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Addressing the Lingering Addressing the Lingering Concerns of Late DES Concerns of Late DES
Safety and Efficacy Safety and Efficacy
Ajay J. Kirtane, MD, SMAjay J. Kirtane, MD, SM
Columbia University Medical Center /Columbia University Medical Center /New York Presbyterian HospitalNew York Presbyterian Hospital
Conflict of Interest DisclosureConflict of Interest Disclosure
•• Ajay J. KirtaneAjay J. Kirtane
–– In the last 12 months, I have received In the last 12 months, I have received honoraria/consultancy fees from Abbott honoraria/consultancy fees from Abbott Vascular, Boston Scientific, and Vascular, Boston Scientific, and Medtronic CardioVascularMedtronic CardioVascular
–– OffOff--label use will be discussedlabel use will be discussed
•• Early Pivotal RCTsEarly Pivotal RCTs–– Marked efficacy compared to BMS at intermediate Marked efficacy compared to BMS at intermediate
durations of followdurations of follow--upup
–– Limited pooled data (overall small numbers)Limited pooled data (overall small numbers)
•• Supplemented by Observational dataSupplemented by Observational data–– Single center analyses (AMC, Single center analyses (AMC, ThoraxcenterThoraxcenter))
•• Even demonstrated efficacy in RCTs and Even demonstrated efficacy in RCTs and observational analyses of complex lesion subsetsobservational analyses of complex lesion subsets
•• Clear, consistent effect on Clear, consistent effect on restenosisrestenosis--related related endpoints, but limited power to assess safety…endpoints, but limited power to assess safety…
Following the Introduction of DESFollowing the Introduction of DESThings were going well…Things were going well…
DES Concerns in the BackgroundDES Concerns in the Background
•• DES impair normal vascular healingDES impair normal vascular healing¡¡ Persistent (?toxic) polymer and drug effectsPersistent (?toxic) polymer and drug effects
•• Vascular inflammation, incomplete Vascular inflammation, incomplete endothelialization, fibrin deposition, endothelialization, fibrin deposition, platelet activation may all have clinical platelet activation may all have clinical sequelaesequelae¡¡ Stent ThrombosisStent Thrombosis¡¡ Abnormal Vasomotion, Aneurysm Formation, Abnormal Vasomotion, Aneurysm Formation,
Late RestenosisLate Restenosis
•• SCAAR (the first time around)SCAAR (the first time around)–– Large multicenter observational studyLarge multicenter observational study
•• Camenzind and Nordmann metaCamenzind and Nordmann meta--analysesanalyses–– Randomized data implicated with a signal Randomized data implicated with a signal
of possible harmof possible harm•• BernBern--Rotterdam AnalysisRotterdam Analysis
–– The pathophysiologic link?The pathophysiologic link?
DES Studies: Initial Potential DES Studies: Initial Potential Concerns Explode in 2006!!!Concerns Explode in 2006!!!
Network MetaNetwork Meta--Analysis: Cumulative Analysis: Cumulative Incidence of Cardiac DeathIncidence of Cardiac Death
Stettler C., et al., Lancet 2007;370:937-48.
AllAll--Cause Mortality: RCT’s (OffCause Mortality: RCT’s (Off--Label)Label)
I-V Overall (I-squared = 0.0%, p = 0.798)
HAAMU-STENT
Passion
PRISON IIMISSION!
