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SVEIKATOS TECHNOLOGIJOS VERTINIMAS:
DEŠINIAJAME SKILVELYJE IMPLANTUOJAMAS BELAIDIS
ŠIRDIES STIMULIATORIUS
HEALTH TECHNOLOGY ASSESSMENT:
LEADLESS PACEMAKERS FOR RIGHT VENTRICLE PACING
2016
VILNIUS
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Valstybinė akreditavimo sveikatos priežiūros veiklai tarnyba
prie Sveikatos apsaugos ministerijos
Autoriai: Medicinos technologijų skyriaus vyr.specialistės:
Kristina Grigaitė
Vitalija Mazgelė
Valstybinė akreditavimo sveikatos priežiūros veiklai tarnyba prie Sveikatos apsaugos ministerijos
Jeruzalės g. 21, LT-08420 Vilnius
Tel. (8 5) 261 5177,
Faks. (8 5) 212 7310,
El. paštas: [email protected]
Sveikatos technologijos vertinimo santrauką galima rasti interneto svetainėje:
http://www.vaspvt.gov.lt/node/486
Interesų konfliktas: Visi autoriai ir recenzentai, įtraukti į sveikatos priežiūros technologijos vertinimą,
deklaravo neturintys interesų konflikto.
Sveikatos priežiūros technologijos vertinimo turiniui ir/ ar struktūrai buvo naudotas EUnetHTA
(www.eunethta.eu) sveikatos priežiūros technologijų vertinimo šerdinis modelis (HTA Core Model®).
_______________________________________________________________________________
State Health Care Accreditation Agency
under the Ministry of Health
Authors: Chief specialists of Medical Technology division:
Kristina Grigaitė
Vitalija Mazgelė
State Health Care Accreditation Agency under the Ministry of Health
Jeruzalės st. 21, LT-08420 Vilnius
Tel. (370 5) 261 5177,
Fax. (370 5) 212 7310,
E. mail: [email protected]
Health technology assessment is available on the website:
http://www.vaspvt.gov.lt/node/486
Conflict of interest: All authors and the reviewers involved in the production of this report have declared
they have no conflicts of interest in relation to the technology assessed.
The HTA Core Model®, developed within EUnetHTA (www.eunethta.eu), has been utilised when
producing the contents and/ or structure of this work.
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TABLE OF CONTENTS
TABLE OF CONTENTS ........................................................................................................................... 3 ABBREVIATIONS .................................................................................................................................... 6 SANTRAUKA ............................................................................................................................................ 7
Sveikatos technologijos vertinimo metodika .......................................................................................... 7 Tikslinė būklė ......................................................................................................................................... 9
Tikslinė populiacija .............................................................................................................................. 10 Šiuolaikinis būklės valdymas ............................................................................................................... 10 Kompensavimas .................................................................................................................................... 10 Pagrindinės technologijos charakteristikos........................................................................................... 11 Investicijos ir prietaisai, reikalingi technologijos naudojimui .............................................................. 12
Pacientų saugumas ................................................................................................................................ 12
Mirštamumas ........................................................................................................................................ 13 Organizmo funkcijos ............................................................................................................................ 13
Gyvenimo kokybė ................................................................................................................................. 13 SVEIKATOS TECNOLOGIJOS FUNKCINĖ VERTĖ .......................................................................... 14 IŠVADOS ................................................................................................................................................. 15 REKOMENDACIJOS .............................................................................................................................. 15
SUMMARY .............................................................................................................................................. 16 Scope..................................................................................................................................................... 16
Target condition .................................................................................................................................... 17 Target population .................................................................................................................................. 17 Current clinical management of the disease or health condition .......................................................... 18
Regulatory & reimbursement status ..................................................................................................... 18 Features of the technology .................................................................................................................... 19
Investments and tools required to use the technology .......................................................................... 20
Patient safety ......................................................................................................................................... 20
Mortality ............................................................................................................................................... 20 Function ................................................................................................................................................ 21
Quality of life ........................................................................................................................................ 21 HEALTH PROBLEM AND CURRENT USE OF THE TECHNOLOGY ............................................. 22
Research questions................................................................................................................................ 22 Overview of the disease or health condition......................................................................................... 22
A0001. For which health conditions, and for what purposes are leadless pacemakers used? .......... 22 A0002. What is the disease or health condition in the scope of this assessment? ............................ 22 A0003. What are the known risk factors for cardiac arrhythmias? .................................................. 23
A0004. What is the natural course of cardiac arrhythmias? ............................................................. 23 Effects of the disease or health condition on the individual and society .............................................. 24
A0005. What is the burden of disease for patients with cardiac arrhythmias? ................................ 24
A0006. What are the consequences of cardiac arrhythmias for the society? ................................... 24 Current clinical management of the disease or health condition .......................................................... 24
A0024. How are cardiac arrhythmias currently diagnosed according to published guidelines and in
practice? ............................................................................................................................................ 24
A0025. How are cardiac arrhythmias currently managed according to published guidelines and in
practice? ............................................................................................................................................ 25 Target population .................................................................................................................................. 26
A0007. What is the target population in this assessment? ............................................................... 26 A0023. How many people belong to the target population? ............................................................ 26
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A0011. How much are leadless pacemakers utilised? ...................................................................... 26
Regulatory & reimbursement status ..................................................................................................... 26 A0020. What is the marketing authorisation status of leadless pacemakers? .................................. 26 A0021. What is the reimbursement status of leadless pacemakers? ................................................ 26
Discussion ............................................................................................................................................. 27 DESCRIPTION AND TECHNICAL CHARACTERISTICS OF THE LEADLESS PACEMAKERS .. 28
Research questions................................................................................................................................ 28 Features of the technology and comparators ........................................................................................ 28
B0001. What are leadless pacemakers and conventional single-chamber ventricular pacemakers? 28 B0002. What is the claimed benefit of leadless pacemakers in relation to conventional single-
chamber ventricular pacemakers? .................................................................................................... 30
B0003. What is the phase of development and implementation of leadless pacemakers and
conventional single-chamber ventricular pacemakers? .................................................................... 30 Administration, Investments, personnel and tools required to use the technology and the
comparator(s) ........................................................................................................................................ 31 B0004. Who administers leadless pacemakers and conventional single-chamber ventricular
pacemakers and in what context and level of care are they provided? ............................................. 31 B0008. What kind of special premises are needed to use leadless pacemakers and conventional
single-chamber ventricular pacemakers? .......................................................................................... 31 B0009. What supplies are needed to use leadless pacemakers and conventional single-chamber
ventricular pacemakers? ................................................................................................................... 31 Discussion ............................................................................................................................................. 31
SAFETY ................................................................................................................................................... 33
Research questions................................................................................................................................ 33 Patient safety ......................................................................................................................................... 33
C0008. How safe are leadless pacemakers in comparison to conventional single-chamber
ventricular pacemakers? ................................................................................................................... 33 C0005. What are the susceptible patient groups that are more likely to be harmed through the use
of the technology? ............................................................................................................................ 33 C0007. Are leadless pacemakers and conventional single-chamber ventricular pacemakers
associated with user-dependent harms? ............................................................................................ 33
Discussion ............................................................................................................................................. 34 CLINICAL EFFECTIVENESS ................................................................................................................ 36
Research questions................................................................................................................................ 36 Mortality ............................................................................................................................................... 36
D0001. What is the expected beneficial effect of leadless pacemakers on mortality? ..................... 36
D0003. What is the effect of leadless pacemakers on the mortality due to causes other than cardiac
arrhythmia? ....................................................................................................................................... 36 Morbidity .............................................................................................................................................. 36
D0005. How do leadless pacemakers affect symptoms and findings (severity, frequency) of cardiac
arrhythmias? ..................................................................................................................................... 36
D0006. How do leadless pacemakers affect progression (or recurrence) of cardiac arrhythmias? .. 36 Function ................................................................................................................................................ 37
D0011. What is the effect of leadless pacemakers on patients’ body functions? ............................. 37 D0016. How does the use of leadless pacemakers affect activities of daily living? ........................ 37
Health-related quality of life ................................................................................................................. 37 D0012. What is the effect of leadless pacemakers on generic health-related quality of life? .......... 37 D0013. What is the effect of leadless pacemakers on disease-specific quality of life? ................... 37
Patient satisfaction ................................................................................................................................ 37 D0017. Was the use of leadless pacemakers worthwhile? ............................................................... 37
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Discussion ............................................................................................................................................. 37
CONCLUSIONS ...................................................................................................................................... 39 RECOMMENDATIONS .......................................................................................................................... 40 REFERENCES ......................................................................................................................................... 41 APPENDIX 1: METHODOLOGY AND DESCRIPTION OF THE EVIDENCES USED .................... 45
Reporting of results............................................................................................................................... 46
Study characteristics ......................................................................................................................... 46 Quality assessment ........................................................................................................................... 46
Limitations ............................................................................................................................................ 46 ADAPTATION TOOLKIT .................................................................................................................. 48 Documentation of the basic search strategies ....................................................................................... 52
Flow charts of study selection .............................................................................................................. 53 Questions used from HTA Core Model Application for Rapid Relative Effectiveness assessment
(version 4.2) .......................................................................................................................................... 54
Health problem and current use of the technology ........................................................................... 54 Description and technical characteristics of technology ................................................................. 54 Safety ............................................................................................................................................... 54 Clinical effectiveness ....................................................................................................................... 55
APPENDIX 2: DESCRIPTION OF THE EVIDENCE USED ................................................................ 56 Evidence tables of individual studies included ..................................................................................... 56
Included studies .................................................................................................................................... 61 Excluded studies ................................................................................................................................... 61
APPENDIX 3: QUALITY ASSESSMENT OF SELECTED STUDIES ................................................ 64
Quality assessment of the selected case series ..................................................................................... 64 The IHE checklist for case series ..................................................................................................... 65
Quality assessment of the selected systematic reviews ........................................................................ 66 The AMSTAR checklist for systematic reviews .............................................................................. 67
Checklist for potential ethical, organisational, social and legal aspects ............................................... 69
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ABBREVIATIONS
% – percent;
ACC – American College of Cardiology;
AF – atrial fibrillation;
AHA – American Heart Association;
ATP – anti-tachycardia pacing;
AV – atrioventricular;
BBB – bundle branch block;
CE – Conformité Européene (European Conformity);
CRT – cardiac resynchronization therapy;
DRG – diagnosis-related group;
ECG – electrocardiogram;
ESC – European Society of Cardiology;
etc. – et cetera;
EU – European Union;
EUR – euro;
FDA – Food and Drug Administration;
Fr – French units;
HRS – Heart Rhythm Society;
i.e. – in essence;
ICD – implantable cardioverter-defibrillator;
ICD-10-AM – International Classification of Diseases, 10th Revision, Australian Modification;
LCP – leadless cardiac pacemaker;
MCRD – monolithic controlled release device;
MRI – magnetic resonance imaging;
NBG – North American Society of Pacing and Electrophysiology (NASPE) and the British Pacing and
Electrophysiology Group (BPEG);
PFO – patent foramen ovale;
SB – sinus bradycardia;
SND – sinus node disease (also sick sinus syndrome);
TGA – Therapeutic Goods Administration;
TPS – transcatheter pacing system;
USA – United States of America;
VVI – single-chamber ventricular pacing;
VVIR – single-chamber ventricular pacing with response modulation;
WiCS™-LV system – Wireless Cardiac Stimulation System.
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SANTRAUKA
Sveikatos technologijos vertinimo metodika
Šis sveikatos priežiūros technologijos vertinimas yra Austrijos Liudviko Boltzmano instituto
sveikatos technologijų vertinimui (angl. Ludwig Boltzmann Institute-Health Technology Assessment,
Austria) atlikto vertinimo „Dešiniajame skilvelyje implantuojamas belaidis širdies stimuliatorius“ (angl.
„Leadless pacemakers for right ventricle pacing”) atnaujinimas ir adaptavimas Lietuvos kontekstui
pagal EUnetHTA metodikas. Europos Komisija inicijuoja ir remia EUnetHTA bei kitų šalių atliktų
sveikatos priežiūros technologijų vertinimų naudojimą ir adaptavimą nacionaliniams Europos šalių
poreikiams.
Pirminis šaltinis, kurio pagalba buvo atrinkti pagrindiniai vertinimo elementai – Sveikatos
technologijų vertinimo šerdinis modelis greitam santykinio veiksmingumo vertinimui, versija 4.2 (angl.
‘HTA Core Model® for Rapid Relative Effectiveness Assessments (version 4.2’)). Be to, kiti EUnetHTA
šerdinio modelio dokumentai (Sveikatos technologijų vertinimo šerdinis modelis medicininių ir
chirurginių intervencijų vertinimui, versija 3.0 (angl. ‘HTA Core Model® for Medical and Surgical
Interventions (version 3.0’))) buvo peržiūrėti ir, esant poreikiui, papildomi vertinimo elementai įtraukti.
2016-ųjų metų rugpjūčio mėn. vykdyta sisteminė literatūros paieška buvo tikslinama naudojant
duomenų filtrą – publikacijos išspausdintos laikotarpyje nuo 2015-ųjų metų gruodžio mėn. 10 d. iki
2016-ųjų metų rugpjūčio mėn. 25 d., imtinai. Dalis informacijos buvo atnaujinta ir panaudota remiantis
Austrijos Liudviko Boltzmano instituto sveikatos technologijų vertinimui (LBI-HTA, Austrija) atliktu
sveikatos technologijų vertinimu, įvardinamu kaip sprendimų paramos dokumentas Nr. 97 „Leadless
pacemakers for right ventricle pacing”.
Belaidžio širdies stimuliatoriaus (BŠS) vertinimo analizė atlikta remiantis mokslinės literatūros
šaltiniais, esančiais:
The Cochrane Library duomenų bazėje;
PubMed (Medline) duomenų bazėje;
CRD duomenų bazėje;
Gamintojų internetiniuose puslapiuose, kurių ieškota rankiniu būdu viešai prieinamoje
erdvėje (internete).
Straipsniai, skirti „Saugumo“ ir „Klinikinio efektyvumo“ skyrių adaptavimui, buvo atrinkti
VASPVT (Valstybinė akreditavimo sveikatos priežiūros veiklai tarnyba prie Sveikatos apsaugos
ministerijos, Lietuva) Medicinos technologijų skyriaus specialistų. Papildomi moksliniai straipsniai
buvo įtraukti arba atmesti vadovaujantis PICO lentele, kuri pateikta santraukoje. Nė vienas
randomizuotas kontroliuojamas tyrimas bei sisteminė literatūros apžvalga nebuvo rastas/ įtrauktas į
vertinimą.
Mokslinių straipsnių įtraukimo ir atmetimo procesą vykdė du tyrėjai. Jei ta pati informacija
dubliavosi keliuose straipsniuose, į vertinimą įtraukti tik tie, kuriuose rezultatai pateikti išsamiausiai
arba straipsniai buvo naujausi. Visais atvejais, tiek atmetant, tiek įtraukiant tyrimus į vertinimą buvo
siekiama bendro sutarimo.
Vertinime naudojamų nekontroliuojamų tyrimų (angl. case series) kokybė buvo įvertinta
specialiu, nekontroliuojamiems tyrimams skirtu, Sveikatos Ekonomikos instituto kontrolės klausimynu
(angl. The IHE checklist), kurio rezultatus galima rasti Austrijos LBI-HTA instituto sveikatos
technologijų vertinime, įvardintame kaip sprendimų paramos dokumentas Nr. 97 „Leadless pacemakers
for right ventricle pacing”; klausimynus individualiai pildė du specialistai. Išsiskyrus nuomonėms,
trečias specialistas buvo įtrauktas į tyrimų kokybės vertinimo procesą.
Palyginamoji analizė buvo negalima, kadangi į vertinimą įtraukti tik nekontroliuojami tyrimai.
LBI-HTA agentūros specialistai „Saugumo“ ir „Klinikinio efektyvumo“ skyriuose pateiktų duomenų
kokybę įvertino remiantis tarptautinėmis Rekomendacijų lygių Vertinimo ir Nustatymo Grupės
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rekomendacijomis (angl. The Grading of Recommendations Assessment, Development and Evaluation,
GRADE). Trijų nekontroliuojamų į vertinimą įtrauktų tyrimų (iš viso 5 straipsniai) pagrindinių
charakteristikų lentelės yra Austrijos LBI-HTA instituto sveikatos technologijų vertinime, kuris
įvardinamas kaip sprendimų paramos dokumentas Nr. 97 „Leadless pacemakers for right ventricle
pacing”.
Atsakant į „Sveikatos problema ir dabartinis technologijos naudojimas“ bei „Techninės
charakteristikos“ skyrių klausimus, į vertinimą įtrauktiems tyrimams jokie apribojimai netaikyti,
informacijos ieškota rankiniu būdu viešai prieinamoje erdvėje (internete).
Į vertinime analizuojamus klausimus atsakyta tekstiniu formatu. Kadangi nėra palyginamųjų
grupių ir duomenys yra heterogeniški, atlikta analizė yra ne kiekybinė, bet kokybinė.
PICO lentelė
Populiacija Pirmojo pasirinkimo gydymo metodas pacientams, turintiems vienos kameros
(vienkamerinio) širdies stimuliatoriaus indikacijas [2,4]:
Pacientai, kuriems diagnozuotas lėtinis prieširdžių virpėjimas (TLK-10-AM:
I48) ir reikalingas širdies stimuliatorius dėl bradikardijos, kuri išsivystė dėl
atrioventrikulinės (AV) blokados (TLK-10-AM: I44);
Pacientai, kuriems diagnozuota bradikardija dėl AV blokados arba sinusinio
mazgo silpnumo sindromo (TLK-10-AM: I49.5)1.
Kontraindikacijos:
Pacientai, kuriems reikalinga ilgalaikė stimuliacija, viršijanti numatytą
prietaiso veikimo laiką (pvz., vaikai);
Pacientai, kuriems reikalingas vienos kameros (prieširdžio) stimuliatorius
arba dviejų kamerų stimuliatorius arba pacientai, kuriems reikalinga širdies
resinchronizavimo terapija.
MESH term: Arrhythmias, Cardiac [C14.280.067] and Arrhythmias, Cardiac
[C23.550.073].
Intervencija Belaidis autonominis ir visiškai implantuojamas vienkamerinis (dešiniojo
skilvelio) širdies stimuliatorius.
Kontekstas: kraujagyslių chirurgija, intervencinė kardiologija; specializuota
ligoninė.
Prietaisai:
Micra™, gamintojas – Medtronic Inc.;
Nanostim™, gamintojas – St. Jude Medical.
MESH term: Pacemaker, Artificial [E07.305.250.750]
Alternatyvos Įprastinis (tradicinis) implantuojamas vienkamerinis dešiniojo širdies
skilvelio stimuliatorius.
MESH term: Pacemaker, Artificial [E07.305.250.750]
Rezultatai
Efektyvumas Mirtingumas dėl širdies–kraujagyslių sistemos ligų;
Sergamumas širdies–kraujagyslių sistemos ligomis;
1 Tik tais atvejais, kai kiti stimuliavimo režimai (dvikamerinis stimuliavimas, prieširdžių stimuliavimas) nėra
rekomenduojami.
