were NS different (10.7 events per 1,000 pt years in ASA group, 11.3 events in placebo group)

Major hemorrhage occurred more often in ASA group (8.6 events/1000 pt years) vs placebo (6.2 events)

McNeil JJ, et al. NEJM 2018;dol:10:1056

ASPREE Trial Again, the event rate was lower than expected

(anticipated 22 events/1000 pt years) possibly due to better health at recruitment and declining CV disease rates

Two other papers published in NEJM

Primary outcome of dementia or persistent physical disability was the same for ASA or Placebo

All-cause mortality was higher in the ASA group but this was driven by cancer-related deaths

McNeil JJ, et al. NEJM 2018;dol:10:1056

ASA for Primary Prevention U.S. Preventive Services Task Force (2016):

Consideration of ASA for Pts 50-69 with a 10 year ASCVD risk score > 10%, no excess risk of bleeding or contraindications to ASA with > 10 yr. survival rate and willing to take aspirin

After ASPREE, ARRIVE and ASCEND trials, they do not challenge the guidelines. They show that Pts > 70, the risk of taking ASA for primary prevention of CVD are likely to outweigh the benefits


ISCHEMIA Trial




Apple Watch Study


CABANA Trial 2,204 Pts randomized to Ablation [Primary and

ancillary ablation and anticoagulation versus Drug Therapy for rate control or rhythm control with anticoagulation

Inclusion: New onset or under-treated PAF or longstanding persistent AF who warranted therapy

> 65 y.o. or < 65 with > 1 CVA/CV risk factor

Eligible for ablation and > 2 rhythm or rate control drugs

Exclusion: No criteria

Packer et al. JAMA 2019 Apr 2; 321(13):1275-1285

CABANA Trial

Primary Endpoint: Composite death, disabling stroke, serious bleeding or cardiac arrest

Secondary Endpoints: all-cause mortality, Death or CV hospitalization

CABANA TrialSubjects

2204

Ablation (1108)

Ablated 1006 (90.8%)Repeat 215 (19.4%)

Completed Follow Up1002 (90.4%) 48.9 mths

Not Ablated 102 (9.2%)

Drug Therapy (1096)

Drug Treated 1092 (99.6%)rhythm control 953 (87.2%)rate control only 126 (11.5%)

Cross Over Ablated 301 (27.5%)

Completed Follow Up966 (88%) 48.2 mths

Crossovers

CABANA: Primary Endpoint

CABANA: All-Cause Mortality or Cardiovascular Hospitalization

CABANA Trial: Conclusions Ablation did not significantly reduce the primary

endpoint and all-cause mortality

The results were affected by cross-overs in both directions and lower than expected event rates.

There was a significant 47% reduction in recurrent AF with ablation compared to drug therapy (at 5 yrs)

Ablation is an acceptable treatment strategy for treating AF with low adverse event rates even in higher risk patients

CABANA Trial Summary: Crossovers: 30% of Pts assigned drug therapy and 10%

of Pts assigned ablations did not have the procedures

On-treatment analysis versus intention-to-treat analysis

No mortality benefit. Who to treat with Ablation:

Symptomatic

Young Pts with short duration of AF

Pts with CHF and PAF


ISCHEMIA Trial




Apple Watch Study


Apple Watch Series 4 September, 2018 Apple announced that the redesigned

Apple Watch Series 4 would feature an electrical heart rate sensor that can take ECGs using a new ECG app

With the app, users can receive a heart rhythm classification within 30 seconds whether the heart is beating normally or if there are signs of atrial fibrillation

The FDA cleared the new ECG app as a class II medical device (de novo classification )

The app is for AF and not for other arrhythmias

Apple Watch Series 4

New technology is less invasive than a Holter monitor, has greater battery life and can be used 24/7

Allows continuous or periodic monitoring that can be difficult to capture on short-term monitors

Crystal AF: Detection Rates

Primary Endpoint: Detection of AF at 6 months Hazard Ratio: 6.43 (1.90, 21.74) p = 0.0006

Secondary Endpoint: Detection of AF at 12 months Hazard Ratio: 7.32 (2.57, 20.81) p < 0.0001

Sanna T ; NEJM 2014;370;2478

Median Time from Randomization to AF Detection (N=42) with ICM was 8.4 months (range 1.4 to 14.9 months)