DIABETES
BASKET (SES only)
Seville
D+L Overall
SES-SMARTSTRATEGY
TAXUS V - complex
SESAMITyphoon
0.84 (0.62, 1.13)
2.00 (0.63, 6.38)
0.70 (0.36, 1.36)
0.50 (0.09, 2.67)0.48 (0.09, 2.59)
1.44 (0.48, 4.33)
0.82 (0.37, 1.84)
1.35 (0.23, 7.78)
0.84 (0.62, 1.13)
0.21 (0.02, 1.71)0.84 (0.36, 1.96)
0.84 (0.38, 1.84)
0.43 (0.11, 1.63)1.01 (0.38, 2.65)
100.00
6.64
20.16
3.103.16
7.36
13.84
2.871.8012.40
14.32
4.909.44
1.1 1 10
4,049 patients, 12 trials, mean F/U 1.5 years4,049 patients, 12 trials, mean F/U 1.5 years
Favors DES Favors BMS
Estimate (95% CI) Weight (%)
0.84 (0.62,1.13)0.84 (0.62,1.13), p=0.24
Random Effects*Fixed Effects (I2=0.0%)
Kirtane et al, Circulation 2009;119: 3198-3206
NOTE: Weights are from random effects analysis
D+L Overall (I-squared = 70.9%, p = 0.000)
Asan Korea (adjusted)
SMART
Melbourne
Massachusetts (matched)
Washington Hosp Center (matched)
Multicenter SVG (adjusted)
I-V Overall
Rotterdam Off-Label
STENT (adjusted)
ACUITY (from RCT)
REAL (adjusted)
Liverpool (matched)
Wake Forest (adjusted)
Mayo FFR Substudy
Cedars Acute MI
GHOST (adjusted)
Sussex ElderlyERACI III (from RCT)
NY State (adjusted, unmatched)
Ontario (matched)
MIDAS (adjusted)
RESTEM
McMaster STEMI (adjusted)
Germany Metabolic Syndrome
Western Denmark (adjusted)
ARTS II (from RCT)
DEScover (unadjusted)
Northern New England (adjusted)
SCAAR (adjusted)
Italian Diabetic Multivessel (adjusted)
NHLBI (off label, adjusted)NHLBI (on label, adjusted)
0.78 (0.71, 0.86)
0.60 (0.46, 0.79)
0.59 (0.48, 0.71)
0.67 (0.23, 1.94)
0.79 (0.71, 0.89)
1.16 (0.78, 1.75)
1.33 (0.47, 3.76)
0.81 (0.78, 0.85)
0.98 (0.85, 1.13)
0.69 (0.55, 0.87)
0.63 (0.49, 0.82)
0.83 (0.70, 0.98)
0.45 (0.24, 0.84)
0.72 (0.55, 0.95)
1.00 (0.21, 4.75)
0.82 (0.37, 1.83)
0.55 (0.36, 0.83)
0.72 (0.30, 1.72)1.18 (0.54, 2.58)
0.84 (0.72, 0.97)
0.71 (0.59, 0.84)
0.66 (0.59, 0.74)
0.73 (0.51, 1.05)
0.17 (0.03, 0.97)
1.47 (0.65, 3.35)
1.00 (0.86, 1.17)
0.74 (0.41, 1.35)
0.53 (0.35, 0.80)
0.51 (0.26, 1.00)
1.03 (0.94, 1.14)
1.22 (0.36, 4.10)
0.94 (0.64, 1.38)1.47 (0.87, 2.48)
100.00
4.35
5.23
0.71
6.15
3.02
0.74
5.85
4.83
4.50
5.55
1.70
4.31
0.35
1.16
2.91
1.001.20
5.77
5.46
6.14
3.40
0.28
1.11
5.72
1.83
2.95
1.53
6.30
0.56
3.192.20
0.78 (0.71, 0.86)
0.60 (0.46, 0.79)
0.59 (0.48, 0.71)
0.67 (0.23, 1.94)
0.79 (0.71, 0.89)
1.16 (0.78, 1.75)
1.33 (0.47, 3.76)
0.81 (0.78, 0.85)
0.98 (0.85, 1.13)
0.69 (0.55, 0.87)
0.63 (0.49, 0.82)
0.83 (0.70, 0.98)
0.45 (0.24, 0.84)
0.72 (0.55, 0.95)
1.00 (0.21, 4.75)
0.82 (0.37, 1.83)
0.55 (0.36, 0.83)
0.72 (0.30, 1.72)1.18 (0.54, 2.58)
0.84 (0.72, 0.97)
0.71 (0.59, 0.84)
0.66 (0.59, 0.74)
0.73 (0.51, 1.05)
0.17 (0.03, 0.97)
1.47 (0.65, 3.35)
1.00 (0.86, 1.17)
0.74 (0.41, 1.35)
0.53 (0.35, 0.80)
0.51 (0.26, 1.00)
1.03 (0.94, 1.14)
1.22 (0.36, 4.10)
0.94 (0.64, 1.38)1.47 (0.87, 2.48)
100.00
4.35
5.23
0.71
6.15
3.02