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Pacientų gyvenimo kokybė;
Fizinis pajėgumas;
Stimuliavimo veikla.
Saugumas Nepageidaujamų įvykių dažnis.
Tyrimų tipas
Efektyvumas Randomizuoti kontroliuojami tyrimai2;
Prospektyviniai nerandomizuoti kontroliuojami tyrimai.
Saugumas Randomizuoti kontroliuojami tyrimai;
Prospektyviniai nerandomizuoti kontroliuojami tyrimai;
Prospektyviniai nekontroliuojami tyrimai ar atvejų registrai, kuriuose
daugiau nei 100 pacientų.
PICO klausimas: Ar dešiniajame skilvelyje implantuojami belaidžiai širdies stimuliatoriai, lyginant
juos su įprastiniais (tradiciniais) širdies stimuliatoriais, yra tokie pat efektyvūs atsižvelgiant į
mirtingumą ir sergamumą širdies–kraujagyslių sistemos ligomis, fizinį pajėgumą bei ar yra dar
efektyvesni ir saugesni atsižvelgiant į gyvenimo kokybės aspektą ir nepageidaujamų įvykių dažnį?
Tikslinė būklė
Belaidžiai širdies stimuliatoriai (BŠS) yra alternatyva tradiciniams širdies stimuliatoriams (ŠS)
įvairių širdies aritmijų gydymui. Natūralus širdies stimuliatorius organizme yra dešiniajame prieširdyje
esantis sinusinis mazgas. Širdies bradiaritmija (bradikardija, susijusi su aritmija) išsivysto dėl sinusinio
mazgo silpnumo (sinusinio mazgo silpnumo sindromas, SND) arba dėl atrioventrikulinės blokados
(širdies laidumo sutrikimai). Taip pat bradikardija gali būti susijusi su prieširdžių virpėjimu. (A0001)
Širdies stimuliacijos tikslas – užtikrinti tinkamą širdies ritmą ir širdies atsaką atkuriant
efektyvią cirkuliaciją bei hemodinamiką, sutrikusią dėl lėto širdies plakimo (bradikardija ar
bradiaritmija: <60 širdies susitraukimų per minutę). Manoma, kad nuolatinė širdies stimuliacija gali
sumažinti simptomus, susijusius su bradikardija (pvz.: galvos svaigimą, nuovargį, alpimą, prastą
ištvermę), arba apsaugoti nuo galimo ritmo sutrikimo blogėjimo. (A0001)
Šio vertinimo tikslinė būklė – širdies aritmijos suaugusiems, kuriems indikuotinas
vienkamerinis širdies skilvelio stimuliavimas. Toks stimuliacijos režimas gali būti taikomas pacientams,
sergantiems lėtiniu prieširdžių virpėjimu dėl kurio reikalingas širdies stimuliatorius skilvelio atsako
koregavimui. (A0002)
Bradiaritmija, kuriai valdyti reikalingas ŠS, gali būti sukelta daugelio veiksnių. Esminės
priežastys: idiopatinė (senėjimo) degeneracija; išeminė širdies liga; infiltracinės ligos (pvz.: sarkoidozė,
amiloidozė, hemochromatozė); kolageno ir kraujagyslių ligos (pvz.: sisteminė raudonoji vilkligė,
reumatoidinis artritas, sklerodermija); įgimtos ligos, įskaitant SND bei atriventrikulinę blokadą;
infekcinės ligos (pvz.: Laimo liga); chirurginės traumos, tokios kaip vožtuvas keitimas, širdies
transplantacija. (A0003)
Priklausomai nuo bradiaritmijos tipo skiriasi širdies stimuliavimo režimai. Pacientai, kuriems
atrioventrikulinė blokada negydyta, gali mirti dėl širdies nepakankamumo arba dėl skilvelinės
tachiaritmijos juos gali ištikti staigi mirtis. Pacientų, sergančių SND, bendras išgyvenamumas bei
staigios mirties rizika yra panaši kaip bendros populiacijos. Vis dėlto, vieningai sutariama, kad
pacientams, sergantiems SND, širdies stimuliavimas gali turėti įtakos simptomų palengvinimui. (A0004)
2 Randomizuoti kontroliuojami tyrimai, kuriuose lyginami belaidžiai ir įprastiniai širdies stimuliatoriai, yra pageidautini, jei
jie yra tinkami (pakankamas pacientų skaičius, intervencija nėra skubi), etiški (klinikinė atsvara, pacientai gali duoti
sutikimą) ir būtini dėl galimo poveikio. Tyrimo vykdytojai bei pacientai negali būti maskuoti, o lyginimas su placebu yra
neetiškas dėl efektyvaus gydymo prieinamumo.
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Tikslinė populiacija
BŠS yra skirtas naudoti kaip įprastų vienkamerinių dešiniojo širdies skilvelio stimuliatorių
pakaitalas. Tikslinė populiacija yra tie pacientai, kuriems yra indikuojamas vienkamerinis dešiniojo
širdies skilvelio stimuliacijos režimas (VVI). (A0007; A0023)
Kai bradikardija kelia grėsmę normaliai kraujotakai, pasireiškia tokie simptomai: nuovargis,
galvos svaigimas, alpimas, dusulys, krūtinės skausmas, silpnumas, sumažėjęs fizinis pajėgumas. Per
pirmuosius 6 mėn. po širdies elektroninių prietaisų (visų tipų) implantacijos mažiau nei 6% pacientų
patiria sunkias komplikacijas, dažniausia iš jų – pakartotinė intervencija dėl laidų sukeltų komplikacijų.
(A0005)
Pacientų, kuriems reikalinga vienkamerinio širdies stimuliatoriaus implantacija, skaičius lieka
neaiškus. Lietuvoje 2015 m. užregistruota daugiau nei 110,000 pacientų, kuriems diagnozuota širdies
aritmija. 2005 m. Lietuvoje buvo atlikta daugiau nei 1,500 širdies stimuliatorių implantacijų operacijų;
šis skaičius didėja kiekvienais metais. (A0006; A0011)
Šiuolaikinis būklės valdymas
Nėra apibrėžta, kokia turėtų būti širdies ritmas riba, žemiau kurios gydymas būtų sindikuotinas.
Sprendžiant širdies stimuliacijos reikalingumą, reikia nustatyti sąsają tarp simptomų ir bradikardijos.
Nuolatinė bradiaritmija nustatoma pagal standartinę elektrokardiogramą (EKG), o protarpinė – pagal
standartinę EKG arba pagal prailgintą EKG. Jei bradikardija yra įtariama, tačiau nediagnozuota, gali
prireikti provokuojančių testų arba elektrofiziologinio tyrimo. (A0024)
Sprendimas dėl širdies stimuliatoriaus implantacijos ir ritmo režimo grindžiamas pagal tris
klinikinius veiksnius: širdies laidumo sutrikimai, simptomų buvimas ir jų sąsaja su bradikardija,
priežasties negrįžtamumas. VVI stimuliavimo režimas gali būti taikomas pacientams, sergantiems
prieširdžių virpėjimu, dėl kurio reikalingas širdies stimuliatorius skilvelio atsako (atrioventrikulinei
blokadai) koregavimui. Pacientams, su nustatyta atrioventrikuline blokada (be prieširdžių virpėjimo)
arba SND, gali būti taikomas vienkamerinis arba dvikamerinis širdies stimuliatorius. Simptominė
bradikardija yra indikacija širdies stimuliatoriaus implantacijos operacijai, jei simptomai yra susiję su
bradikardija ir bradikardijos atsiradimo priežastis yra negrįžtama. (A0025)
Kompensavimas
Nanostim™: Po LEADLESS I tyrimo, baigto 2013 m. spalio mėn., BŠS gamintojas St. Jude
Medical gavo patvirtinimą, kad Nanostim™ BŠS gavo CE ženklą ir gali būti naudojamas Europos
Sąjungoje. Tyrimas, skirtas patikrinti Nanostim™ BŠS Jungtinėse Amerikos Valstijose, buvo pradėtas
2014 m. Medicinos priemonės (prietaiso) vis dar nepatvirtino nei JAV Maisto ir vaistų administracija
(FDA), nei Kanados federalinis sveikatos apsaugos departamentas „Health Canada“, nei Australijos
Terapinių prekių administracija (TGA). Planuojama, kad FDA patvirtinimą Nanostim™ BŠS gaus
2016–2017. (A0020; A0021)
Micra™ Transcatheter Pacing System: 2015 m. BŠS gamintojas Medtronic medicinos
priemonei (prietaisui) Micra™ Transcatheter Pacing System (TPS) gavo CE ženklą. Tyrimas, skirtas
įvertinti Micra™ BŠS klinikinius rezultatus JAV, buvo pradėtas 2013 m. lapkričio mėn., o JAV Maisto
ir vaistų administracija medicinos priemonę (prietaisą) patvirtino 2016 m. balandžio mėn. (A0020;
A0021)
Nėra tikslių duomenų apie šių įrenginių kainą, tačiau akivaizdu, kad vienkameriniai belaidžiai
širdies stimuliatoriai kainuoja brangiau nei įprastiniai (Australijoje jų kainos yra 11,300 EUR, palyginus
su įprastiniais, kurių kainos 4,200 EUR). Italijos sveikatos technologijų vertinimo agentūros AGENAS
ataskaitoje skelbiama, kad Nanostim™ prietaiso (gamintojas St. Jude Medical) ir jo implantavimo kaina
– 11,500 EUR. Gamintojas Medtronic Inc. nepateikia prietaiso Micra ™ TPS kainos. (A0020; A0021)
11
(Belaidžiai) širdies stimuliatoriai Lietuvoje yra kompensuojami atsižvelgiant į DRG kodus
F12A bei F12B (Širdies stimuliatoriaus (visos sistemos) implantavimas ar pakeitimas), kurių kainos
atitinkamai yra 2,817.74 EUR ir 1,439.21 EUR. (A0020; A0021)
Pagrindinės technologijos charakteristikos
Belaidžiai širdies stimuliatoriai yra autonominiai (savarankiški) intrakardialiniai širdies
prietaisai, atliekantys tas pačias funkcijas kaip įprasti ŠS, tačiau gerokai mažesnio dydžio, todėl su
įvedimo kateteriu gali būti visiškai implantuoti dešiniajame širdies skilvelyje. (B0001) Pirmasis visiškai į endokardą implantuojamas stimuliatoriaus prototipas buvo pristatytas 1970
m. Nuo to laiko buvo kuriamos kelios skirtingos belaidės sistemos su skirtingais energijos šaltiniais bei
skirtingais prisitvirtinimo mechanizmais; galiausiai CE ženklą gavo dvi belaidės vienkamerinės
dešiniojo skilvelio stimuliavimo sistemos: Nanostim™ belaidis širdies stimuliatorius ir Micra™
transkateterinio stimuliavimo sistema. Šių dviejų prietaisų techninės charakteristikos panašios: tai
vienos kameros stimuliatoriai, įmontuoti hermetiškai sandarioje kapsulėje, abiejų nustatymai
programuojami. Dydis maždaug dešimt kartų mažesnis nei įprasto vienos kameros ŠS – ~1cm³, sveria
~2 gramus. Numatomas prietaisų baterijos ilgaamžiškumas – ~10 m. (kaip ir įprastinio ŠS). Implantacija
į dešinįjį skilvelį atliekama per šlaunies veną, naudojant 18 Fr (Nanostim™) ir 23 Fr (Micra™) dydžio
kateterius; prietaiso proksimalinį galą galima prijungti prie įvedimo ir išėmimo kateterių, todėl
skilvelyje galima pakeisti prietaiso padėtį arba jį išimti (eksplantuoti). Teoriškai, abi sistemos suteikia
galimybę prietaisą eksplantuoti ar pakeisti jo padėtį po implantacijos; apie eksplantaciją yra ir praktinių-
mokslinių duomenų iš tyrimų su gyvūnais bei žmonėmis. Vis dėlto, šiuo metu turimų duomenų trūksta ir
manoma, jog, esant atitinkamoms aplinkybėms, yra racionaliau į širdies skilvelį šalia išjungto prietaiso
implantuoti naują stimuliatorių. (B0001; B0003) Pagrindinis dviejų BŠS sistemų skirtumas – skirtingi prisitvirtinimo endokarde mechanizmai:
Nanostim™ BŠS turi įsukamą vienos vijos spiralę, be to, papildomai prietaisas tvirtinamas trimis
siūlėmis; Micra™ BŠS prisitvirtina savaime išsiskleidžiančiais (angl. self-expanding) kabliukais
pagamintais iš nikelio ir titano lydinio (nitinolio). (B0001)
Įprastinis ŠS, kurį sudaro maitinimo elementas ir elektroninė schema, atsakinga už energijos iš
maitinimo elemento transformavimą į elektros impulsus, stimuliuojančius širdį (schema kontroliuoja
siunčiamų impulsų dažnį bei elektros impulsų tiekiamų į širdį intensyvumą), yra implantuojama į po
raktikauliu suformuotą odos „kišenę“ (angl. pectoral subcutaneous pocket). Stimuliavimo laidas
užbaigia elektrinį kelią tarp ŠS ir širdies, per jį elektriniai impulsai siunčiami į širdį. Atsižvelgiant į
būklės sudėtingumą, ŠS gali stimuliuoti tiek vieną (vienkameriniai), tiek dvi kameras (dvikameriniai);
dvikameriniams ŠS reikalingi du laidai. (B0001)
Lyginant su įprastiniu ŠS, tam, jog užtikrintų savo funkcijas, BŠS nereikalinga suformuota
odos „kišenė“ kairėje krūtinės pusėje ir nereikalingi į kraujagysles įvesti stimuliavimo laidai, per
kuriuos impulsai pasiekia širdies prieširdžius ar skilvelius. Minėti faktai leidžia išvengti su šiomis
sudedamosiomis prietaiso dalimis susijusių komplikacijų. Operacinio pjūvio vietoje (kišenėje) būdingos
vietinės komplikacijos – odos erozija, hematoma, paraudimas, patinimas, žaizdos infekcija. 6-iems
pacientams iš 10-ies, šios komplikacijos apriboja peties regiono, kuriame įsodintas ŠS, judesius. Su
stimuliavimo laidais susiję nepageidaujami įvykiai: venų obstrukcija (nepraeinamumas), įtrūkimai
stimuliavimo laidų paviršiuje (izoliacijos įtrūkimai), stimuliavimo laidų „atsijungimas“ nuo ŠS,
elektrinių signalų trukdžiai, stimuliavimo laidų lūžiai (nutrūkimas), infekcija. Pavojingiausi
nepageidaujami įvykiai yra tie, kuriems pašalinti reikalinga chirurginė intervencija, ypač pavojingos
infekcijos, dėl kurių reikia atlikti ŠS eksplantaciją. (B0001; B0002)
Dar vienas BŠS implantacijos privalumas susijęs su trumpesne procedūros ir gijimo laikotarpio
trukme bei geresne gyvenimo kokybe, kadangi po procedūros nelieka rando, nėra iškilimo, peties
judesiai išlieka neapriboti. (B0002)
12
Apskaičiuota, jog apytiksliai 75% pacientų, kuriems implantuotas ŠS, per laiką atsiranda
indikacijų, kai reikia atlikti magnetinio rezonanso tomografijos tyrimus. Vis dėlto, yra žinoma, jog tokie
tyrimai pacientams, su implantuotu įprastu ŠS, gali būti žalingi paciento sveikatai ir sutrikdyti prietaiso
veiklą. Micra™ BŠS suteikia galimybę pacientams saugiai atlikti magnetinę tomografiją su 1.5 ir 3
Tesla galingumo magnetinio rezonanso tomografais, neseniai (2016 m. kovo mėn.) ir Nanostim™ BŠS
gamintojai paskelbė apie tokią galimybę (tik su 1.5 Tesla galingumo prietaisais). (B0002)
Investicijos ir prietaisai, reikalingi technologijos naudojimui
Tiek BŠS, tiek įprastinio vienkamerinio ŠS implantavimo procedūros gali būti atliekamos tik
specializuotuose intervencinės kardiologijos skyriuose. BŠS implantacijos metu reikalingi
fluoroskopijos procedūrai naudojami prietaisai, kad stimuliatorius būtų tinkamai implantuotas į dešinįjį
skilvelį.
Kaip ir prieš atliekant bet kokią naują procedūrą, prieš BŠS implantaciją reikalingas specialus
pasiruošimas bei papildomi mokymai. Specialistai kardiologai gali atlikti abi minėtas procedūras, tačiau
specialus pasiruošimas yra privalomas. (B0004; B0008; B0009)
Pacientų saugumas
Sunkių, su prietaiso naudojimu susijusių, nepageidaujamų įvykių dažnis, trijuose į vertinimą
įtrauktuose nekontroliuojamuose tyrimuose, varijavo nuo 4 iki 6.5%. Vis dėlto, svarbu atkreipti dėmesį,
jog rezultatai gauti remiantis 3-mis nerandomizuotais moksliniais tyrimais, todėl duomenys apie
belaidžių širdies stimuliatorių saugumo aspektą yra preliminarūs. (C0008)
LEADLESS I tyrime širdies sužalojimas (širdies tamponada (angl. cardiac tamponade))
nustatytas vienam pacientui, LEADLESS II tyrime tokio pobūdžio sužalojimai (širdies perforacijos
su/be tamponados ar perikardo efuzijos3 (angl. cardiac perforations with/without tamponade or
pericardial effusions)) nustatyti 8 pacientams, o “Micra™ Transcatheter Pacemaker Study” tyrime
širdies sužalojimai (širdies perforacijos ar efuzijos (angl. cardiac perforations or effusions)) diagnozuoti
11 pacientų. 6 pacientams, kuriems buvo implantuotas Nanostim™ BŠS, nustatytas prietaiso
pasislinkimas iš implantavimo vietos; tokie nepageidaujami įvykiai nenustatyti pacientams, kuriems
buvo implantuoti Micra™ BŠS.
Nustatyti ir kiti, su prietaisu ar su implantacijos procedūra susiję, paciento gyvybei pavojų
keliantys nepageidaujami įvykiai: kraujagyslių komplikacijos, širdies ritmo sutrikimai (aritmija)
procedūros metu, padidėjusios ribinės (slenkstinės) stimuliavimo vertės ir dėl to reikalinga prietaiso
eksplantacija bei naujo prietaiso implantacija. (C0008)
Šiuo metu turimų duomenų nepakanka, jog būtų nustatytos pacientų grupės, kurioms yra
didžiausia rizika patirti nepageidaujamus įvykius. Taip pat nėra visiškai aišku ar ilgalaikėje
perspektyvoje, praėjus keleriems metams po implantacijos, bus įmanoma prietaisą saugiai eksplantuoti.