CRYSTAL AF: Time to First AF Detection

Apple Heart StudyACC meeting in New Orleans, March 2019

Prospective, single-arm, open label study

Used iPhone 5S or later and Apple Watch Series 1,2 or 3 (did not include patients with Apple Watch Series 4)

419,297 self-enrolled participants (free from AF/Flutter at baseline), mean age 41 y.o. and 42% women

Mobile app was used with the smartwatch’s light sensor (photoplethysmography)

Apple Heart Study If an irregular tachogram (plot of time between heart

beats) was present then more frequent tachograms were collected

Tachograms were analyzed by the app

The participate was notified (by the watch) if 5 of 6 episodes were suggestive of AF

The participate was prompted to contact a telehealth physician via the app (available 24/7 in the US)

Based on video consult the participate would be directed to seek urgent/emergency care and wear an ECG patch (sent by mail) for up to 7 days

Apple Heart Study Co-primary endpoints: AF longer than 30 seconds on

the ECG patch and the tachogram (if > 65 y.0.)

Secondary endpoints: simultaneous AF on the ECG patch and Apple watch and self-reported contact with a health care provider

Results: of the 419,297 participants, 0.52% (2,161) received an irregular pulse notification [3.2% of participates over 65 y.o. to .16% younger than 40 y.0.]

89% of participants with any AF on ECG patch had at least an hour-long episode of AF

Apple Heart Study 450 participates wore an ECG patch and simultaneous

smartwatch detection. If a notification occurred:

84% of the time the patch showed AF

Tachogram positive predictive value was 71%

Notification on the watch had a positive predictive value of 84% (or 16% false positive result)

57% of participates notified contacted a non-study provider:

28% started on a new medication

33% referred to a specialist

36% underwent additional testing

Apple Watch Series 4: ProblemsGood diagnostic test applied to a population with low pre-test probability there will be a lot of false positives

Detection of nuisance arrhythmias that don’t require Tx

24 hr monitoring may show brief arrhythmias that could lead to additional tests and therapies with their own complications

Could cause patient anxiety

Young Pts with a near zero pre-test probability will be exposed

Wearable Technology KardiMobile and AliveCor received FDA approval in

April, 2019 to detect bradycardia and tachycardia events

A month later, both companies received FDA approval for novel six lead personal ECG devices, also cleared to detect arrhythmias

Wearables can also detect: Heart rate, heart rate variability and sleep patterns

Developing sensors: respiratory rates, O2 sat, BP measurements and autonomic tone (measured by sweat)

Current Wearable Technology 28.7 million US adults are expected to use a

smartwatch in 2019

60 million are expected to use wearable technology in 2019 (up 9.2% from 2018)

> 8 million US adults aged 55 or older are expected to use a wearable device in 2019 (up 15% from 2018)

Source: www.emarketer.com/content/wearables-2019. July, 2019

http://www.emarketer.com/content/wearables-2019


ISCHEMIA Trial




Apple Watch Study


Drug Labels and QT Prolongation Complexity of modern drugs and the number of

medications taken by the average Pt make the prescribing information overwhelming.

Azithromycin – a commonly prescribed antibiotic is known to prolong the QT

Is an ECG recommended before prescribing?

Is routine QT monitoring during therapy needed?

Is ECG monitoring needed for a subset of Pts?

What drugs are contraindicated when a drug is prescribed that can prolong the QT interval?

Drug Labels and QT Prolongation

Drug Labels and QT Prolongation Label for azithromycin:

More than 14,000 words in 29 pages

More than 500 facts and instructions on safe Rx

Embedded deep in the text:

“Prolongation of QT interval and cases of TdP have been reported. This risk, which can be fatal…”

One example of information needed for the safe use of a medication but can be difficult for the health care provider to find.

Drug Labels and QT ProlongationCredibleMeds is a valuable resource

https://crediblemeds.org/blog/crediblemeds-launches-mobile-app-expand-access-online-qtdrug/

https://crediblemeds.org/blog/crediblemeds-launches-mobile-app-expand-access-online-qtdrug/


ISCHEMIA Trial




Apple Watch Study


william bowden, do, facc january 22, 2020 · partner 3 trial safety and effectiveness of the...

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