0.74
5.85
4.83
4.50
5.55
1.70
4.31
0.35
1.16
2.91
1.001.20
5.77
5.46
6.14
3.40
0.28
1.11
5.72
1.83
2.95
1.53
6.30
0.56
3.192.20
1.1 1 10
AllAll--Cause Mortality: Observational StudiesCause Mortality: Observational Studies169,595 patients, 31 registries, mean F/U 2.5 years169,595 patients, 31 registries, mean F/U 2.5 years
Favors BMS
Estimate (95% CI) Weight (%)
0.78 (0.71,0.86), p<0.0010.81 (0.78,0.85)
Favors DES
*Random Effects (I2=71%)Fixed Effects
Kirtane et al, Circulation 2009;119: 3198-3206
Time since PCI in yearsTime since PCI in years
Cum
ulat
ive
Inci
denc
e, %
Cum
ulat
ive
Inci
denc
e, %
55
44
33
22
11
0000 11 22 33 44
Cumulative Incidence of ARC Def/Prob STCumulative Incidence of ARC Def/Prob STover 4 yrs after DES (CYPHER & TAXUS)over 4 yrs after DES (CYPHER & TAXUS)
2.1% (17)2.1% (17)—— CYPHER Stent (n=878)CYPHER Stent (n=878)
2.1% (26)2.1% (26)——TAXUS Stent (n=1401)TAXUS Stent (n=1401)
Cypher & TaxusCypher & TaxusPooled AnalysesPooled Analyses11
11 Mauri et al; N Engl J Med 2007;356:1020Mauri et al; N Engl J Med 2007;356:1020--99
5.7% [95% CI]5.7% [95% CI]CYPHER & TAXUSCYPHER & TAXUS(n=8,146)(n=8,146)
BernBern--RotterdamRotterdam22
22 Wenaweser et al; J Am Coll Cardiol 2008;52:1134Wenaweser et al; J Am Coll Cardiol 2008;52:1134--4040
Drug-Eluting Stents….the good, the bad, and the ugly!
Drug-Eluting Stents….the good, the bad, and the ugly!
48 months48 months
40 mos40 mos
BMS DES
IncompleteIncompleteappositionapposition
Late stentthrombosis
-20
-15
-10-5
0
5
1015
20
25
Prox. Ref. Prox. Stent Distal Distal Ref.
Abn VasomotionAbn Vasomotion
*P<0.001*P<0.001 vs. controlvs. control
Sirolimus Sirolimus Control Control
** **
Delayed Healing!Delayed Healing!
AngioscopyAngioscopy
BMS
DESLate loss = 0
Eos
Giant cells
IVUSIVUS
InflammationInflammation
DES Use in 2010: Persistent ConcernsLinking pathology with clinical outcomes
• Safety¡ We may feel better about mortality
now, but LST is a real phenomenon!!¡ Do we know how to prevent LST?
• Efficacy¡ Late catch-up of ISR/TLR may limit
the long-term absolute efficacy of DES
Potential Strategies to Address STPotential Strategies to Address ST•• Early ST (similar to BMS)Early ST (similar to BMS)
¡¡ PCI optimization (?IVUS), patient/lesion PCI optimization (?IVUS), patient/lesion selection, antiplatelet therapy with appropriate selection, antiplatelet therapy with appropriate response to itresponse to it
•• Late STLate ST¡¡ DES designs to reduce inflammation and DES designs to reduce inflammation and
improve healingimprove healing•• Polymer adaptations / Drug durationPolymer adaptations / Drug duration•• PolymerPolymer--free systemsfree systems
¡¡ ?DAPT duration?DAPT duration
IVUS Correlates of VLSTIVUS Correlates of VLSTDES VLSTDES VLST
(n=23)(n=23)BMS VLSTBMS VLST
(n=7)(n=7) P valueP value