Tokiu atveju, alternatyvi stimuliatoriaus pakeitimo strategija galėtų būti – šalia neveikiančio prietaiso,
implantuoti naująjį BŠS. BŠS yra nedidelis (užima ~1cm³), todėl įvertinus širdies skilvelio anatominius
parametrus, tai reali galimybė. Remiantis moksliniais skaičiavimais, dešiniajame skilvelyje įmanoma
implantuoti bent 3 Micra™ BŠS, tačiau tiksliai šiuos klausimus galėtų atsakyti tik tolimesni moksliniai
tyrimai. (C0005; C diskusija)
Tiek BŠS, tiek įprastinio vienkamerinio ŠS implantavimo procedūros yra susijusios su
nepageidaujamais įvykiais, kurie įvyksta dėl specialisto nepatyrimo, kompetencijos stokos. Viename
moksliniame tyrime buvo analizuota, kaip komplikacijų dažnis susijęs su specialisto patirtimi; rezultatai
rodo, jog atliekant 10 pirmųjų implantacijos procedūrų, su procedūra susijusių nepageidaujamų įvykių
dažnis siekia 6.8%, o atliekant vėlesnes procedūras sumažėja – 3.6% (p=0.56). (C0007)
3 Perikardo efuzija – kraujo išsiliejimas į perikardą.
13
Mirštamumas
Nėra tikimasi, kad BŠS galėtų turėti didesnį teigiamą poveikį mirtingumui negu įprastiniai VVI
širdies stimuliatoriai. Bendras mirtingumo dažnis svyravo nuo 3 iki 5%, o mirtingumas, susijęs su
širdies-kraujagyslių ligomis, nuo 0.8 iki 1%. (D0001)
Su procedūra susijęs mirtingumas buvo aprašytas visuose trijuose tyrimuose. LEADLESS I
tyrime vienam pacientui implantacijos metu pasireiškė perforacija, pacientas mirė dėl masinio smegenų
arterijų išeminio infarkto. LEADLESS II tyrime įvardintos dvi su procedūra susijusios mirtys: vienam
pacientui BŠS implantacija komplikavosi kirkšnies hematoma, o kitas pacientas dėl nesėkmingos BŠS
implantacijos patyrė komplikuotą perikardo eksudaciją. „Micra™ Transcatheter Pacemaker Study“
tyrime vienas pacientas mirė dėl su procedūra susijusių komplikacijų: implantacijos procedūra užtruko
ilgiau nei įprasta dėl atrioventikulinio mazgo abliacijos bei inkstų ligos, vis dėlto mirties priežastis buvo
metabolinė acidozė. (D0003)
Organizmo funkcijos
BŠS sistema buvo sukurta siekiant išvengti ŠS generatoriaus „kišenės“ ir transveninių laidų
(BŠS sistemoje elektrodai išdėstyti kapsulėje), tokiu būdu panaikinant svarbiausias komplikacijų
priežastis, susijusias su įprastomis ŠS sistemomis, ir gaunant panašią naudą. (D diskusija)
Pažymėtina, kad per didelė skilvelių stimuliacija gali būti susijusi su blogesniais širdies–
kraujagyslių rodmenų rezultatais. Kai kurie autoriai pastebėjo, kad BŠS gali padidinti aritmijos riziką
dėl didesnio BŠS kontakto endokarde, lyginant su įprastinėmis širdies stimuliatorių sistemomis; vis
dėlto, prospektyviniuose tyrimuose papildomų aritmijos atvejų nebuvo nustatyta. (D diskusija).
Gyvenimo kokybė
Generatoriaus „kišenės“ nebuvimas turi tam tikrų privalumų, susijusių tiek su pacientų
komfortu (gyvenimo kokybe), tiek su mažesne infekcinių įvykių rizika. Su sveikata susijusi gyvenimo
kokybė nebuvo vertinta nė viename tyrime, o, be to, neaišku, ar laidų/ generatoriaus sukeliamų
komplikacijų išvengimas duoda atitinkamos naudos pacientams. (D diskusija)
14
SVEIKATOS TECNOLOGIJOS FUNKCINĖ VERTĖ
Vadovaujantis Ligų, vaistinių preparatų ir medicinos pagalbos priemonių įrašymo į
kompensavimo sąrašus ir jų keitimo tvarkos aprašu, patvirtintu Lietuvos Respublikos sveikatos
apsaugos ministro 2002 m. balandžio 5 d. įsakymu Nr. 159 „Dėl Ligų, vaistinių preparatų ir medicinos
pagalbos priemonių įrašymo į kompensavimo sąrašus ir jų keitimo tvarkos aprašo patvirtinimo“, buvo
įvertinta šios sveikatos technologijos – dešiniajame skilvelyje implantuojamo belaidžio širdies
stimuliatoriaus – kaip medicinos pagalbos priemonės (MPP), funkcinė vertė. Belaidžio širdies
stimuliatoriaus funkcinė vertė buvo vertinta bradikardijos (kartu su prieširdžių virpėjimu ir plazdėjimu
(pagal TLK-10-AM: I48)), atrioventrikulinės blokados (pagal TLK-10-AM: I44) bei sinusinio mazgo
silpnumo sindromo (pagal TLK-10-AM: I49.5) atvejais (1 lentelė).
1 lentelė. Dešiniajame skilvelyje implantuojamo belaidžio širdies stimuliatoriaus funkcinė vertė.
Funkcinės vertės
kriterijai Balai Pastabos
Ligos įtaka sveikatai 2
Prieširdžių virpėjimas ir plazdėjimas bei
sinusinio mazgo silpnumo sindromas daro įtaką
neįgalumui/ darbingumui ir gyvenimo kokybei.
Ligai progresuojant gali kilti grėsmė paciento
gyvybei.
Socialinė MPP svarba 2
Didžiąja dalimi (daugiau nei 50%) gali atkurti
prarastas funkcijas, sumažinti neįgalumą/
atkurti darbingumą.
MPP inovatyvumas 1
MPP iš dalies pakeis šiuo metu naudojamą
alternatyvią MPP: MPP bus naudojama kartu
su šiuo metu naudojama alternatyvia MPP toms
pačioms indikacijoms.
MPP klinikinis
efektyvumas 1
MPP klinikinis efektyvumas panašus į
alternatyvios MPP, nors mokslinių įrodymų
trūksta.
MPP ekonominis
efektyvumas 0*
MPP klinikinis efektyvumas panašus į
alternatyvios MPP, tačiau vertinamos MPP
kaina yra aukštesnė.
Galutinis balas 6
*Ekonominio efektyvumo aspektas nebuvo vertintas.
15
IŠVADOS
1. BŠS siūlomas kaip alternatyva vienkameriniams širdies stimuliatoriams. Vienkamerinis skilvelio
stimuliacijos režimas gali būti taikomas pacientams, kuriems diagnozuotas prieširdžių virpėjimas
(arba ne) ar sinusinio mazgo silpnumo sindromas; dėl šių indikacijų atsiradusios
atrioventrikulinės blokados koregavimui reikalingas širdies stimuliatorius, tačiau jis skiriamas
tik simptomų, susijusių su bradiaritmija, palengvinimui.
2. Rinkoje yra dvi belaidžių širdies stimuliatorių sistemos – Nanostim™ ir Micra™; abu prietaisai
yra vienkameriniai širdies stimuliatoriai, turintys panašias technines charakteristikas bei CE
ženklą. Pagrindinis dviejų BŠS sistemų skirtumas – skirtingi prisitvirtinimo endokarde
mechanizmai: Nanostim™ BŠS turi įsukamą vienos vijos spiralę, be to, papildomai prietaisas
tvirtinamas trimis siūlėmis; Micra™ BŠS prisitvirtina savaime išsiskleidžiančiais kabliukais
pagamintais iš nikelio ir titano lydinio (nitinolio).
3. BŠS technologijos saugumas nėra pakankamai moksliškai pagrįstas – duomenys preliminarūs,
grindžiami tik 3 nekontroliuojamų tyrimų rezultatais. Sunkių, su prietaiso naudojimu susijusių,
nepageidaujamų įvykių dažnis į vertinimą įtrauktuose tyrimuose varijavo nuo 4 iki 6.5%.
Dažniausiai pacientams nustatyti širdies sužalojimai (širdies perforacijos su/be tamponados,
perikardo efuzijos, širdies tamponados). Nustatyti 6 (0.95%) atvejai, kai prietaisas pasislinko iš
implantavimo vietos; visi šie atvejai įvyko pacientams, kuriems buvo implantuotas Nanostim™
BŠS, o ne Micra™ BŠS.
4. Mirštamumo rodikliai, lyginant BŠS su įprastais vienkameriniais stimuliatoriais, reikšmingai
nesiskiria. Vis dėlto, manoma, kad generatoriaus kišenės nebuvimas turi privalumų, lemiančių
didesnį paciento komfortą (gyvenimo kokybę) ir mažesnę infekcijų riziką, nors nei klinikinis
efektyvumas, nei gyvenimo kokybė tyrimuose nebuvo analizuoti.
REKOMENDACIJOS
1. Prieš priimant sprendimus dėl belaidžio širdies stimuliatoriaus naudojimo, rekomenduojama
įvertinti galimų nepageidaujamų įvykių riziką, nes, nepaisant BŠS sistemų pranašumų,
informacija apie šios sveikatos priežiūros technologijos saugumą ir efektyvumą yra ribota.
Reikalingi papildomi moksliniai įrodymai (randomizuoti kontroliuojami tyrimai), kurie
nustatytų/ palygintų klinikinę bei ekonominę vertinamos sveikatos priežiūros technologijos ir
įprastinių širdies stimuliatorių naudą.
16
SUMMARY
Scope
PICO for leadless pacemakers for right ventricle pacing Population First line treatment of patients with indications for single-chamber ventricular
pacemakers [2,4]:
Patients with chronic atrial fibrillation (AF; ICD-10 I.48) who require a
pacemaker for persistent or intermittent bradycardia due to slow ventricular
response (atrioventricular (AV) block, ICD-10 I.44);
Patients with persistent or intermittent bradycardia due to AV block or
symptomatic sinus node disease (SND, ICD-10 I.49.5)4.
Contraindications:
Patients requiring long-term pacing exceeding estimated device longevity (NB.
children);
Patients with indications for atrial single-chamber pacemakers or dual-chamber
pacemakers or with indications for cardiac resynchronisaton therapy.
MESH term: Arrhythmias, Cardiac [C14.280.067] and Arrhythmias, Cardiac
[C23.550.073].
Intervention Leadless self-contained and fully implantable VVI(R) pacemaker.
Setting: Vascular surgery, Interventional cardiology; specialist hospital, general
hospital.
Products:
Micra™ TPS, Medtronic Inc.;
Nanostim™, St. Jude Medical.
MESH term: Pacemaker, Artificial [E07.305.250.750]
Comparison Conventional VVI(R) pacemaker.
MESH term: Pacemaker, Artificial [E07.305.250.750]
Outcomes
Efficacy Cardiovascular mortality;
Cardiovascular morbidity;
Patient related quality of life;
Exercise capacity;
Pacing performance.
Safety Complication rate.
Study design
Efficacy Randomised controlled trials (Non-inferiority)5;
4 Only in specific instances, where other pacing modes (dual-pacing, atrial pacing) are not recommended 5 Randomised controlled trials comparing leadless pacemakers with traditional pace-makers are desired, since they are
appropriate (adequate number of patients, inter-vention not urgent) and ethical (clinical equipoise, patients able to give
consent) and necessary due to small plausible effect sizes. Blinding of operators and patients how-ever is not possible, and
placebo-controlled trials would be unethical due to the avail-ability of an effective treatment
17
Prospective non-randomised controlled trials.
Safety Randomised controlled trials;
Prospective non-randomised controlled trials;
Prospective case series or registries with >100 patients.
PICO research question: Are leadless pacemakers in comparison to conventional pacemakers in
patients with indications for right ventricle pacing as effective concerning cardiovascular morbidity
and mortality, exercise capacity, and more effective and safe concerning patient-related quality of life
and complication rate? ESC – European Society of Cardiology; AV – atrioventricular; TPS – transcatheter pacing system; VVIR – Single-chamber
ventricular pacing with response modulation.
Target condition
Leadless pacemakers are developed as alternatives for traditional permanent cardiac
pacemakers for the treatment of a variety of cardiac arrhythmias. The natural pacemaker of the heart is
the sinus node located in the right atrium. Cardiac bradyarrhythmias (bradycardia associated with
arrhythmia) are mainly due to either the incapacity of the sinus node to produce enough number of
impulses per minute (sinus node disease) or the disturbance in atrioventricular (AV) conduction. Also,
bradycardia can be associated with atrial fibrillation (AF), which is an abnormal heart rhythm
characterized by rapid and irregular beating. (A0001)
The purpose of cardiac pacing is to provide an appropriate heart rate and heart response to
reestablish effective circulation and more normal haemodynamics that are compromised by a slow heart
rate (bradycardia or bradyarrhythmia: <60 beats per minute). Permanent pacemaker implantation is
further considered to alleviate symptoms associated with a bradyarrhythmia (e.g. dizziness, light-
headedness, syncope, fatigue, poor exercise tolerance) or to prevent the possible worsening of the
rhythm disturbance. (A0001)
In the scope of this assessment are cardiac arrhythmias in adults for which single-chamber
ventricular pacing (VVI) is indicated. VVI pacing mode is the method of choice for patients with
chronic atrial fibrillation who require a pacemaker due to slow ventricular response (atrioventricular
block, Class I recommendation). (A0002)
Bradyarrhythmias requiring cardiac pacing can be caused by a variety of aetiologies. Intrinsic
causes are: idiopathic (ageing) degeneration; ischaemic heart disease; infiltrative diseases (e.g.
sarcoidosis, amyloidosis, haemochromatosis); collagen vascular diseases (e.g. systemic lupus
erythematosus, rheumatoid arthritis, scleroderma); congenital diseases, including sinus node and AV
node disease; infective diseases (e.g. Lyme disease); surgical trauma: valve replacement (including
percutaneous aortic replacement), heart transplantation. (A0003)
The natural history and the role of pacing differ depending on the type of bradyarrhythmia. In
patients with untreated AV block, death can occur due to heart failure secondary to low cardiac output
or to sudden cardiac death caused by prolonged asystole or bradycardia-triggered ventricular
tachyarrhythmia. Total survival and the risk of sudden cardiac death of patients with sinus node disease
(SND) are similar to the general population. There is a strong consensus that patients with SND will
benefit from cardiac pacing for symptom relief (only). (A0004)
Target population
Leadless pacemakers are intended to be used as replacement for conventional single-chamber
right ventricular pacemakers. The target population consists of the patients in which this pacing mode is
indicated. (A0007; A0023)
Symptoms are present if bradycardia is severe enough to compromise blood flow: they may
comprise fatigue, dizziness, syncope (fainting), dyspnoea, chest pain, weakness and a reduced exercise
18
capacity. Up to 6% of patients experience major complications within the first 6 months following
implantation of cardiac electronic devices (all types), with lead-related reintervention being the single
most common complication. (A0005)
The prevalence of indications requiring single-chamber pacemaker implantation is unclear. In
2015 over 110,000 patients with cardiac arrhythmias were recorded in Lithuania. There were about
1,500 pacemaker implantations in Lithuania in 2005, and the number is growing each year. (A0006;
A0011)
Current clinical management of the disease or health condition
There is no defined heart rate below which treatment is indicated. When deciding on the need
for cardiac pacing, the correlation between symptoms and bradyarrhythmia needs to be established. The
diagnosis of bradyarrhythmia is usually made from a standard electrocardiogram (ECG) when
persistent, and from a standard ECG or more prolonged ECG recordings when intermittent. Provocative
testing or an electrophysiological study may be required when a bradycardia is suspected but not
documented. (A0024)
The decision regarding pacemaker implantation and choice of pacing mode is based on three
clinical factors: the location of the conduction abnormality, the presence of symptoms and their
association with the bradyarrhythmia, and the absence of a reversible cause. VVI pacing mode is the
method of choice for patients with chronic atrial fibrillation who require a pacemaker due to slow
ventricular response (atrioventricular block, Class I recommendation). In patients with acquired AV
block (but no AF) or sinus node disease, the condition can be managed with either a single or dual
chamber pacemaker. Also, sinus bradycardia is only an indication for pacing if bradycardia is
symptomatic, if the symptoms can be attributed to sinus bradycardia and if a reversible cause can be
excluded. (A0025)
Regulatory & reimbursement status
Nanostim™: After the LEADLESS trial in October 2013, St. Jude Medical received CE mark
approval (for European commercialization) to market the Nanostim™ leadless pacemaker in the
European Union. A trial designed to investigate Nanostim™ for the United States Food and Drug
Administration (FDA) approval was initiated in February 2014. The device has not yet been approved
by FDA, Health Canada or Therapeutic Goods Administration (Australia). FDA approval of the device
is sought in 2016–2017. (A0020; A0021)
Micra™ Transcatheter Pacing System: Medtronic received CE mark for Micra™
Transcatheter Pacing System (TPS) in 2015. An FDA approval study on Micra™ TPS was initiated in
November 2013 and based on the favorable clinical results of the study, the FDA approved the Micra™
Transcatheter Pacing System for clinical use on April 2016. (A0020; A0021)
As yet there are no data available about the cost of these devices. Leadless pacemakers in
Australia are, however, significantly more expensive in comparison to conventional single chamber
pacemakers (11,300 EUR vs. 4,200 EUR). In a Horizon Scanning report published by the Italian group
AGENAS, the reported cost of the Nanostim device and implantation was 11,500 EUR, according to St
Jude Medical; however, costs were not available for the Micra™ TPS device from Medtronic Inc.
(Leadless) cardiac pacemakers are currently reimbursed in Lithuania via the DRG code F12A
and F12B Implantation or changing of a pacemaker (prices are 2,817.74 EUR and 1,439.21 EUR,
respectively). (A0020; A0021)
19
Features of the technology
Leadless cardiac pacemakers (LCP) are self-contained intracardiac devices that are designed to
have the same function as traditional cardiac pacemakers, but are miniaturized and can be implanted
entirely inside the right ventricle of the heart via a steerable catheter. (B0001)
The first prototype of a completely endocardial implantable pacemaker was presented in 1970.
Since then, different leadless systems with different energy sources and myocardial fixation systems
have been developed, resulting in the CE certification of two right ventricular single-chamber
pacemaker systems: the Nanostim™ leadless cardiac pacemaker and the Micra™ TPS. These devices
share common characteristics, as they are both programmable, single-chamber ventricular pacemakers,
self-contained in a hermetically sealed capsule. Both have a volume of up to 1cm³, weight just 2 g and
thus are approximately ten times smaller than conventional VVI pacemakers. The devices have an
estimated battery longevity of approximately ten years, which is comparable to conventional
pacemakers. Both systems are delivered through the femoral vein, via 18 Fr (Nanostim™ LCP) and 23
Fr (Micra™ TPS) catheters, and have a docking feature which allows attachment to a catheter for
delivery, repositioning and retrieval. In theory, both systems offer a device retrieval option, allowing
repositioning or retrieval of the devices following implantation. There are some data on the removal of
implanted systems in animal studies and in humans. However, retrieval of the device requires
confirmation and rationale is to add another pacemaker into the right ventricle and this is possible due to
the small size of the device. (B0001; B0003)
Main differences between the systems are related to the fixation mechanism: Nanostim™ LCP
uses a screw-in helix and a secondary fixation mechanism of three nylon tines, whereas the Micra™
TPS uses four self-expanding nitinol tines. (B0001)
In conventional pacemakers, a separate pulse generator containing the battery and the
machinery for sensing and timing of the electrical impulses is placed in a (most commonly) pectoral
subcutaneous pocket. The electrical impulses are delivered from the generator directly to the heart
through one or more transvenous leads, depending on the desired pacing mode. The majority of
conventional pacemakers are capable of several pacing modes. (B0001)
In contrast to traditional pacemakers, leadless pacemakers do not require the placement of an
external pulse generator in a surgical pocket in the chest and the transmission of impulses through
transvenous leads. The claimed benefit is accordingly the avoidance of complications associated with
these two components of traditional pacemaker implantation. The subcutanous pocket has a potential for
local complications such as skin erosion, pocket haematoma and pocket infection. In up to six out of ten
patients, it causes reduced mobility in the shoulder region where the pulse generator is placed. Lead-
related complications include venous obstructions, insulation breaks, lead dislodgements, electrical
malfunction, lead fractures and infection. Of particular concern are infections requiring lead extraction,
as the procedure is associated with a high risk of complications. The longer the leads are in place, the
greater the risk. (B0001; B0002)
Additional benefits are expected with regards to shorter procedure and recovery times and a
better quality of life as a result of the maintenance of shoulder mobility and the absence of a lump or
scar. (B0002)
Moreover, it is estimated that up to 75% of pacemaker patients are expected to develop an
indication for an MRI scan over the lifetime of their device. Pre-clinical MRI testing has consistently
shown the incompatibility of traditional pacing systems and the MRI environment, which may
compromise the patient’s health and/or damage the device. In addition, the Micra™ Transcatheter
Pacing System is designed to allow patients to safely undergo MRI scans, in both 1.5 and 3 Tesla MRI
scanners; the Nanostim™ device allows patients to safely undergo MRI scans in 1.5 Tesla MRI
scanners. (B0002)
20
Investments and tools required to use the technology
Both LCP and traditional pacemakers are provided in specialised centres with interventional
cardiology in the cardiac catheterization, laboratory sedative medication and local anaesthesia. LCP
implantation further requires fluoroscopy to guide positioning of the device.
Setting and staff required for LCP implantation do not differ from traditional pacemaker
procedures. As with any novel implantation method or procedure, there is a learning curve for
implantation of the leadless pacemaker and additional training for medical specialists will be required.
(B0004; B0008; B0009)
Patient safety
The rates of serious adverse device effects ranged between 4% and 6.5% in the three case
series. However, data on the safety of transcatheter pacing are preliminary and have been limited to a
few reports from nonrandomized studies. (C0008)
There was one patient with cardiac injury (cardiac tamponade) in the LEADLESS I trial, eight
injuries (cardiac perforations with/without tamponade or pericardial effusions) in LEADLESS II and 11
injuries (cardiac perforations or effusions) in the Micra™ Transcatheter Pacemaker Study. Six
dislodgements were reported with the Nanostim™ device, but none with the Micra™ TPS system. Other
serious adverse events that were attributable either to the device or the procedure included vascular
complications, arrhythmia during device implantation and elevated pacing thresholds requiring retrieval
and implantation of a new device. (C0008)
There are not enough data to answer the question about the susceptible patient groups that are
more likely to be harmed through the use of the technology. Also, it is unknown whether long-term
retrieval of the pacemaker after several years of implantation in patients will be possible. An alternative
replacement strategy could be – to place an additional device next to the initial device, without
compromising the right ventricular volume capacity and overall function. For this strategy, it is
important to realize that the LCP only takes up 1.0 ml of volume in the right ventricle, but also that
evidence of these strategies is currently lacking. (C0005; C discussion)
Leadless pacemakers and conventional single-chamber ventricular pacemakers are associated
with user-dependent harms due to the risk of serious adverse events related with the implantation
procedure. The influence of operator experience on the rate of device-related serious adverse events was
assessed in one case serie; The rate of device related serious adverse events was 6.8% for the initial 10
cases versus 3.6% for the subsequent implants (p=0.56). (C0007)
Mortality
Leadless pacemakers are not expected to have a beneficial effect on mortality compared to
conventional VVI pacemakers. Overall mortality ranged from 3 to 5% and cardiac mortality ranged
from 0.8 to 1%. (D0001)
Procedural mortality was reported in all three studies. In LEADLESS I trial, one patient had a
perforation during the implantation procedure and died of a massive cerebral artery ischaemic infarct.
Two procedure-related (but classified as non-device-related) deaths were reported in the LEADLESS II
cohort: in one patient LCP implantation was complicated by a large groin haematoma; the second
subject underwent an unsuccessful LCP implant complicated by pericardial effusion. In the Micra
Transcatheter Pacemaker Study cohort, one death was adjudicated as related to the transcatheter
implantation procedure: the patient had a prolonged procedure time due to a concomitant AV node
ablation and end stage renal disease and the cause of death was perceived to be metabolic acidosis.
(D0003)
21
Function
A leadless intracardiac transcatheter pacing system has been designed to avoid the need for a
pacemaker pocket and transvenous lead (the electrodes are positioned on the pacemaker capsule),
thereby eliminating an important source of complications associated with traditional pacing systems
while providing similar benefits. (D discussion)
Notably, excessive ventricular pacing has been associated with worse cardiovascular outcomes.
Some have proposed that LCPs may increase risk of arrhythmia due to their larger point of endocardial
contact when compared to conventional pacing systems, although excessive arrhythmic events have not
been noted in prospective trials. (D discussion)
Quality of life
The lack of a generator pocket has some advantages as well both in terms of patient comfort
(and quality of life) and infectious risk. However, health-related quality of life was not assessed in the
studies. Also, it is unclear, if the avoidance of lead/ generator complications translates in a relevant
benefit for the patients. (D discussion)
22
HEALTH PROBLEM AND CURRENT USE OF THE TECHNOLOGY
Research questions ID Question
A0001 For which health conditions, and for what purposes are leadless pacemakers used?
A0002 What is the disease or health condition in the scope of this assessment?
A0003 What are the known risk factors for cardiac arrhythmias?
A0004 What is the natural course of cardiac arrhythmias?
A0005 What are the consequences of cardiac arrhythmias for the society?
A0006 What is the burden of disease for patients with cardiac arrhythmias?
A0007 What is the target population in this assessment?
A0023 How many people belong to the target population?
A0011 How much are leadless pacemakers utilised?
A0020 What is the marketing authorisation status of leadless pacemakers?
A0021 What is the reimbursement status of leadless pacemakers?
A0024 How are cardiac arrhythmias currently diagnosed according to published guidelines
and in practice?
A0025 How are cardiac arrhythmias currently managed according to published guidelines and
in practice?
Overview of the disease or health condition
A0001. For which health conditions, and for what purposes are leadless pacemakers used?
Leadless pacemakers are developed as alternatives for traditional permanent cardiac
pacemakers for the treatment of a variety of cardiac arrhythmias. The natural pacemaker of the heart is
the sinus node located in the right atrium. It generates around 70 regular electrical impulses per minute
(at rest), that are conducted across the rest of the heart. This triggers contraction of the atriums followed
by the contraction of the ventricles allowing the blood flow. Cardiac bradyarrhythmias (bradycardia
associated with arrhythmia) are mainly due to either the incapacity of the sinus node to produce enough
number of impulses per minute (sinus node disease) or the disturbance in atrioventricular (AV)
conduction.
Atrial fibrillation is an abnormal heart rhythm characterized by rapid and irregular beating, but
can be associated with bradycardia. The principal reason to place a pacemaker in a patient with atrial
fibrillation (AF) is to treat symptomatic bradycardia. Pacing has not been shown to prevent the
development of AF.
The purpose of cardiac pacing is to provide an appropriate heart rate and heart response to
reestablish effective circulation and more normal haemodynamics that are compromised by a slow heart
rate (bradycardia or bradyarrhythmia: <60 beats per minute). Permanent pacemaker implantation is
further considered to alleviate symptoms associated with a bradyarrhythmia (e.g. dizziness, light-
headedness, syncope, fatigue, poor exercise tolerance) or to prevent the possible worsening of the
rhythm disturbance [1].
A0002. What is the disease or health condition in the scope of this assessment?
In the scope of this assessment are cardiac arrhythmias in adults for which single-chamber
ventricular pacing (VVI) is indicated. Guidelines for implantation of permanent pacemakers have been
23
established by the American College of Cardiology, the American Heart Association and the Heart
Rhythm Society (ACC/AHA/HRS) [2,3] and by the European Society of Cardiology (ESC) [4].
VVI pacing mode is the method of choice for patients with chronic atrial fibrillation (AF; ICD-
10-AM: I44) who require a pacemaker due to slow ventricular response (atrioventricular (AV) block,
Class I recommendation [4]).
This pacing mode may be considered for patients with AV block, even in the absence of AF, on
an individual basis, but in general is not considered the first choice [4]. In patients with sinus node
disease (SND, also sick sinus syndrome) as well as in patients with atrial fibrillation, pacing is only
indicated if bradycardia causes symptoms. Dual-chamber pacing is recommended over VVI pacing
[2,3,4].
A0003. What are the known risk factors for cardiac arrhythmias?
Bradyarrhythmias requiring cardiac pacing can be caused by a variety of aetiologies [4].
Intrinsic causes are:
Idiopathic (ageing) degeneration;
Ischaemic heart disease;
Infiltrative diseases (e.g. sarcoidosis, amyloidosis, haemochromatosis);
Collagen vascular diseases (e.g. systemic lupus erythematosus, rheumatoid arthritis,
scleroderma);
Congenital diseases, including sinus node and AV node disease;
Infective diseases (e.g. Lyme disease);
Rare genetic diseases;
Surgical trauma: valve replacement (including percutaneous aortic replacement), heart
transplantation;
Intended or unintended AV block due to catheter ablation procedure.
Extrinsic causes are:
Physical training (sports);
Vagal reflex: vasovagal, situational, carotid sinus syndrome;
Idiopathic paroxysmal AV block;
(Adverse) drug effects;
Cocaine abuse and other recreational drugs;
Electrolyte imbalance: hypokalaemia, hyperkalaemia;
Metabolic disorders: hypothyroidism, hypothermia, anorexia nervosa;
Neurological disorders;
Obstructive sleep apnoea.
A0004. What is the natural course of cardiac arrhythmias?
The natural history and the role of pacing differ depending on the type of bradyarrhythmia. In
patients with untreated AV block, death can occur due to heart failure secondary to low cardiac output
or to sudden cardiac death caused by prolonged asystole or bradycardia-triggered ventricular
tachyarrhythmia. Several observational studies indicate that pacing prevents recurrence of syncope and
improves survival [4].
Total survival and the risk of sudden cardiac death of patients with SND are similar to the
general population [5,6]. There is a strong consensus that patients with SND will benefit from cardiac
pacing for symptom relief (only) [4].
24
Effects of the disease or health condition on the individual and society
A0005. What is the burden of disease for patients with cardiac arrhythmias?
Symptoms are present if bradycardia is severe enough to compromise blood flow: they may
comprise fatigue, dizziness, syncope (fainting), dyspnoea, chest pain, weakness and a reduced exercise
capacity.
Major complications associated with the implantation of a single-chamber right ventricular
pacemaker include lead-related reinterventions, local infections requiring reintervention, device-related
systemic infections, endocarditis, pneumothorax requiring drainage, cardiac perforation, pocket
revisions because of pain, generator-lead interface problems requiring reintervention, haematomas
requiring reintervention, deep venous thrombosis, Twiddler’s syndrome, wound revisions, stroke,
myocardial infarctions, and procedure-related deaths. Minor complications include haematomas
resulting in a prolonged hospital stay, hospital readmissions, additional outpatient visits, wound
infections treated with antibiotics, conservatively treated pneumothorax, and lead dislodgements without
reintervention [7,8].
Up to 6% of patients experience major complications within the first 6 months following
implantation of cardiac electronic devices (all types), with lead-related reintervention being the single
most common complication, followed by infections, pneumothorax and cardiac perforation. For single-
chamber pacemakers, this risk is however significantly lower, with 3.3% experiencing any major
complication [8]. Also the risk of lead complications is lower for single-chamber right ventricular
pacemakers compared to other pacemaker types [9].
A0006. What are the consequences of cardiac arrhythmias for the society?
The prevalence of indications requiring single-chamber pacemaker implantation is unclear. In
2015 over 110,000 patients with cardiac arrhythmias were recorded in Lithuania [10]. Each year there
are about 6,000 pacemaker implantations in Austria, of which approximately one third are single-
chamber pacemakers [11,12]. There were about 1,500 pacemaker implantations in Lithuania in 2005,
and the number is growing each year [13].
Current clinical management of the disease or health condition
A0024. How are cardiac arrhythmias currently diagnosed according to published guidelines and
in practice?
There is no defined heart rate below which treatment is indicated. When deciding on the need
for cardiac pacing, the correlation between symptoms and bradyarrhythmia needs to be established. The
diagnosis of bradyarrhythmia is usually made from a standard electrocardiogram (ECG) when
persistent, and from a standard ECG or more prolonged ECG recordings (ambulatory monitoring or
implantable loop recorder) when intermittent. Provocative testing or an electrophysiological study may
be required when a bradycardia is suspected but not documented. This strategy is based on the
assumption that provoked abnormalities will have the same mechanism as spontaneous episodes. (Long-
term) ECG monitoring has the advantage of high diagnostic accuracy, whereas provocative testing is
faster, but more prone to misdiagnosis [4].
25
A0025. How are cardiac arrhythmias currently managed according to published guidelines and in
practice?
The decision regarding pacemaker implantation and choice of pacing mode is based on three
clinical factors: the location of the conduction abnormality, the presence of symptoms and their
association with the bradyarrhythmia, and the absence of a reversible cause (Figure 1).
SND – sinus node disease; AV – atrioventricular; AF – atrial fibrillation; AVM – AV delay management.
For nomenclature of pacing modes see Table 1 (question B0001): Revised NBG code for pacing nomenclature [14]
Figure 1. Choice of the pacing mode (ESC guidelines, [4])
VVI pacing mode is the method of choice for patients with chronic atrial fibrillation (AF; ICD-
10-AM: I44) who require a pacemaker due to slow ventricular response (atrioventricular (AV) block,
Class I recommendation [4]).
Atrioventricular (AV) block is defined as a delay or interruption in the transmission of an
impulse from the atria to the ventricles due to an anatomical or functional impairment in the conduction
system. The conduction can be delayed, intermittent, or absent. The commonly used classification
includes first degree (slowed conduction without loss of atrioventricular synchrony), second degree
(intermittent loss of atrioventricular conduction, often in a regular pattern, e.g., 2:1, 3:2, or higher
degrees of block), and third degree or complete AV block [1].
In patients with acquired AV block (but no AF) or sinus node disease (SND), the condition can
be managed with either a single or dual-chamber pacemaker. Dual-chamber pacing is recommended
over single chamber ventricular pacing for avoiding pacemaker syndrome, lowering the risk of
developing AF and improving quality of life (class IIa recommendation, [4]). However, the decision
should take into account the increased complication risk and costs of dual-chamber pacing.
Sinus bradycardia (SB) is a rhythm in which fewer impulses than the normal number arise from
the sinoatrial node. It is caused by a primary sinus node dysfunction or by other conditions (drugs, acute
myocardial infarction, obstructive sleep apnoea, etc.). In general, SB is only an indication for pacing if
bradycardia is symptomatic, if the symptoms can be attributed to SB and if a reversible cause can be
26
excluded. Dual-chamber pacing is the pacing mode of first choice and unnecessary right ventricular
pacing should be avoided since it may cause AF and deterioration of heart failure. In the subset of
patients with SND in whom AV conduction is intact, single-chamber is feasible (AAI mode); atrial
pacemakers are recommended over ventricular pacemakers [4].
Target population
A0007. What is the target population in this assessment?
A0023. How many people belong to the target population?
Leadless pacemakers are intended to be used as replacement for conventional single-chamber
right ventricular pacemakers. The target population consists of the patients in which this pacing mode is
indicated. There are no data available on the number of patients belonging to the target population.
A0011. How much are leadless pacemakers utilised?
Estimates of the expected yearly utilisation of leadless pacemaker vary from 270 to 2,400
implantations in Austria. There were about 1,500 pacemaker implantations in Lithuania in 2005, but the
number is growing each year [13]. However, the specific and current number of pacemaker
implantations in Lithuania is unknown without data from National Health Insurance Fund.
Regulatory & reimbursement status
A0020. What is the marketing authorisation status of leadless pacemakers?
A0021. What is the reimbursement status of leadless pacemakers?
Nanostim™ Leadless Pacemaker (St. Jude Medical, USA)
Europe: After the LEADLESS trial in October 2013, St. Jude Medical received CE mark
approval (for European commercialization) to market the Nanostim™ leadless pacemaker in the
European Union (EU). According to the EU registry, the Leadless Observational Study (NCT02051972)
is ongoing in Europe with sites in the United Kingdom, Germany, Italy, the Czech Republic, France,
Spain, and the Netherlands with a planned enrolment of 1,000 patients and follow-up for 5 years. Data
from 300 patients with 6 months of follow-up will be used to meet the post market clinical follow-up
requirements for CE marking.
The United States, Canada and Australia: A trial designed to investigate Nanostim™ for the
United States Food and Drug Administration (FDA) approval was initiated in February 2014
(NCT02030418). Sites from the USA, Canada and Australia participated in the LEADLESS II study.
The enrolments (667 patients) were completed in 2015 and the pre-specified safety/effectiveness
endpoints were met. FDA has provided approval to enrol up to 900 additional patients in the continued
access phase and enrolments are underway. The device has not yet been approved by FDA, Health
Canada or Therapeutic Goods Administration (TGA) (Australia). FDA approval of the device is sought
in 2016–2017.
Japan: Enrolments in the Leadless Japan pre-market study are underway and the plan is to enrol
22 Japanese patients in the study to meet the primary endpoint analysis [15].
Micra™ Transcatheter Pacing System (TPS) (Medtronic Inc., Ireland)
Medtronic received CE mark for Micra™ Transcatheter Pacing System (TPS) in 2015. An
FDA approval study on Micra™ TPS was initiated in November 2013 (NCT02004873). The FDA
evaluated data from a clinical trial of 719 patients implanted with the Micra device, which found that 98
percent of patients in the trial had adequate heart pacing (known as pacing capture threshold) six months
27
after the device was implanted. Complications occurred in fewer than 7 percent of participants in the
clinical trials and included prolonged hospitalizations, blood clots in the legs (deep vein thrombosis) and
lungs (pulmonary embolism), heart injury, device dislocation and heart attacks [16]. Based on the
favorable clinical results of the Micra Transcatheter Pacing Study, the FDA approved the TPS system
for clinical use on April 2016 [17,18].