QCA: Index RVDQCA: Index RVD 2.972.97 3.663.66 0.0100.010QCA: Post Stent MLDQCA: Post Stent MLD 2.702.70 4.084.08 <0.001<0.001
IVUS at Time of VLST (DES Median <3 yrs, BMS Median 9 yrs)
Total stented lengthTotal stented length 32.932.9 18.618.6 0.0010.001Minimal Lumen CSAMinimal Lumen CSA 4.204.20 4.734.73 0.5640.564Mimimal Stent CSAMimimal Stent CSA 6.156.15 7.427.42 0.4130.413Mean Neointimal AreaMean Neointimal Area 3.073.07 5.035.03 0.0140.014Neointimal Vol. indexNeointimal Vol. index 0.420.42 0.510.51 0.0690.069Incomplete AppositionIncomplete Apposition 17 (73.9%)17 (73.9%) 0 (0%)0 (0%) 0.0010.001Neointimal RuptureNeointimal Rupture 10 (43.5%)10 (43.5%) 7 (100%)7 (100%) <0.010<0.010
Lee, CW et al, JACC 2010;55:1936–42
Pathologic Causes of LST: CV PathPathologic Causes of LST: CV Path•• Stent Malapposition (40%)Stent Malapposition (40%)•• AMI Indication (40%)AMI Indication (40%)•• Bifurcation Indication (30%)Bifurcation Indication (30%)•• Necrotic Core Penetration/Prolapse (25%)Necrotic Core Penetration/Prolapse (25%)•• Long Stenting (>40 mm) (20%)Long Stenting (>40 mm) (20%)•• Hypersensitivity Reaction (15%)Hypersensitivity Reaction (15%)•• Unknown/Other (5%)Unknown/Other (5%)•• Stent Underexpansion (<5%)Stent Underexpansion (<5%)
R. Virmani, TCT 2009R. Virmani, TCT 2009
Comparison of Coronary Vasomotion Between DES and BMS
-0.9
7.3
10.7
-4.3
1.4
-8-6-4-202468
101214
PES SES BES ZES BMS
Din
ves
sel d
iam
eter
(%) @
9-1
2 m
os
Proximal Segment
-3.4
5.2
8.6
-4.3
13.9
-8-6-4-202468
101214
PES SES BES ZES BMS
Din
ves
sel d
iam
eter
(%) @
9-1
2 m
os
Distal Segment
N=8N=15
N=21N=7
N=10
N=10N=17
N=23N=9
N=12
Hamilos MI et al. Circ Cardiovasc Int 2009
Endeavor Pooled Safety Analysis Endeavor Pooled Safety Analysis ARC Definite/Probable ST to 5 yearsARC Definite/Probable ST to 5 years
Time After Initial Procedure (days)
Cum
ulat
ive
Inci
denc
e of
D
ef/P
rob
Thro
mbo
sis
360 720 1080 14400%
0
4%
EndeavorEndeavor 21322132 21312131 20432043 19871987 16811681 11161116
% CI% CI 0.05%0.05% 0.62%0.62% 0.71%0.71% 0.71%0.71% 0.80%0.80% 0.80%0.80%
DriverDriver 596596 595595 570570 559559 543543 538538
% CI% CI 0.17%0.17% 1.35%1.35% 1.35%1.35% 1.52%1.52% 1.52%1.52% 1.71%1.71%
3%
2%
1800
1%
Endeavor Driver
0.8%
1.7%
Before 1 yearBefore 1 yearEndeavor: 0.6%Endeavor: 0.6%Driver: 1.3%Driver: 1.3%
Before 1 yearBefore 1 yearEndeavor: 0.6%Endeavor: 0.6%Driver: 1.3%Driver: 1.3%
After 1 year (VLST)After 1 year (VLST)Endeavor: 0.2%Endeavor: 0.2%Driver: 0.4%Driver: 0.4%
After 1 year (VLST)After 1 year (VLST)Endeavor: 0.2%Endeavor: 0.2%Driver: 0.4%Driver: 0.4%
SE2926383 REV A Information contained herein intended for healthcare professionals outside the U.S. and Japan only
Number at risk
XIENCE V 669 661 658 651 640 627 627 622 615 614 613 612 611
TAXUS 332 325 323 317 314 305 303 302 298 298 297 296 294
Stent Thrombosis (ARC Definite/Probable)