As yet there are no data available about the cost of these devices. Conventional single chamber
pacemakers currently available in Australia are listed on the Australian Prostheses List at a price of
around 4,200 EUR (priced between 881 EUR and 4,406 EUR). Leadless pacemakers are, however,
significantly more expensive in comparison to conventional single chamber pacemakers (11,300 EUR
vs. 4,200 EUR). In a Horizon Scanning report published by the Italian group AGENAS, the reported
cost of the Nanostim device and implantation was 11,500 EUR, according to St Jude Medical; however,
costs were not available for the Micra™ TPS device from Medtronic Inc. [19].
(Leadless) cardiac pacemakers are currently reimbursed in Lithuania via the DRG code F12A
and F12B Implantation or changing of a pacemaker (prices are 2,817.74 EUR and 1,439.21 EUR,
respectively) [20].
Discussion
Millions of people worldwide experience irregular heartbeats, called arrhythmias, at some point
in their lives. Most of the time, they are harmless and happen in healthy people free of heart disease.
However, some abnormal heart rhythms can be serious or even deadly [21]. As for instance, bradycardia
is a sign of a problem with the heart's electrical system. It means that the heart's natural pacemaker isn't
working right or that the electrical pathways of the heart are disrupted. In severe forms of bradycardia,
the heart beats so slowly that it doesn't pump enough blood to meet the body's needs. Men and women
age 65 and older are most likely to develop a slow heart rate that needs treatment, usually with a
pacemakers [22].
Nearly 1 million people worldwide are implanted with pacemakers each year [17,23,24,25],
and despite advances in pacemaker and lead technology, nearly 10 % of patients undergoing device
implantation suffer from procedure-related complications that are associated with significant health care
cost, patient morbidity, and mortality [17,25]. However, now there are leadless pacemakers that are
developed as alternatives for traditional permanent cardiac pacemakers for the treatment of a variety of
cardiac arrhythmias bradyarrhythmias [1,26]. Leadless pacemaker does not require the use of wired
leads to provide an electrical connection between the pulse-generating device and the heart and is
implanted directly in the right ventricle chamber of the heart [16].
Leadless pacemakers are only appropriate for patients with a single-chamber pacing indication
and not suitable for dual-chamber sensing and pacing. In Europe, VVI indications account for 20% to
30% of all new pacemaker implantations, but on a global scale, the percentage of VVI pacing is higher
due to the high number of single-chamber pacemakers in developing countries [24].
In a number of patients, the implantation of a transvenous pacemaker system is precluded
because of conditions such as compromised venous access, the need to preserve veins for
haemodialysis, thrombosis, a history of infection, or the need for an indwelling venous catheter. While
leadless pacemakers potentially represent the only treatment alternative in these patients, it remains to
be demonstrated that these patients are not at increased risk for complications associated with the
implantation procedure [15].
28
DESCRIPTION AND TECHNICAL CHARACTERISTICS OF THE
LEADLESS PACEMAKERS
Research questions ID Question
B0001 What are leadless pacemakers and conventional single-chamber ventricular
pacemakers?
B0002 What is the claimed benefit of leadless pacemakers in relation to conventional single-
chamber ventricular pacemakers
B0003 What is the phase of development and implementation of leadless pacemakers and
conventional single-chamber ventricular pacemakers?
B0004 Who administers leadless pacemakers and conventional single-chamber ventricular
pacemakers and in what context and level of care are they provided?
B0008 What kind of special premises are needed to use leadless pacemakers and conventional
single-chamber ventricular pacemakers?
B0009 What supplies are needed to use leadless pacemakers and conventional single-chamber
ventricular pacemakers?
Features of the technology and comparators
B0001. What are leadless pacemakers and conventional single-chamber ventricular pacemakers?
Leadless cardiac pacemakers (LCP) are self-contained intracardiac devices that are designed to
have the same function as traditional cardiac pacemakers, but are miniaturized and can be implanted
entirely inside the right ventricle of the heart via a steerable catheter [27]. In conventional pacemakers, a
separate pulse generator containing the battery and the machinery for sensing and timing of the
electrical impulses is placed in a (most commonly) pectoral subcutaneous pocket. The electrical
impulses are delivered from the generator directly to the heart through one or more transvenous leads,
depending on the desired pacing mode [28]. The majority of conventional pacemakers are capable of
several pacing modes, such as single-chamber ventricular (VVI) or atrial pacing, or dual chamber
pacing. The current generation of single-unit LCP can only be used for single-chamber pacing,
specifically right ventricular pacing [28,29]. Pacing modes are classified according to a standardised
code (Table 1).
This limitation does not apply to multi-component leadless pacing systems using ultrasound or
induction to deliver electrical impulses from a separate generator to the heart; these systems are however
not the subject of the present report, which is restricted to fully self-contained leadless pacemakers.
Table 1. Revised NBG code for pacing nomenclature [14].
Position I II III IV V
Category Chamber(s)
paced
Chamber(s)
sensed
Response to
sensing
Rate
modulation
Multisite
pacing
0 = None
A = Atrium
V = Ventricle
D = Dual
(A+V)
0 = None
A = Atrium
V = Ventricle
D = Dual (A+V)
0 = None
T = Triggered
I = Inhibited
D = Dual (T+I)
0 = None
R = Rate
modulation
0 = None
A = Atrium
V = Ventricle
D = Dual
(A+V)
29
Marketed products
Currently two leadless pacing systems are available: the Nanostim™ leadless cardiac
pacemaker and the Micra™ transcatheter pacing system (TPS) (see Table 2 for a comparison of the
specifications). These devices share common characteristics, as they are both programmable, single-
chamber ventricular pacemakers, self-contained in a hermetically sealed capsule [30]. Both have a
volume of up to 1 cm³, weight just 2 g and thus are approximately ten times smaller than conventional
VVI pacemakers [23,27,28]. The devices have an estimated battery longevity of approximately ten
years, which is comparable to conventional pacemakers [27,28]. Both systems are delivered through the
femoral vein, via 18 Fr (Nanostim™ LCP) and 23 Fr (Micra™ TPS) catheters, and have a docking
feature which allows attachment to a catheter for delivery, repositioning and retrieval [31]. The tip of the
capsule includes a monolithic controlled release device (MCRD). The MCRD elutes glucocorticosteroid
to reduce acute inflammation at the implantation site [30]. In theory, both systems offer a device
retrieval option, allowing repositioning or retrieval of the devices following implantation [27,28,32].
There are some data on the removal of implanted systems in animal studies [23] and in humans [25,33].
However, retrieval of the device requires confirmation and rationale is to add another pacemaker into
the right ventricle and this is possible due to the small size of the device. In younger patients, this might
cause problems down the line due to a large amount of systems being placed within the ventricle
[23,25].
Main differences between the systems are related to the fixation mechanism: Nanostim™ LCP
uses a screw-in helix and a secondary fixation mechanism of three nylon tines, whereas the Micra™
TPS uses four self-expanding nitinol tines [28].
There is another completely leadless ultrasound-based pacing system called Wireless Cardiac
Stimulation System (WiCSTM-LV system), manufactured by EBR Systems, Inc. (Sunnyvalle, CA,
USA). However, this system is specifically designed to deliver left ventricular endocardial pacing [24]
for cardiac resynchronization therapy (CRT) [17].
Table 2. Specifications of fully self-contained leadless cardiac pacemakers.
Nanostim™ leadless cardiac
pacemaker
Micra™ transcatheter pacing
system
Manufacturer St. Jude Medical Medtronic
Volume (cm³) 1 0.8
Size (h x w), maximum
thickness, mm
42 x 5.99 25.9 x 6.7
Weight, g 2 2
Fixation mechanism Screw-in helix (+ nylon tines) Self-expanding nitinol tines
Pacing mode VVI(R) VVI(R)
Battery longevity (years) 9.8 10
Battery Lithium carbon mono-fluoride Lithium silver vanadium oxide/
carbon mono-fluoride
Device retrieval option Yes Practically no
CE mark Yes, October 2013 Yes, April 2015
FDA approval No, investigational device Yes, April 2016
According to the manufacturer’s website [34] Nanostim™ leadless pacemaker is indicated for:
Chronic atrial fibrillation with 2 or 3° atrioventricular block (AV) or bifascicular bundle branch
block (BBB),
Normal sinus rhythm with 2 or 3° AV or BBB block and a low level of physical activity or short
expected lifespan, or
30
Sinus bradycardia with infrequent pauses or unexplained syncope with electrophysiological
findings.
According to the product manual [35], the Micra™ Transcatheter Pacing System is indicated
for use to improve cardiac output, prevent symptoms, or protect against arrhythmias related to cardiac
impulse formation or conduction disorders. The device is indicated for use in patients who are
experiencing exercise intolerance or exercise restrictions related to an arrhythmia. The device is
designed to be used only in the right ventricle.
B0002. What is the claimed benefit of leadless pacemakers in relation to conventional single-
chamber ventricular pacemakers?
In contrast to traditional pacemakers, leadless pacemakers do not require the placement of an
external pulse generator in a surgical pocket in the chest and the transmission of impulses through
transvenous leads. The claimed benefit is accordingly the avoidance of complications associated with
these two components of traditional pacemaker implantation. The subcutanous pocket has a potential for
local complications such as skin erosion, pocket haematoma and pocket infection. In up to six out of ten
patients, it causes reduced mobility in the shoulder region where the pulse generator is placed [23,36].
Lead-related complications include venous obstructions, insulation breaks, lead dislodgements,
electrical malfunction, lead fractures and infection. Of particular concern are infections requiring lead
extraction, as the procedure is associated with a high risk of complications. The longer the leads are in
place, the greater the risk. Therefore, these risks are unlikely to affect older individuals; they are a
significant consideration when counseling younger patients or those with a longer expected life span
[7,9,32].
Additional benefits are expected with regards to shorter procedure and recovery times and a
better quality of life as a result of the maintenance of shoulder mobility and the absence of a lump or
scar. Moreover, it is estimated that up to 75% of pacemaker patients are expected to develop an
indication for an MRI scan over the lifetime of their device. Pre-clinical MRI testing has consistently
shown the incompatibility of traditional pacing systems and the MRI environment, which may
compromise the patient’s health and/or damage the device. In addition, the Micra™ Transcatheter
Pacing System is designed to allow patients to safely undergo MRI scans, in both 1.5 and 3 Tesla MRI
scanners. Micra™ is equipped with the MRI SureScan™ feature, which permits a mode of operation
that allows a patient to safely undergo an MRI procedure. In contrast to traditional pacing systems,
SureScan™ pacemakers have hardware modifications that reduce or eliminate MRI associated hazards
such as device malfunction or device heating [37].
In March 2016, the manufacturer of the Nanostim™ leadless pacemakers also announced CE
Mark approval and availability for patients with Nanostim™ device to undergo MRI scans in 1.5 Tesla
scanners [38].
B0003. What is the phase of development and implementation of leadless pacemakers and
conventional single-chamber ventricular pacemakers?
The first-in-human pacemaker implantation was performed in Stockholm on 8 October 1958 by
Ake Senning and Rune Elmquist on a patient desperately in need of a pacemaker due to a third degree
atrio-ventricular block. Currently, conventional single-chamber ventricular pacemakers are a well-
established standard technique [4,29].
The notion of miniaturized intracardiac pacemaker systems that could eliminate the need for
transvenous leads was conceptualized early in the development of pacemaker technology. Initial
pacemakers were limited by poor lead and battery longevity [17]. The first prototype of a completely
endocardial implantable pacemaker was presented in 1970. Since then, different leadless systems with
31
different energy sources and myocardial fixation systems have been developed, resulting in the CE
certification of two right ventricular single-chamber pacemaker systems (Nanostim™; St. Jude Medical,
St. Paul, MN, USA, and Micra™; Medtronic, Minneapolis, MN, USA) [23,31]. Leadless pacemakers
still are an emerging technology, not yet established in use. The technology represents a modification of
the existing pacemaker technology.
Administration, Investments, personnel and tools required to use the technology and the
comparator(s)
B0004. Who administers leadless pacemakers and conventional single-chamber ventricular
pacemakers and in what context and level of care are they provided?
B0008. What kind of special premises are needed to use leadless pacemakers and conventional
single-chamber ventricular pacemakers?
B0009. What supplies are needed to use leadless pacemakers and conventional single-chamber
ventricular pacemakers?
Both LCP and traditional pacemakers are provided in specialised centres with interventional
cardiology in the cardiac catheterization, laboratory sedative medication and local anaesthesia. LCP
implantation further requires fluoroscopy to guide positioning of the device.
Setting and staff required for LCP implantation do not differ from traditional pacemaker
procedures. As with any novel implantation method or procedure, there is a learning curve for
implantation of the leadless pacemaker and additional training for medical specialists will be required.
Unlike an angiogram or electrophysiologic study where catheters are inserted and promptly removed,
implantation of a pacemaker via the femoral vein requires strict surgical sterile precautions (careful
prep, hat, mask, etc.). Preoperative prophylactic antibiotics should be administered as with any
implanted device [23,39].
Discussion
Since the first cardiac pacemaker was implanted in 1958, improvements in pacing technology
have been coupled to advances in engineering, material design, and computer sciences. In 1970,
Spickler and colleagues reported on the first experimental use of a leadless and completely intracardiac
pacemaker in dogs with complete heart block. The pacemaker consisted of a capsule measuring 8 mm
by 18 mm and containing the electrodes, Betacel power source, and circuitry. Despite being such a
remarkable technological achievement at the time, it failed to advance into clinical use in part due to
concerns about radiation toxicity. It was not until almost 45 years after its conception that the idea of a
self-contained intracardiac pacemaker came to fruition [17,40].
Despite the hype around this new technology, it is important to realize that the current
generation of single component LCPs have their own unanswered questions and limitations; single-
chamber pacing is indicated in only a small number of patients. The vast majority of patients in need for
cardiac pacing require a dual-chamber pacing system [17,29,33,40].
Other relevant issue is the retrieval or explantation of the device; both devices utilize a
catheter-based snare retrieval approach. In animal studies it was successfully shown that the LCP could
be easily retrieved and replaced as needed; there are case reports describing the successful extraction of
a leadless pacemaker during short-term follow-up in humans as well. Noteworthy, encapsulation of a
transcatheter implantable pacemaker is not yet fully understood, and the timing of optimal device
implantation and retrieval needs to be determined [23,31]. Success in very late retrieval or extraction of
the devices is unknown [32]. Therefore, it is possible to program intracardiac pacemakers into an Off
mode, which allows the scenario of implanting an additional device at the end of battery life or in case
of malfunction. Although space in the right ventricle is limited, recent evidence has indicated that the
32
human right ventricle is able to accommodate at least three Micra™ devices within traditional, clinically
accepted pacing locations [29,37].
Also, this novel technique has learning curve-associated problems, which must be kept into
consideration. This is important because there are differences in implant procedure for each specific
device used, i.e. use of 23Fr catheter than 18Fr, when implanting MicraTM device as opposed to
NanostimTM. Also, NanostimTM is fixed to the heart using screws and MicraTM mainly by tines [23]. The
FDA panel members noted that training was also needed, because the tube that is fed through the blood
vessels is wider and tougher to maneuver than thinner catheters commonly used in other minimally
invasive procedures [41]. Both manufacturers have proposed training programmes in their FDA
submissions. However the extent to which the learning effect is able to significantly reduce acute
complications remains to be demonstrated [15].
Leadless technology is already the beginning of a new era in cardiac pacing, but due to the
existing limitations and unclear long-term performance, it will not replace conventional pacemaker
systems yet. At the moment, it is an additional tool in the treatment of patients in need for single-
chamber pacing. In the future, it is hoped that these devices will be used to manage key cardiovascular
disorders especially advanced heart failure requiring synchrony and bradycardia. After testing safety and
feasibility of LCPs as a whole, the most important developments needed are increased ease of operation
during implant and replacement, a longer battery life, and long-term working guarantee. With time it is
hoped that LCPs will evolve into a dual chamber device that allows for resynchronization therapy and
can function as an ICD, which can have both anti-tachycardia pacing (ATP) and defibrillator capability.
Medtronic MicraTM is already approved for full body MRI scans and adaptation of other devices to MRI
compatibility may also hasten LCPs’ clinical acceptance [23,29,40].
33
SAFETY
Research questions ID Question
C0008 How safe are leadless pacemakers in comparison to conventional single-chamber
ventricular pacemakers?
C0005 What are the susceptible patient groups that are more likely to be harmed through the
use of the technology?
C0007 Are leadless pacemakers and conventional single-chamber ventricular pacemakers
associated with user-dependent harms?
Patient safety
C0008. How safe are leadless pacemakers in comparison to conventional single-chamber
ventricular pacemakers?
The rates of serious adverse device effects ranged between 4% and 6.5% in the three case
series. These studies are non-randomized and so the evaluation of this new technique over contemporary
systems is incomplete.
There was one patient with cardiac injury (cardiac tamponade) in the LEADLESS I trial [25],
eight injuries (cardiac perforations with/without tamponade or pericardial effusions) in LEADLESS II
[33] and 11 injuries (cardiac perforations or effusions) in the Micra™ Transcatheter Pacemaker Study
[42,43].
Six dislodgements were reported with the Nanostim™ device [33], but none with the Micra™
TPS system [42,43]. Other serious adverse events that were attributable either to the device or the
procedure included vascular complications [33], arrhythmia during device implantation [43] and
elevated pacing thresholds requiring retrieval and implantation of a new device [33,43].
C0005. What are the susceptible patient groups that are more likely to be harmed through the use
of the technology?
There are not enough data to answer this question. However, in one case serie [25] one patient
had a patent foramen ovale (PFO), through which the deflectable delivery sheath had inadvertently
transited; thereby permitting LCP access to the left ventricle. Although the patient did not experience
any permanent clinical sequelae, it is possible that had the event not been recognized it could have led to
an adverse outcome.
C0007. Are leadless pacemakers and conventional single-chamber ventricular pacemakers
associated with user-dependent harms?
Leadless pacemakers and conventional single-chamber ventricular pacemakers are associated
with user-dependent harms due to the risk of serious adverse events related with the implantation
procedure.
The influence of operator experience on the rate of device-related serious adverse events was
assessed in one case serie [33]. Cases were stratified according to the first 10 devices implanted by an
operator (470 implants) versus subsequent implants by the same operator (56 implants). The rate of
device related serious adverse events was 6.8% for the initial 10 cases versus 3.6% for the subsequent
implants (p=0.56).
34
Discussion
For more than half a century, permanent cardiac pacing for symptomatic bradycardia has been
achieved with systems that consist of a surgically implanted subcutaneous electrical generator connected
to one or more transvenous leads that deliver the pacing therapy to the heart [42]. Although the efficacy
and safety of transvenous pacemaker therapy have incrementally improved and they help to improve
quality of life and reduce mortality in at-risk patients, this therapy is associated with procedure- and
device-related complications [24,25]. Approximately 10% of patients experience a short-term
complication related to transvenous implantation of the pacemaker. These may be due to either the pulse
generator (hematoma, skin breakdown, pocket infection) or venous access and lead implantation
(pneumothorax, cardiac tamponade, lead dislodgement). In the long-term, transvenous leads, often
considered the weakest link of the cardiac pacing system, can potentiate venous obstruction and are
prone to insulation breaks, conductor fracture and infection [17,25,33,40]. The incidence of pacemaker
lead fracture is about 1–4%. Most patients need immediate medical attention when lead fracture is
suspected especially if they are pacemaker-dependent [23].
The pursuit of leadless pacing options has long been of interest to reduce the complications that
can lead to interruption of pacemaker therapy, to hospitalization, or to death. As a result of advances in
battery chemistry and component design, pacemakers are now small enough to place within the heart;
leadless pacemakers can overcome many issues due to absence of leads and no requirement for a
surgical pocket [23,42].
However, data on the safety of transcatheter pacing are preliminary and have been limited to a
few reports from nonrandomized studies. Also, the initial experience with these two (Micra™,
Nanostim™) LCPs has highlighted several important safety considerations with the implantation
procedure and delivery systems [17,42]. Furthermore, there is the possibility of complications with a
leadless pacing system not seen with conventional pacing systems.
It is worth mentioning, there were two halts to the Nanostim™ trials in 2014 and 2015, due to
reports of serious adverse events, including perforation of the heart and dislodgement of the device; the
two products differ in the rates of dislocations (6 with Nanostim™ LCP vs. 0 with the Micra™ TCP).
The differences might be due to the different fixation technologies of the two products (see Table 2
(question B0001)). It is recommended to re-assess the fixation technology of the Nanostim™ LCP [15].
Also, the LCP has a wider diameter than conventional pacing leads, which raises the possibility of
mechanically-induced pro-arrhythmia [25]. Perforations related to leadless cardiac pacemakers may be
due in part to the relatively large diameter of the device as well [33].
The other issue is the implantation of LPC; the delivery of the implant requires a different
approach than that used for transvenous leads, with substantially larger venous access tools. Torturous
venous systems and anatomic variations may introduce additional challenges to implantation, therefore
this technique necessitates a solid training program for new implanters. Larger studies and serial follow-
up will be necessary to assess this, and other, potential complications [24,25,42].
Also, it is unknown whether long-term retrieval of the pacemaker after several years of
implantation in patients will be possible. Acute and subacute retrieval of the LCP is feasible, and
preclinical evidence shows that the device can be extracted up to 5 months post-implantation. The
device may get encapsulated over time and therefore may be difficult to capture and retrieve. Long-term
animal studies are under way that will evaluate the feasibility of late device retrieval. An alternative
replacement strategy could be to place an additional device next to the initial device, without
compromising the right ventricular volume capacity and overall function. For this strategy, it is
important to realize that the LCP only takes up 1.0 ml of volume in the right ventricle, but also that
evidence of these strategies is currently lacking [24].
Leadless cardiac devices have the potential to revolutionize the field, significantly reduce the
short and long-term complications related to transvenous leads, and improve patient morbidity and
mortality. However, despite the remarkable advantages of leadless pacing systems, the data are still
35
quite limited and broad implementation of these technologies need to occur in a cautious and deliberate
fashion as the peri-procedural risks remains high; randomized control trials will be necessary to
determine clinical and cost benefit of LCPs as compared with conventional pacemaker systems [17].
36
CLINICAL EFFECTIVENESS
Research questions ID Question
D0001 What is the expected beneficial effect of leadless pacemakers on mortality?
D0003 What is the effect of leadless pacemakers on the mortality due to causes other than
cardiac arrhythmia?
D0005 How do leadless pacemakers affect symptoms and findings (severity, frequency) of
cardiac arrhythmias?
D0006 How do leadless pacemakers affect progression (or recurrence) of cardiac arrhythmias
D0011 What is the effect of leadless pacemakers on patients’ body functions?
D0016 How does the use of leadless pacemakers affect activities of daily living
D0012 What is the effect of leadless pacemakers on generic health-related quality of life?
D0013 What is the effect of leadless pacemakers on disease-specific quality of life?
D0017 Was the use of leadless pacemakers worthwhile?
Mortality
D0001. What is the expected beneficial effect of leadless pacemakers on mortality?
Leadless pacemakers are not expected to have a beneficial effect on mortality compared to
conventional VVI pacemakers.
Overall mortality ranged from 3 to 5%. Cardiac mortality was reported in two studies with
0.8% [33] and 1% [42,43], respectively.
D0003. What is the effect of leadless pacemakers on the mortality due to causes other than cardiac
arrhythmia?
Procedural mortality was reported in all three studies [24,25,33,42,43]. In LEADLESS I trial,
one patient had a perforation during the implantation procedure, leading to cardiac tamponade. He died
of a massive cerebral artery ischaemic infarct five days later [24,25]. Two procedure-related (but
classified as non-device-related) deaths were reported in the LEADLESS II cohort: in one patient LCP
implantation was complicated by a large groin haematoma, the patient suffered fatal cardiac arrest 14
days later. The second subject underwent an unsuccessful LCP implant complicated by pericardial
effusion, developed atrial fibrillation two days after the operation and died 8 days after the failed LCP
implant [33]. In the Micra Transcatheter Pacemaker Study cohort, one death was adjudicated as related
to the transcatheter implantation procedure: the patient had a prolonged procedure time due to a
concomitant AV node ablation and end stage renal disease and the cause of death was perceived to be
metabolic acidosis [42].
Morbidity
D0005. How do leadless pacemakers affect symptoms and findings (severity, frequency) of cardiac
arrhythmias?
None of the studies reported results on symptoms associated with cardiac arrhythmias.
D0006. How do leadless pacemakers affect progression (or recurrence) of cardiac arrhythmias?
None of the studies reported results on progression of cardiac arrhythmias.
37
None of the studies reported pacing-induced arrhythmias.
Function
D0011. What is the effect of leadless pacemakers on patients’ body functions?
None of the studies reported results on patient’s body functions.
D0016. How does the use of leadless pacemakers affect activities of daily living?
None of the studies reported results on exercise capacity.
Health-related quality of life
D0012. What is the effect of leadless pacemakers on generic health-related quality of life?
D0013. What is the effect of leadless pacemakers on disease-specific quality of life?
None of the studies reported results on health-related quality of life.
Patient satisfaction
D0017. Was the use of leadless pacemakers worthwhile?
None of the studies reported results on patient satisfaction.
Discussion
For almost 60 years, pacemaker therapy has been the standard of care for various
bradyarrhythmias [24]. Permanent cardiac pacing for symptomatic bradycardia has been achieved with
systems that consist of a surgically implanted subcutaneous electrical generator connected to one or
more transvenous leads that deliver the pacing therapy to the heart. Although cardiac pacemakers are
effective (improved quality of life and reduced mortality in at-risk patients), approximately one in eight
patients has an early complication, frequently related to the lead or leads or to the subcutaneous
“pocket” [24,25,42].
Recently, a leadless cardiac pacemaker has been introduced to potentially overcome some of
these short- and long-term outcomes [24]. Leadless pacemakers are not expected to have a beneficial
effect on mortality compared to conventional VVI mode pacemakers. A leadless intracardiac
transcatheter pacing system has been designed to avoid the need for a pacemaker pocket and
transvenous lead (the electrodes are positioned on the pacemaker capsule) [37,42], thereby eliminating
an important source of complications associated with traditional pacing systems while providing similar
benefits [43].
The lack of a generator pocket has some advantages as well both in terms of patient comfort
(and quality of life) and infectious risk [23,32]. However, there are no data on clinical efficacy
endpoints and, in particular, health-related quality of life was not assessed in the studies. Also, it is
unclear, if the avoidance of lead/ generator complications translates in a relevant benefit for the patients.
In most patients receiving a traditional pacemaker, health-related quality of life increases in the first year
after pacemaker implantation – the occurrence of an inhospital adverse event however did not have any
impact on how health-related quality of life was perceived 1 year after the pacemaker implantation [44].
The major limitation of the first generation of single component leadless cardiac pacemakers is
their ability to perform single-chamber (right ventricle) pacing only, limiting the use of such a device to
a population that would not derive benefit from dual-chamber pacing or cardiac resynchronization
38
therapy. Notably, excessive ventricular pacing has been associated with worse cardiovascular outcomes
[40]. Further challenges include cost, physician training, worldwide accessibility, and long-term follow-
up results. Hence, without the results of long-term trials, it is not possible to make a final decision about
leadless cardiac pacemakers [23].
39
CONCLUSIONS
1. Leadless pacemaker is offered as an alternative to conventional single- chamber pacemakers.
Single-chamber ventricular pacing (VVI) mode is the method of choice for patients with (or
without) chronic atrial fibrillation or with sinus node disease who require a pacemaker due to
slow ventricular response (atrioventricular block), only indicated to alleviate symptoms
associated with a bradyarrhythmia.
2. There are two wireless cardiac pacemaker systems from different manufacturers – Nanostim™
and Micra™; these devices share common characteristics, as they both are single-chamber
ventricular pacemakers and have CE Mark approval. Main differences between the systems are
related to the fixation mechanism: Nanostim™ LCP uses a screw-in helix and a secondary
fixation mechanism of three nylon tines, whereas the Micra™ TPS uses four self-expanding
nitinol tines.
3. The data on the safety of transcatheter pacing are preliminary and have been limited to a few
reports from nonrandomized studies. The rates of serious adverse device effects ranged between
4 and 6.5% in the three case series. However, In most cases cardiac injuries (cardiac perforations
with/without tamponade, pericardial effusions, cardiac tamponade) were diagnosed. Also, six
dislodgements (0.95%) were reported with the Nanostim™ device, but none with the Micra™
TPS system.
4. Leadless pacemakers are not expected to have a beneficial effect on mortality compared to
conventional VVI pacemakers. Potentially the lack of a generator pocket has some advantages in
terms of patient comfort (and quality of life) and infectious risk; however, there are no data on
clinical efficacy endpoints and, in particular, health-related quality of life was not assessed in the
studies.
40
RECOMMENDATIONS
1. The data concerning safety and efficacy of the leadless pacing systems are still quite limited, and
before deciding on usage of these systems it is recommended to evaluate the potential risk of
adverse events. Evidence-based data (randomized controlled trials) will be necessary to
determine clinical and cost benefit of LCPs as compared with conventional pacemaker systems.
41
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45
APPENDIX 1: METHODOLOGY AND DESCRIPTION OF THE
EVIDENCES USED
This health technology assessment (“Leadless pacemakers for right ventricle pacing”) which
was implemented by the LBI-HTA (Ludwig Boltzmann Institute-Health Technology Assessment,
Austria) was updated and adapted for the context of Lithuania. The European Commission initiates and
supports the usage and adaptation of EunetHTA’s and other countries health technology assessments for
national needs of the European countries.
A working version of the HTA Core Model® for Rapid Relative Effectiveness Assessments
(version 4.2) was used as the primary source for selecting the assessment elements. Additionally,
assessment elements from other EUnetHTA Core Model Applications (HTA Core Model® for Medical
and Surgical Interventions (version 3.0)) were screened and included, if believed relevant to the present
assessment.
The systematic literature search was conducted with time limitation between 10th December
2015 and 25th August 2016, inclusive. Also, information for the assessment was updated and used from
the LBI-HTA decision support document No. 97 (“Leadless pacemakers for right ventricle pacing”).
The adaptation of the assessment was based primarily on a basic systematic literature search in
the following sources:
Cochrane Library database;
PubMed (Medline);
CRD database;
Hand searches including articles from the manufacturers.
Relevant literature sources and articles for the adaptation for the ‘Safety’ and ‘Clinical
effectiveness’ domains were selected by the VASPVT (State Health Care Accreditation Agency under
the Ministry of Health, Lithuania). References were included or excluded according to the PICO scheme
described in the summary. In terms of study design, no RCTs or SRs were found.
Selection of relevant documents was performed by two independent researchers. If the same
data were duplicated in multiple articles, only results from the most comprehensive or most recent
article were included. Consensus was found in all cases about the inclusion and exclusion of individual
studies.
The relevant information from the feasible studies was retrieved without any further analysis.
For all studies the methodological quality was assessed using the IHE checklist for case series (see more
in LBI-HTA decision support document No. 97 “Leadless pacemakers for right ventricle pacing”) by
two review authors independently from each other. In case of disagreement a third researcher was
involved to solve the differences.
Incidentally, a comparative analysis was not applicable, since the available studies are case
series. LBI-HTA used the Grading of Recommendations Assessment, Development and Evaluation
(GRADE) methodology to assess the quality of the evidence for ‘Clinical effectiveness’ and ‘Safety’.
Evidence tables of single arm studies (3 studies) included for clinical effectiveness and safety can be
found on LBI-HTA decision support document No. 97 “Leadless pacemakers for right ventricle pacing”.
A manual search and basic search were performed for ‘Health problem and current use’ and
‘Description and technical characteristics’.
Most of the research questions were answered in plain text format. The analysis is qualitative
and not quantitative due to a lack of comparison groups and heterogeneity of the data.
46
Reporting of results
Study characteristics
There are no comparative studies to assess the effectiveness and the safety of leadless
pacemakers. We identified five references to three prospective multi-centre single arm studies that
reported the performance of leadless pacemakers [24,25,33,42,43] in a total of 633 participants (efficacy
cohorts). In the same five references [24,25,33,42,43] the safety of leadless pacemakers was assessed in
a total of 1,284 participants. All studies were sponsored by device manufacturers. Study characteristics
and results of included studies are displayed in LBI-HTA decision support document No. 97 “Leadless
pacemakers for right ventricle pacing”.
All three studies included patients with indications for VVI pacing, with a restriction on non-
pacemaker dependent patients in one study [24,25]. For the majority of the study participants, pacing
was indicated due to atrial fibrillation with AV block (range 56–67%). Other indications were sinus
node dysfunction (range 15–35%) and AV block (range 8.7–18%). For the latter two indications,
reasons for the selection of VVI pacing mode were the expectation of only infrequent need for pacing,
advanced age of the patient, patient preference, conditions that precluded implantation of a transvenous
pacemaker system or significant comorbidities.
Mean age of the study participants was 76 years in all three studies. The study populations were
predominantly male (range 59–67%). Comorbidities were frequent, with almost 80% of the participants
suffering from hypertension.
None of the studies reported results on the outcomes defined as crucial (health related quality
of life (HRQoL), exercise capacity) to assess clinical effectiveness.
Overall mortality ranged from 3 to 5%; cardiac mortality was reported in two studies with 0.8%
and 1%. Four deaths were reported as procedure-related.
The rates of serious adverse device effects ranged between 4% and 6.5% in the three case
series. In total, 20 patients experienced a cardiac injury. Six device dislodgements were reported with
the Nanostim™ device, but none with the Micra™ TPS system.
Other serious adverse events that were attributable either to the device or the procedure
included vascular complications, arrhythmia during device implantation and elevated pacing thresholds
requiring retrieval and implantation of a new device.
Quality assessment
The strength of evidence was rated according to GRADE (Grading of Recommendations
Assessment, Development and Evaluation) scheme [45] for each endpoint individually. Each study was
rated by two independent researchers from LBI. In case of disagreement a third researcher was involved
to solve the difference. A more detailed list of criteria applied can be found in the recommendations of
the GRADE Working Group [45].
Overall, the strength of evidence for the effectiveness and safety of leadless pacemakers in
comparison to conventional pacemakers is very low [15].
The ranking according to the GRADE scheme for the research question and the quality
assessment table of the selected three single arm studies can be found in the LBI-HTA (Ludwig
Boltzmann Institute-Health Technology Assessment, Austria) decision support document No. 97
“Leadless pacemakers for right ventricle pacing” [15].
Limitations
The available studies are non-randomised and there is no direct comparison of the benefit of
LCP over contemporary single-chamber systems, so no de-finitive conclusion can be drawn on the
47
superiority or even non-inferiority of the new technology compared to standard therapy. Indirect
comparisons with historical data from previous pacemaker studies are difficult, since most studies
include patients with dual-chamber pacemakers or other implantable cardiac devices, for which
complication rates are considerably higher than for single-chamber pacemakers [7,8,9]. There are no
data on clinical efficacy endpoints and, in particular, HRQoL was not assessed in the studies. It is
unclear, if the avoidance of lead/generator complications translates in a relevant benefit for the patients.
In most patients receiving a traditional pacemaker, HRQoL increases in the first year after pacemaker
implantation – the occurrence of an inhospital adverse event however did not have any impact on how
HRQoL was perceived 1 year after the pacemaker implantation [44].
In a number of patients, the implantation of a transvenous pacemaker system is precluded
because of conditions such as compromised venous access, the need to preserve veins for
haemodialysis, thrombosis, a history of infection, or the need for an indwelling venous catheter. While
leadless pacemakers po-tentially represent the only treatment alternative in these patients, it remains to
be demonstrated that these patients are not at increased risk for complications associated with the
implantation procedure [15].
Finally, safety data are available only for 6 months follow-up. Battery longevity of leadless
pacemakers was estimated to be up to ten years, but actual longevity has not been measured and might
be overestimated [46]. So far, there is no definitive answer how pacemaker-dependent patients can be
treated after the battery expires. Retrievability of the leadless pacemaker after a prolonged implantation
time has not been studied at later timepoints and might be compromised by complete encapsulation of
the devices observed in autopsies [47]. So far, there is no experience on the feasibility of the
implantation of additional LCP in the heart chamber.
48
ADAPTATION TOOLKIT
Table I. Speedy sifting questions [48]
Speedy sifting questions:
Assessment of relevance Answers
1. Are the policy and research questions being addressed relevant to
your questions?
Yes.
2. What is the language of this HTA report? Is it possible to
translate this report into your language?
Yes.
3. Is there a description of the health technology being assessed? Yes; pages 5, 15.
4. Is the scope of the assessment specified? Yes; page 9.
5. Has the report been externally reviewed? Yes; page 2.
6. Is there any conflict of interest? Yes; page 2.
7. When was the work that underpins this report done? Does this
make it out of date for your purposes? No; pages 1, 12, 46.
8. Have the methods of the assessment been described in the HTA
report? Yes; pages 5, 11, 31.
HTA available at: http://eprints.hta.lbg.ac.at/1094/1/DSD_97.pdf
49
Table II. Technology’s use domain questions [48]
Questions Answers
To assess relevance:
1.What is the research question considered? Is the research question
considered within this section of the report relevant to your question?
Yes; pages 5, 9.
To assess reliability:
2. Were conditions, target group, relevant interventions or comparisons
between interventions and relevant outcomes appropriately defined?
Yes; pages5, 9, 15,
19, 22, 44.
3. Is the information provided on technology use and development complete
and comprehensive? Are the methods and sources used when elaborating the
background information well documented?
Partly, update
needed.
4. Are patterns of utilisation, diffusion, indications and time trends adequately
described?
Partly, update
needed.
5. Is an analysis of the regulatory status of the technology provided (market
admission, status in other countries)?
Yes; pages 15, 17.
Update needed.
To assess transferability:
6. Is there any consideration of when and how technical characteristics affect
outcomes?
Yes; page 15.
7. Are there any differences in the use of this technology within the target
setting (compared to the uses described in the HTA report for adaptation)?
No.
Table III. Safety domain questions [48]
Questions Answers
To assess relevance:
1. Were harms or safety assessed? Yes; pages 6, 27.
2. Is the scope of the safety assessment relevant to your question? Yes; pages 5, 9
To assess reliability:
3. Was the search for studies reasonably comprehensive? Yes; pages 12, 46.
4. Were special sources consulted (disease registers, routinely data collected
(on utilisation, costs, adverse effects, etc.), consumer associations, etc..)