Months
Sten
t thr
ombo
sis
(%)
3-year HR0.78 [0.26, 2.39]
p=0.67
1.6%
1.2%
1.6%
1.2%
0.3%
0.9%
TAXUSXIENCE V
ZEST-LATE + REAL-LATE:Cardiac Death or Myocardial Infarction
Aspirin Alone
Clopidogrel + Aspirin
Clopidogrel +Aspirin
Aspirin Alone
0.5
0.7 1.2
1.8
Park SJ et al, NEJM 2010
Log-rank p=0.17
TAXUS II, IV, V, VI: Death and MI within7 Days of TLR and Stent Thrombosis
Total intent-to-treat population:3445 patients (median F/U 3.2 yrs)
Control 1727Control 1727
Stent Stent thrombosisthrombosis
14 pts14 pts
12 patients with 12 patients with death or MIdeath or MI
TAXUS 1718TAXUS 1718
Stent thrombosis Stent thrombosis 20 pts20 pts
19 patients with 19 patients with death or MIdeath or MI
ΣΣ: 23 Pts with Death or MI: 23 Pts with Death or MI(4 Deaths + 21 MIs)(4 Deaths + 21 MIs)
ΣΣ: 23 Pts with Death or MI : 23 Pts with Death or MI (3 Deaths + 23 MIs)(3 Deaths + 23 MIs)
IschemiaIschemia--driven driven TLRTLR
135 pts135 pts
4 patients with 4 patients with death or MIdeath or MI
IschemiaIschemia--driven driven TLRTLR
290 pts290 pts
11 patients with 11 patients with death or MIdeath or MI
Stone et al, Circulation 2007
20
Potential Effect of Excess VLST with DES:A Decision Analysis
Incremental VLST Risk in DES (% per year, Years 2-4)
Diff
eren
ce in
QA
LY (D
ES-B
MS)
Favors DES
Favors BMS
Garg, P et al, JACC 2008
No difference between DES and BMS at absolute VLST Difference of 0.14%
DES Efficacy ConcernsDES Efficacy Concerns•• Overemphasis on relative risk Overemphasis on relative risk
reductions (40reductions (40--50%) vs. absolute risk 50%) vs. absolute risk reductions (which are based upon reductions (which are based upon baseline risk) may not be clinically baseline risk) may not be clinically soundsound¡¡ Routine angiographic followRoutine angiographic follow--up may up may
have exaggerated the benefits of DES have exaggerated the benefits of DES over BMSover BMS
•• Late catchLate catch--up ISR/TLR may limit the up ISR/TLR may limit the longlong--term efficacy of DESterm efficacy of DES
22572257 21322132 20982098 20692069 18681868749749 697697 675675 658658 603603
Number at riskNumber at riskTAXUS DESTAXUS DESEXPRESS BMSEXPRESS BMS
Primary Efficacy Endpoint: Primary Efficacy Endpoint: Ischemic TLRIschemic TLR
Isch
emic
TLR
(%)
Isch
emic
TLR
(%)
00
11
22
33
44
55
66
77
88
99
1010
Time in MonthsTime in Months00 11 22 33 44 55 66 77 88 99 1010 1111 1212
7.5%7.5%
4.5%4.5%
HR = 0.59HR = 0.59P=0.002P=0.002
TAXUS DES (n=2257)TAXUS DES (n=2257)EXPRESS BMS (n=749)EXPRESS BMS (n=749)
Which is more impressive?
1. 41% reduction in ischemic TLR
2. Need to treat 33 patients with DES to prevent one BMS TLR event
3% difference
11--Year TLR According to BMS Risk ScoreYear TLR According to BMS Risk Score(N=2915)(N=2915)
N=946 (32.5%) N=1520 (52.1%) N=449 (15.4%)
Stone GW. ACC 2009.Stone GW. ACC 2009.