Yes; pages 12, 45.
5. What are the sources of information/ data (e.g. surveillance databases,
declaration of incidents, safety report, RCT, case reports)?
Yes; pages 12, 46.
6. Were the criteria used for deciding which studies to include in the HTA
report reported?
Yes; pages 9, 13,
44.
7. Was bias in the selection of studies avoided? Yes; pages 14, 31,
43.
8. Did the selection of studies (in particular the choice of eligible study
designs) minimise the possibility of including studies with a high propensity
for bias?
Yes; pages 14, 31,
43.
9. Were the criteria used for assessing the validity of the included studies
reported?
Yes; page 43.
10. a) Were the inclusion criteria used for the primary studies appropriate to
the study question posed by the HTA report?
b) Were the criteria used to assess the validity of the primary study
appropriate?
Yes; pages 9, 13.
Yes; pages 5, 31.
11. Which risks have been reported and how were they measured? Yes; page 43.
12. a) Were the study outcomes valid?
b) Were the study outcomes pertinent?
Partly; page 28.
Partly; page 28.
13. Are the number of patients, their representativeness and the quality of No; pages 28, 39.
50
the data high enough to exclude a modest but clinically relevant rate of
serious
complications? I.e. what is the potential for overlooking a possible serious
adverse event?
14. Is there a possibility for a „class‟ effect adverse reaction or safety
problem?
No.
To assess transferability:
15. Does the population described for eligibility match the population to
which it is targeted in the target setting?
Yes; pages 9, 28.
16. Are there any reasons to expect differences in complication rates (e.g.
epidemiology, genetic issues, healthcare system (quality of care,
surveillance))?
Yes; page 28.
17. Are the requirements for its use (special measures needed for
use/ implementation, maintenance, etc.) available in the target setting?
Yes; page 17.
18. Is the necessary expertise (knowledge and skills) available in the target
setting?
Yes; page 17.
19. a) Is safety particularly dependent on training?
b) Are there types of teams to which the procedure should be limited for
safety reasons?
c) Is there a need for special training or certification to deliver the
intervention
properly?
d) Would it be possible (affordable) to organise such training, if any?
Unknown; pages 6,
33.
Yes; pages 9, 17.
Yes; page 17.
Unknown.
Table IV. Effectiveness domain questions [48]
Questions Answers
To assess relevance:
1. a) What is the research question considered?
b) Is the research question considered within this section of the HTA report
relevant to your HTA question?
Yes; pages 5, 9.
Yes; page 25.
2. Are the outcome measures relevant for your HTA question? Yes; pages 9, 25.
3. Were the search methods used to find studies relevant to the main
question(s) stated?
Yes; pages 12, 45,
46.
To assess reliability:
4. Was the search for studies reasonably comprehensive? Yes; pages 12, 46.
5. Were the criteria used for deciding which studies to include in the HTA
report reported?
Yes; pages 9, 13, 44.
6. Was bias in the selection of studies avoided? Yes; pages 14, 31,
43.
7. Did the selection of studies (in particular the choice of eligible study
designs) minimise the possibility of including studies with a high propensity
for bias?
Yes; pages 14, 31,
43.
8. Were the criteria used for assessing the validity of the included studies
reported?
Yes; pages 31, 43.
9. Was the validity of all studies referred to in the text assessed using
appropriate criteria (either in selecting studies for inclusion or in analysing the
studies that are cited)?
Yes; pages 31, 43.
10. Were the methods used to combine the findings of the relevant studies (to
reach a conclusion) reported?
No.
51
11. Were the findings of the relevant studies combined appropriately with
respect to the main question the HTA report addresses?
No.
12. Were the conclusions made by the authors supported by the data and/ or
analysis reported in the HTA report?
Yes; pages 6, 33, 35.
13. How likely is it that the relevance of this HTA report has changed due to
additional research that had started, completed or been published since this
Health Technology Assessment report?
Unlikely.
To assess transferability:
14. Would you expect the baseline risk of patients within your own setting to
be the same as the baseline risk of those patients considered within the HTA
report for adaptation? (assuming that patients receive the same treatment and
same comparator).
Yes.
52
Documentation of the basic search strategies
Database: PubMed (MEDLINE)
Search date: 2016-08-25
Results: 44 hits.
Searches Results
1. Pacemaker, Artificial[MeSH] 24170
2. Cardiac Pacing, Artificial[MeSH] 21728
3. pacemaker* 41504
4. (Pacemaker, Artificial[MeSH] OR Cardiac Pacing, Artificial[MeSH] OR pacemaker*) 56850
5. leadless 129
6. leadless pac* 71
7. transcatheter pac* 10
8. (leadless OR leadless pac* OR transcatheter pac*) 131
9. (Pacemaker, Artificial[MeSH] OR Cardiac Pacing, Artificial[MeSH] OR pacemaker*)
AND (leadless OR leadless pac* OR transcatheter pac*)
99
10. (Pacemaker, Artificial[MeSH] OR Cardiac Pacing, Artificial[MeSH] OR pacemaker*)
AND (leadless OR leadless pac* OR transcatheter pac*) Filters activated: Publication date
from 2015/12/10 to 2016/08/25, English.
44
Database: Cochrane Library
Search date: 2016-08-25
Results: 1 hit.
Searches Results
1. MeSH descriptor: [Pacemaker, Artificial] explode all trees 704
2. MeSH descriptor: [Cardiac Pacing, Artificial] explode all trees 1337
3. pacemaker* 1867
4. #1 OR #2 OR #3 2667
5. (leadless or transcatheter*) near pacing 2
6. leadless 1
7. #5 OR #6 3
8. #4 AND #7 3
9. #4 AND #7 Publication Year from 2015 to 2016 1
Database: CRD database
Search date: 2016-08-25
Results: 0 hits.
Searches Results
1. MeSH DESCRIPTOR Pacemaker, Artificial EXPLODE ALL TREES 100
2. MeSH DESCRIPTOR Cardiac Pacing, Artificial EXPLODE ALL TREES 139
3. (pacemaker*) 193
4. #1 OR #2 OR #3 284
5. (leadless) 1
6. ((leadless OR transcatheter*) NEAR pacing) 1
7. #5 OR #6 2
8. #4 AND #7 2
9. (#4 AND #7) WHERE LPD FROM 10/12/2015 TO 25/08/2016 0
53
Flow charts of study selection
Table V. Flow chart showing selection of studies.
Records identified
through PubMed
(Medline) searching
(n = 44)
Scr
een
ing
In
clu
ded
E
ligib
ilit
y
Iden
tifi
cati
on
Records identified
through Cochrane
Library searching
(n = 1)
Records after duplicates removed
(n = 49)
Records screened
(n = 49)
Records excluded (n = 44) with
reasons:
Wrong population: n=6
Wrong intervention: n=1
Wrong study design: n=25
Wrong research question: n=7
Background: n=5
Full-text articles assessed
for eligibility
(n = 5)
Studies included in qualitative synthesis:
non-RCT (n = 5)
Records identified
through CRD
database searching
(n = 0)
Additional
records from
HTA [15]
(n = 5)
54
Questions used from HTA Core Model Application for Rapid Relative Effectiveness
assessment (version 4.2)
Health problem and current use of the technology [49]
ID Question
A0001 For which health conditions, and for what purposes are leadless pacemakers used?
A0002 What is the disease or health condition in the scope of this assessment?
A0003 What are the known risk factors for cardiac arrhythmias?
A0004 What is the natural course of cardiac arrhythmias?
A0005 What are the consequences of cardiac arrhythmias for the society?
A0006 What is the burden of disease for patients with cardiac arrhythmias?
A0007 What is the target population in this assessment?
A0023 How many people belong to the target population?
A0011 How much are leadless pacemakers utilised?
A0020 What is the marketing authorisation status of leadless pacemakers?
A0021 What is the reimbursement status of leadless pacemakers?
A0024 How are cardiac arrhythmias currently diagnosed according to published guidelines
and in practice?
A0025 How are cardiac arrhythmias currently managed according to published guidelines
and in practice?
Description and technical characteristics of technology [49]
ID Question
B0001 What are leadless pacemakers and conventional single-chamber ventricular
pacemakers?
B0002 What is the claimed benefit of leadless pacemakers in relation to conventional single-
chamber ventricular pacemakers
B0003 What is the phase of development and implementation of leadless pacemakers and
conventional single-chamber ventricular pacemakers?
B0004 Who administers leadless pacemakers and conventional single-chamber ventricular
pacemakers and in what context and level of care are they provided?
B0008 What kind of special premises are needed to use leadless pacemakers and conventional
single-chamber ventricular pacemakers?
B0009 What supplies are needed to use leadless pacemakers and conventional single-chamber
ventricular pacemakers?
Safety [49]
ID Question
C0008 How safe are leadless pacemakers in comparison to conventional single-chamber
ventricular pacemakers?
C0005 What are the susceptible patient groups that are more likely to be harmed through the
use of the technology?
C0007 Are leadless pacemakers and conventional single-chamber ventricular pacemakers
associated with user-dependent harms?
55
Clinical effectiveness [49]
ID Question
D0001 What is the expected beneficial effect of leadless pacemakers on mortality?
D0003 What is the effect of leadless pacemakers on the mortality due to causes other than
cardiac arrhythmia?
D0005 How do leadless pacemakers affect symptoms and findings (severity, frequency) of
cardiac arrhythmias?
D0006 How do leadless pacemakers affect progression (or recurrence) of cardiac arrhythmias
D0011 What is the effect of leadless pacemakers on patients’ body functions?
D0016 How does the use of leadless pacemakers affect activities of daily living
D0012 What is the effect of leadless pacemakers on generic health-related quality of life?
D0013 What is the effect of leadless pacemakers on disease-specific quality of life?
D0017 Was the use of leadless pacemakers worthwhile?
56
APPENDIX 2: DESCRIPTION OF THE EVIDENCE USED
Evidence tables of individual studies included
Table VI. Results from observational studies of leadless pacemakers.
Study (acronym, ID no.) LEADLESS I – Evaluation of a new
cardiac pacemaker (NCT01700244)
The LEADLESS II pacemaker IDE
study (NCT02030418)
Micra Transcatheter Pacing Study
(NCT02004873)
Reference [24,25] [33] [42,43]
STUDY DESCRIPTION
Country Czech Republic; Germany; Netherlands Australia; Canada; USA
USA, Australia, Austria, Canada, Czech
Republic, China, Denmark, France,
Greece, Hungary, India, Italy, Japan,
Malaysia, Netherlands, Serbia, South
Africa, Spain, United Kingdom
Sponsor St. Jude Medical St. Jude Medical Medtronic
Conflict of Interests R.E.K., V.Y.R., J.K. grant support from
Nanostim Inc.; R.E.K. grant support from
St. Jude Medical; J.K. speaker fees; J.S.
honoraria for lectures; V.Y.R. stock
options; J.R.G. grant support; J.K. and
A.A.M.W. in advisory boards.
Not available. P.R., G.Z.D., C.S., K.S., L.V.A.B.,
R.E.K., L.C., S.Z., C.N., J.H., M.L.,
T.A.S. consulting fees/ honoraria; R.O.
consulting fees/ honoraria, speaker‘s
bureau; L.M. consulting fees/ honoraria,
speaker‘s bureau, research grants,
fellowship support; V.L., K.S., M.D.B.,
T.J.S. Employment, Significant,
Medtronic; D.R. consulting fees/
honoraria, research grants.
Intervention/ Product Implantation of a leadless cardiac
pacemaker/Nanostim™ LCP
Implantation of a leadless cardiac
pacemaker/Nanostim™ LCP
Implantation of a leadless cardiac
pacemaker/Micra™ TPS
Comparator NA NA Dual-chamber pacemaker
Study design Single cohort feasibility trial Single cohort safety/efficacy study Single cohort safety/efficacy study with
historical control
Duration of the study December 2012 – April 2013 February 2014 – September 2015 November 2013 – May 2015
Randomisation method None None None
Blinding method Open label
Open label
Open label
57
(investigator, patient,
outcomes assessor)
Intervention (n=) 33 300 (Primary cohort)
526 (Full cohort)
297 (Efficacy cohort)
725 (Safety cohort)
Control (n=) 0 0 0
Population Patients indicated for VVI pacing who are
not Pacemaker dependant
Patients indicated for VVI(R) pacing Patients indicated for VVI(R) pacing
Inclusion criteria Chronic atrial fibrillation with 2 or 3° AV
or bifascicular bundle branch block (BBB
block); or
Normal sinus rhythm with 2 or 3° AV or
BBB block and a low level of physical
activity or short expected lifespan (but at
least one year); or
Sinus bradycardia with infrequent pauses
or unexplained syncope with EP findings.
Chronic and/or permanent atrial
fibrillation with 2 or 3° AV or bifascicular
bundle branch block (BBB block),
including slow ventricular rates (with or
without medication) associated with atrial
fibrillation; or
Normal sinus rhythm with 2 or 3° AV or
BBB block and a low level of physical
activity or short expected lifespan (but at
least one year); or
Sinus bradycardia with infrequent pauses
or unexplained syncope with EP findings.
Class I or II indication for pacing
(bradycardia due to atrial
tachyarrhythmia, sinus node dysfunction,
atrioventricular node dysfunction, or other
causes).
Exclusion criteria Pacemaker dependent;
Known pacemaker syndrome, have
retrograde VA conduction or suffer a
drop in arterial blood pressure with the
onset of ventricular pacing;
Pre-existing pacing or defibrillation
leads;
Pre-existing pulmonary arterial (PA)
hypertension or significant
physiologically-impairing lung
disease;
Current implantation of an implantable
cardioverter defibrillator (ICD) or
cardiac resynchronization therapy
(CRT);
Pacemaker syndrome, retrograde VA
conduction or drop in arterial blood
pressure with the onset of ventricular
pacing;
Pre-existing endocardial pacing or
defibrillation leads; or
Pre-existing pulmonary arterial (PA)
hypertension or significant
physiologically-impairing lung disease;
Current implantation of either
conventional or subcutaneous
implantable cardioverter defibrillator
(ICD) or cardiac resynchronization
therapy (CRT);
Mechanical tricuspid valve prosthesis;
Entirely pacemaker dependent (escape
rhythm <30 bpm)* (restriction was
lifted following review of the Early
Performance Assessment);
Existing or prior pacemaker, ICD or
CRT device implant;
Unstable angina pectoris, acute
myocardial infarction within 30d,
Current implantation of neurostimulator
or any other chronically implanted
electronic device, mechanical tricuspid
valve, implanted vena cava filter, or left
ventricular assist device;
Morbidly obese;
Femoral venous anatomy unable for
58
Mechanical tricuspid valve prosthesis;
Presence of implanted vena cava filter;
Presence of implanted leadless cardiac
pacemaker;
Hypersensitivity to <1mg of
dexamethasone sodium phosphate;
Life-expectancy <12m; pregnant or
breastfeeding women
Implanted vena cava filter;
Implanted leadless cardiac pacemaker;
Evidence of thrombosis in one of the
veins used for access during the
procedure;
Recent cardiovascular or peripheral
vascular surgery within 30 days of
enrolment;
Allergic or hypersensitive to <1mg of
dexamethasone sodium phosphate;
Life-expectancy <12m; pregnant or
breastfeeding women
transcatheter procedure;
Intolerance to device material or
hypersensitivity to <1mg
dexamethasone;
Life-expectancy <12m; pregnant or
breastfeeding women
Primary outcome
(including measurement
tools and measurement
times)
S: Complication-free rate (freedom of
SADE at 90 days)
S: Complication-free rate (freedom of
SADE) at 6 months
E: Therapeutically acceptable pacing
capture threshold (≤2.0 V at 0.4 msec)
and a therapeutically acceptable sensing
amplitude (R wave ≥5.0 mV, or a value
equal to or greater than the value at
implantation) through 6 months
S: Freedom from major complications
related to the Micra™ TPS and/or
procedures at 6-month post-implant
(within 183 days)
E: Adequate pacing capture threshold
at 6 months (≤2 V at a pulse width of
0.24 ms and stable (increase of ≤1.5
V))
Secondary outcome
(including measurement
tools and measurement
times)
S: Implant success rate (% of subjects
leaving the implant procedure with an
implanted and functioning LCP device)
E: Pacemaker performance
characteristics, LCP performance during
magnet testing (predischarge) and 6-
minute walking test (at 2 weeks)
S: Non–device-related SAE during 6
months of follow-up.
S: SADE and Non-device-related SAE
during follow-up (Full cohort)
E: Automated ventricular capture
management (VCM) feature by
comparing the percentage of subjects with
a VCM within +0.5 V of pacing capture
thresholds evaluated manually at 6
months
Rate response during treadmill testing in a
subset of subjects
Micra™ TPS longevity estimates at 6
months, electrical performance, implant
procedure ambulatory ECG monitoring,
quality of life, and device orientation
S: Adverse Events
Freedom from SADE at 12 months
Follow-up (months) 12 6 (Primary cohort) 6
59
Mean (±SD) of 6.9±4.2 (Full cohort)
Loss to follow-up, n (%) 0 0 0
POPULATION CHARACTERISTICS
Age (mean), y 76.5±8.4 75.7±11.6
75.8±12.1 (Full cohort)
75.9±10.9 (Safety cohort) vs. 71.1±12.1
Male, n (%) 22 (67) 193 (64.3)
325 (61.8) (Full cohort)
426 (58.8) (Safety cohort) vs. 1469 (55.1)
Pacing indication, n (%) Permanent AF with AV block (including
AF with slow ventricular response) 22
(67)
Sinus rhythm with 2nd/3rd degree AV
block and significant comorbidities 6 (18)
Sinus bradycardia with infrequent pauses
or unexplained syncope 5 (15)
AF with AV block 294 (55.9)
Sinus rhythm with high-grade AV block
46 (8.7)
Sinus bradycardia with infrequent pauses
or syncope 186 (35.4) (Full cohort)
Bradycardia associated with persistent or
permanent atrial tachyarrhythmia (64)
Sinus-node dysfunction (17.5)
AV block (14.8)
Other reasons (3.7)
Comorbidities Diabetes, 143 (27.2)
CAD, 201 (38.2)
CHF, 82 (15.6)
Hypertension, 420 (79.8)
Valvular Disease, 106 (20.2)
Diabetes, 207 (28.6); COPD, 90 (12.4);
Renal dysfunction, 145 (20.0); CAD, 203
(28.0); AF, 526 (72.6); CHF, 123 (17.0);
Hypertension, 570 (78.6); Valvular
Disease, 306 (42.2)
OUTCOMES
EFFICACY
Pacing performance N/A (no threshold defined) 270/300 (90%, 95% CI 86.0–93.2) 292/297 (98.3)
Quality of life NR NR NR
SAFETY
Implant success rate, n (%) 32 (97) 504/526 (95.8) 719/725 (99.2)
Overall Mortality, n (%) 1 (3) 28/526 (5.3) 29/725 (4)
Procedure-related mortality,
n(%)
1 (3) 2/526 (0.4) 1/725 (0.1*)
Cardiac mortality, n (%) NR 4/526 (0.8) 7/725 (1.0)
Cardiac morbidity, n (%) NR NR NR
Overall Adverse Events, n
(%)
NR NR NR
Serious Adverse Events, n NR NR NR
60
(%)
Non-device-related SAE, n
(%)
NR 29/526 (5.5)
NR
Overall Adverse Device
Effects (ADE), n (%)
NR NR NR
Serious Adverse Device
Effects (SADE), n (%)
2 (6) 34/526 (6.5)
25/725 (4.0*)
Hospitalization, n (%) 9 (27) NR 12/725 (2.3*)
Loss of device function, n
(%)
NR NR 1/725 (0.1*)
Cardiac injury, n (%) 1 (3) 8/526 (1.5) 11/725 (1.6*)
Device dislodgement, n (%) 0 6/526 (1.1) 0
Elevated pacing thresholds
requiring retrieval/
replacement, n (%)
0 4/526 (0.8) 2/725 (0.3%*)
Legend: LCP – Leadless cardiac pacemaker, IDE – Investigational device exemption; TPS – Transcatheter pacing system; NA – not applicable; NR – not reported; SAE – Serious
adverse events; VCM – Ventricular capture management; AF – Atrial fibrillation; AV – atrioventricular; COPD –Chronic obstructive pulmonary diseases; CAD – Coronary artery
disease; CHF – Congestive Heart failure; CI – Confidence interval; ADE –Adverse device events; SADE – Serious adverse device events.