Regression of Neointima after BMSRegression of Neointima after BMS
T. Kimura et al. NEJM 1996;334:561-6
72 lesions with sequential studies through 3 yrs
+0.14 mm Increase in MLD from years 1-3
Late Late RestenosisRestenosis after DES?after DES?Animal DataAnimal Data
0
0.2
0.4
0.6
0.8
1
1.2
SES PES BMS
28 days90 days
Finn et al. JACC Intv 2009;2:300-02
P<0.001
P<0.001P=NS
NIH
Thi
ckne
ss
Post-PCI 6-8-months0
0.1
0.2
0.3
0.4
0.5
2 yrs
Polymer-free DES
Bioabsorbable Polymer DES
SES
ISAR Data: Late Loss at 2 Years
PES
Byrne et al, JACC Interv 2009; ISAR-TEST-3, Heart 2009
BMS versus DES Clinical Trials:BMS versus DES Clinical Trials:Late EventsLate Events
0
4
8
12
16
20
24
Year 1 Year 2 Year 3 Year 4 Year 5
% P
ts
SES BMS
23.1
6.9
Years 2-5Average annual hazard
SES = 1.4%BMS = 1.8%
SIRIUS 5-Years
0
4
8
12
16
20
24
Year 1 Year 2 Year 3 Year 4 Year 5%
Pts
PES BMS
Years 2-5Average annual hazard
PES = 1.6%BMS =2.0%
TAXUS 5-Years
R. Chacko et al. JACC Intv. 2009;2:498-503 M. Leon et al. JACC Intv. 2009;2:504-12
17.6
7.5
c/o D. Cutlip
0
0.1
0.2
0.3
0.4
SES PES Overall
8 Months 5 Years
0.12±0.36
0.25±0.49 0.19
± 0.44
0.30±0.51
0.37 ±0.51 0.33
±0.51∆0.17
∆0.12∆0.14
P8 months<0.001
P5 years=0.21
SIRTAX-LATE: Late Loss Over Time
%
L. Raber, TCT 2009
SIRTAX-LATE: Evolution of MLDPaired Angiograms
01
23
(mm
)
before after 8 months 5 years
SESPESoverall
RVD
MLDP=ns
P=ns
P=ns
L. Raber, TCT 2009
SPIRIT II: In-stent Late Loss in 132 Patientswith Serial 6 Month and 2 Year Angio FU
0%10%20%30%40%50%60%70%80%90%
100%
-0.75 -0.5 -0.25 0 0.25 0.5 0.75 1 1.25 1.5 1.75 2
In-stent Late Loss (mm)
0%10%20%30%40%50%60%70%80%90%
100%
-0.75 -0.5 -0.25 0 0.25 0.5 0.75 1 1.25 1.5 1.75 2
In-stent Late Loss (mm)
% o
f Les
ions
6 Months 2 Years
XIENCE V
XIENCE V
TAXUS*XIENCE V
TAXUS+
XIENCE V: 0.17 ± 0.32 (nL=97)TAXUS: 0.33 ± 0.32 (nL=35)
P=0.004P=0.004
XIENCE V: 0.33 ± 0.37 (nL=97)TAXUS: 0.34 ± 0.34 (nL=35)
P=0.60P=0.60
For patients having TLR, values of late loss observed prior to 6 month or 2 year FU were imputed
Claessen BE. Circ Cardiovasc Intervent 2009
Pivotal Trials TLR: DES ArmsPivotal Trials TLR: DES ArmsRates of TLR Over TimeRates of TLR Over Time
ENDEAVOR II(Yr 5 N = 577/598)
TLR
(%)
1 2 3 4 5
5.9
Years of Follow-up
TLR
(%)
TAXUS IV(Yr 5 N = 618/662)
1 2 3 4 5
4.4
Years of Follow-up
SIRIUS(Yr 5 N = 501/533)
TLR
(%)
1 2 3 4 5
4.9
Years of Follow-up6
6.57.2 7.2 7.5
5.6
6.9
7.89.1
6.36.8
7.9
9.4
11.9
•• Overall safety is very comparable to BMS with Overall safety is very comparable to BMS with followfollow--up generally ≤5 yearsup generally ≤5 years
¡¡ DAPT adherence is critical early onDAPT adherence is critical early on
•• Late stent thrombosis remains a concern, and realLate stent thrombosis remains a concern, and real--world data 5 years and beyond is now emergingworld data 5 years and beyond is now emerging
¡¡ How to prevent late stent thrombosis?How to prevent late stent thrombosis?
•• Relative DES efficacy is unquestionably improved vs. Relative DES efficacy is unquestionably improved vs. BMS, but BMS, but absolute differences absolute differences in TLR rates may vary in TLR rates may vary by overall patient risk and if late catchby overall patient risk and if late catch--up is a real up is a real phenomenonphenomenon
Late DES Issues: Safety and EfficacyLate DES Issues: Safety and Efficacy
What of These Lingering Concerns?What of These Lingering Concerns?
•• Webster’s Definition ofWebster’s Definition of “lingering”“lingering”¡¡ a: to remain alive although gradually a: to remain alive although gradually
dyingdying¡¡ b : to remain existent although often b : to remain existent although often
waning in strength, importance, or waning in strength, importance, or influenceinfluence
Improvements/Innovations in DES technology should hopefully allow these concerns to rest in peace!