* 183 days Kaplan-Meier estimates.
Included studies
HTA
1. Kisser A, Emprechtinger R. Leadless pacemakers for right ventricle pacing. Decision Support Document
No. 97; 2016. Vienna: Ludwig Boltzmann Institute for Health Technology Assessment.
Non-RCTs
2. Knops RE, Tjong FVY, Neuzil P, Sperzel J, Miller MA, Petru J, Simon J, Sediva L, de Groot JR,
Dukkipati SR, Koruth JS, Wilde AAM, Kautzner J, Reddy VY. Chronic performance of a leadless
cardiac pacemaker: 1-year follow-up of the LEADLESS trial. Journal of the American College of
Cardiology. 2015;65(15):1497-504.
3. Reddy VY, Exner DV, Cantillon DJ, Doshi R, Bunch TJ, Tomassoni GF, Friedman PA, Estes NA 3rd, Ip
J, Niazi I, Plunkitt K, Banker R, Porterfield J, Ip JE, Dukkipati SR. Percutaneous Implantation of an
Entirely Intracardiac Leadless Pacemaker. The New England Journal of Medicine. 2015 Sep
17;373(12):1125-35.
4. Reddy VY, Knops RE, Sperzel J, Miller MA, Petru J, Simon J, Sediva L, de Groot JR, Tjong FV,
Jacobson P, Ostrosff A, Dukkipati SR, Koruth JS, Wilde AA, Kautzner J, Neuzil P. Permanent leadless
cardiac pacing: results of the LEADLESS trial. Circulation. 2014;129(14):1466-71.
5. Reynolds D, Duray GZ, Omar R, Soejima K, Neuzil P, Zhang S, Narasimhan C, Steinwender C, Brugada
J, Lloyd M, Roberts PR, Sagi V, Hummel J, Bongiorni MG, Knops RE, Ellis CR, Gornick CC, Bernabei
MA, Laager V, Stromberg K, Williams ER, Hudnall JH, Ritter P, Micra Transcatheter Pacing Study
Group. A Leadless Intracardiac Transcatheter Pacing System. New Englands Journal of Medicine. 2015;
374:533-541.
6. Ritter P, Duray GZ, Steinwender C, Soejima K, Omar R, Mont L, Boersma LVA, Knops RE, Chinitz L,
Zhang S, Narasimhan C, Hummel J, Lloyd M, Simmers TA, Voigt A, Laager V, Stromberg K, Bonner
MD, Sheldon TJ, Reynolds D, Micra Transcatheter Pacing Study Group. Early performance of a
miniaturized leadless cardiac pacemaker: the Micra Transcatheter Pacing Study. European Heart Journal.
2015; 36 (37): 2510-9.
Excluded studies
Reference Exclusion
criteria
1. Chen K, Zheng X, Dai Y, Wang H, Tang Y, Lan T, Zhang J, Tian Y, Zhang B, Zhou X,
Bonner M, Zhang S. Multiple leadless pacemakers implanted in the right ventricle of swine.
Europace. 2016 Jan 31.
Wrong
population.
2. Soejima K, Edmonson J, Ellingson ML, Herberg B, Wiklund C, Zhao J. Safety evaluation of
a leadless transcatheter pacemaker for magnetic resonance imaging use. Heart Rhythm. 2016
Jun 29.
Wrong study
design.
3. Seriwala HM, Khan MS, Munir MB, Riaz IB, Riaz H, Saba S, Voigt AH. Leadless
pacemakers: A new era in cardiac pacing. Journal of Cardiology. 2016 Jan;67(1):1-5.
Background.
4. Tjong FV, Brouwer TF, Smeding L, Kooiman KM, de Groot JR, Ligon D, Sanghera R,
Schalij MJ, Wilde AA, Knops RE. Combined leadless pacemaker and subcutaneous
implantable defibrillator therapy: feasibility, safety, and performance. Europace. 2016 Mar 3.
Wrong
population.
5. Karjalainen PP, Nammas W, Paana T. Transcatheter leadless pacemaker implantation in a
patient with a transvenous dual-chamber pacemaker already in place. Journal of
Electrocardiology. 2016 Jul-Aug;49(4):554-6.
Wrong study
design.
6. Kypta A, Blessberger H, Lichtenauer M, Kammler J, Lambert T, Kellermair J, Nahler A,
Kiblboeck D, Schwarz S, Steinwender C. Subcutaneous Double "Purse String Suture"-A Safe
Method for Femoral Vein Access Site Closure after Leadless Pacemaker Implantation. Pacing
and Clinical Electrophysiology. 2016 Jul;39(7):675-9.
Wrong research
question.
7. Arias MA, Rubio MA, Miguel R, Pachón M. Thrombus formation at the tip of a leadless
pacemaker causing multiple unnecessary repositioning. Heart Rhythm. 2016 Jul 5.
Wrong research
question.
8. Rutzen-Lopez H, Silva J, Helm RH. Leadless Cardiac Devices-Pacemakers and Implantable
Cardioverter-Defibrillators. Current Treatment Options in Cardiovascular Medicine. 2016
Aug;18(8):49.
Background.
9. Da Costa A, Romeyer-Bouchard C, Guichard JB, Gerbay A, Isaaz K. Is the new Micra-
leadless pacemaker entirely safe? International Journal of Cardiology. 2016 Jun 1;212:97-9.
Wrong study
design.
10. Cay S, Ozeke O, Ozcan F, Topaloglu S, Aras D. An important advantage of the leadless Wrong study
62
pacemakers: magnetic resonance imaging compatibility. Europace. 2016 Apr;18(4):628-9. design.
11. Fudim M, Fredi JL, Ball SK, Ellis CR. Transcatheter Leadless Pacemaker Implantation for
Complete Heart Block Following CoreValve Transcatheter Aortic Valve Replacement.
Journal of Cardiovascular Electrophysiology. 2016 Jan;27(1):125-6.
Wrong
population.
12. Sperzel J. Leadless pacemakers and MRI compatibility: authors' reply. Europace. 2016
Apr;18(4):629.
Wrong study
design.
13. Huynh K. Device therapy: Newly designed leadless pacemaker. Nature Reviews: Cardiology.
2016 Jan;13(1):5.
Wrong study
design.
14. Pachón M, Puchol A, Arias MA. Leadless Pacemaker After Complicated Hematoma. Revista
Espanola de Cardiologia (English ed.). 2016 Jun;69(6):607.
Wrong study
design.
15. Ubrich R, Kreiser K, Sinnecker D, Schneider S. Magnetic resonance imaging at 1.5-T in a
patient with implantable leadless pacemaker. European Heart Journal. 2016 Aug
7;37(30):2441.
Wrong study
design.
16. Jung W, Sadeghzadeh G, Kohler J, Jäckle S, Beyersdorf F, Siepe M. Successful retrieval of
an active fixation leadless pacemaker in a 74-year-old woman 506 days post-implant.
Europace. 2016 Jul 1.
Wrong research
question.
17. Tjong FV, Brouwer TF, Kooiman KM, Smeding L, Koop B, Soltis B, Shuros A, Wilde
AA, Burke M, Knops RE. Communicating Antitachycardia Pacing-Enabled Leadless
Pacemaker and Subcutaneous Implantable Defibrillator. Journal of the Americal College of
Cardiology. 2016 Apr 19;67(15):1865-6.
Wrong study
design.
18. Huynh K. Newly designed leadless pacemaker. Nature Reviews: Cardiology. 2016
Mar;13(3):123.
Wrong study
design.
19. Bhargava R, Bhargava B. Leadless pacemaker and cremation. Heart of Asia. 2016 Jan
7;8(1):1-2.
Wrong research
question.
20. Wilson DG, Yue A, Roberts PR, Morgan JM. Leadless pacing: The old with the new.
International Journal of Cardiology. 2016 Jan 15;203:407-8.
Wrong study
design.
21. Kypta A, Blessberger H, Kammler J, Lambert T, Lichtenauer M, Brandstaetter W, Gabriel M,
Steinwender C. Leadless Cardiac Pacemaker Implantation After Lead Extraction in Patients
With Severe Device Infection. Journal of Cardiovascular Electrophysiology. 2016 Jun 14.
Wrong research
question.
22. Kypta A, Blessberger H, Lichtenauer M, Steinwender C. Temporary leadless pacing in a
patient with severe device infection. BMJ Case Report. 2016 May 17;2016.
Wrong study
design.
23. Arkles J, Cooper J. The Emerging Roles of Leadless Devices. Current Treatment Options in
Cardiovascular Medicine. 2016 Feb;18(2):14.
Background.
24. Omdahl P, Eggen MD, Bonner MD, Iaizzo PA, Wika K. Right Ventricular Anatomy Can
Accommodate Multiple Micra Transcatheter Pacemakers. Pacing and Clinical
Electrophysiology. 2016 Apr;39(4):393-7.
Wrong
population.
25. Lau CP, Lee KL. Transcatheter Leadless Cardiac Pacing with Limited Venous Access. Pacing
and Clinical Electrophysiology. 2016 May 25.
Wrong study
design.
26. Bongiorni MG, Zucchelli G, Coluccia G, Soldati E, Barletta V, Paperini L, Menichetti F, Di
Cori A, Segreti L, Del Prete E, Ceravolo R. Leadless cardiac pacemaker implant in a patient
with two deep brain stimulators: A peaceful cohabitation beyond prejudices. International
Journal of Cardiology. 2016 Aug 8;223:136-138.
Wrong study
design.
27. Falk V, Starck CT. Cardiac pacing - Will the future be exclusively leadless? Expert Review
of Medical Devices. 2016 May;13(5):421-2.
Wrong study
design.
28. Bhargava M, Bhargava R. A Leadless Cardiac Pacemaker. The New England Journal of
Medicine. 2016 Feb 11;374(6):593.
Wrong study
design.
29. Xiao Y, Zhou S, Liu Q. A Leadless Cardiac Pacemaker. The New England Journal of
Medicine. 2016 Feb 11;374(6):593-4.
Wrong study
design.
30. Dizon JM, Nazif TM, Hess PL, Biviano A, Garan H, Douglas PS, Kapadia S, Babaliaros V,
Herrmann HC, Szeto WY, Jilaihawi H, Fearon WF, Tuzcu EM, Pichard AD, Makkar R,
Williams M, Hahn RT, Xu K, Smith CR, Leon MB, Kodali SK. Chronic pacing and adverse
outcomes after transcatheter aortic valve implantation. Heart. 2015 Oct;101(20):1665-71.
Wrong
population.
31. Seifert M, Butter C. Evaluation of wireless stimulation of the endocardium, WiSE,
technology for treatment heart failure. Expert Review of Medical Devices. 2016
Jun;13(6):523-31.
Wrong study
design.
32. Austin C, Kusumoto F. Innovative pacing: Recent advances, emerging technologies, and
future directions in cardiac pacing. Trends in Cardiovascular Medicine. 2016 Jul;26(5):452-
63.
Wrong study
design.
63
33. Kypta A, Blessberger H, Lichtenauer M, Steinwender C. Dawn of a new era: the completely
interventionally treated patient. BMJ Case Reports. 2016 Mar 18.
Wrong study
design.
34. Bordachar P, Marquié C, Pospiech T, Pasquié JL, Jalal Z, Haissaguerre M, Thambo JB.
Subcutaneous implantable cardioverter defibrillators in children, young adults and patients
with congenital heart disease. International Journal of Cardiology. 2016 Jan 15;203:251-8.
Wrong
intervention.
35. Baruteau AE, Pass RH, Thambo JB, Behaghel A, Le Pennec S, Perdreau E, Combes N,
Liberman L, McLeod CJ. Congenital and childhood atrioventricular blocks: pathophysiology
and contemporary management. European Journal of Pediatrics. 2016 Jun 28.
Wrong research
question.
36. Tsiachris D, Tousoulis D. Conventional pacing system: It cannot be done better, it can only
change. Hellenic Journal of Cardiology. 2016 Mar-Apr;57(2):107-8.
Wrong study
design.
37. McCune C, McKavanagh P, Menown IB. A Review of the Key Clinical Trials of 2015:
Results and Implications. Cardiology and Therapy. 2016 Jun 8.
Wrong research
question.
38. Chan KH, McGrady M, Wilcox I. A Leadless Intracardiac Transcatheter Pacing System. The
New England Journal of Medicine. 2016 Jun 30;374(26):2604.
Wrong study
design.
39. Reynolds DW, Ritter P. A Leadless Intracardiac Transcatheter Pacing System. The New
England Journal of Medicine. 2016 Jun 30;374(26):2604-5.
Wrong study
design.
40. Kypta A, Blessberger H, Lichtenauer M, Steinwender C. Complete encapsulation of a
leadless cardiac pacemaker. Clinical Research in Cardiology. 2016 Jan;105(1):94.
Wrong study
design.
41. Kypta A, Blessberger H, Kammler J, Lichtenauer M, Lambert T, Silye R, Steinwender C.
First Autopsy Description of Changes 1 Year After Implantation of a Leadless Cardiac
Pacemaker: Unexpected Ingrowth and Severe Chronic Inflammation. Canadian Journal of
Cardiology. 2015 Dec 29.
Wrong
population.
42. Garweg C, Ector J, Willems R. Leadless cardiac pacemaker as alternative in case of
congenital vascular abnormality and pocket infection. Europace. 2016 Feb 18.
Wrong study
design.
43. Borgquist R, Ljungström E, Koul B, Höijer CJ. Leadless Medtronic Micra pacemaker almost
completely endothelialized already after 4 months: first clinical experience from an explanted
heart. European Heart Journal. 2016 Apr 7.
Background.
44. Reddy VY. A Leadless Cardiac Pacemaker. The New England Journal of Medicine. 2016 Feb
11;374(6):594.
Background.
64
APPENDIX 3: QUALITY ASSESSMENT OF SELECTED STUDIES
Quality assessment of the selected case series
Table VII. Quality assessment of the selected case series. LEADLESS I
(NCT01700244)
LEADLESS II
(NCT02030418)
Micra Transcatheter
Pacing Study
(NCT02004873)
Reference/ID [24,25] [33] [42,43]
Study objective
1. Is the hypothesis/aim/objective of the study
stated clearly in the abstract, introduction, or
methods section?
Yes Yes Yes
Study population
2. Are the characteristics of the participants
included in the study described?
Yes Yes Yes
3. Were the cases collected in more than one
centre?
Yes Yes Yes
4. Are the eligibility criteria (inclusion and
exclusion criteria) for entry into the study explicit
and appropriate?
Yes Yes Yes
5. Were participants recruited consecutively? Yes Yes Unclear
6. Did participants enter the study at similar point
in the disease?
No No No
Intervention and co-intervention
7. Was the intervention clearly described in the
study?
Yes Yes Yes
8. Were additional interventions (co-interventions)
clearly reported in the study?
No No No
Outcome measures
9. Are the outcome measures clearly defined in the
introduction or methods section?
Yes Yes Yes
10. Were relevant outcomes appropriately
measured with objective and/or subjective
methods?
Yes Yes Yes
11. Were outcomes measured before and after
intervention?
No No No
Statistical Analysis
12. Were the statistical tests used to assess the
relevant outcomes appropriate?
Yes Yes Yes
Results and Conclusions
13. Was the length of follow-up reported? Yes Yes Yes
14. Was the loss to follow-up reported? Yes Yes Yes
15. Does the study provide estimates of the random
variability in the data analysis of relevant
outcomes?
No No Yes
16. Are adverse events reported? Yes Yes Yes
17. Are the conclusions of the study supported by
results?
Yes Yes Yes
Competing interest and source of support
18. Are both competing interest and source of
support for the study reported?
Yes Yes Yes
Overall Risk of bias Low Low Low
65
The IHE checklist for case series
Case Series: 18-criteria checklist
Study objective
1.Is the hypothesis/ aim/ objective of the study stated
clearly in the abstract, introduction, or methods section?
Study population
2.Are the characteristics of the participants included in the
study described?
3.Were the cases collected in more than one centre?
4.Are the eligibility criteria (inclusion and exclusion
criteria) for entry into the study explicit and appropriate?
5.Were participants recruited consecutively?
6.Did participants enter the study at a similar point in the
disease?
Intervention and co-intervention
7.Was the intervention clearly described in the study?
8.Were additional interventions (co-interventions) clearly
reported in the study?
Outcome measure
9.Are the outcome measures clearly defined in the
introduction or methods section?
10.Were relevant outcomes appropriately measured with
objective and/or subjective methods?
11.Were outcomes measured before and after intervention?
Statistical analysis
12.Were the statistical tests used to assess the relevant
outcomes appropriate?
Results and conclusions
13.Was the lenght of follow-up reported?
14.Was the loss to follow-up reported?
15.Does the study design provide estimates of the random
variability in the data analysis of relevant outcomes?
16.Are adverse events reported?
17.Are the conclusions of the study supported by results?
Competing interests and sources of support
18.Are both competing interests and sources of support for
the study reported?
66
Quality assessment of the selected systematic reviews
Table VIII. Quality assessment of the selected systematic review (HTA).
Kisser, 2016 [15]
1.Was an ‘a priori’ design provided? Yes
2.Was there duplicate study selection and data extraction? CA
3.Was a comprehensive literature search performed? Yes
4.Was a status of publication (i.e. grey literature) used as an
inclusion criterion?
Yes
5.Was a list of studies (included and excluded) provided? No
6.Were the characteristics of the included studies provided? Yes
7.Was the scientific quality of the included studies assessed and
documented?
Yes
8.Was the scientific quality of the included studies used
appropriately in formulating conclusions?
Yes
9.Were the methods used to combine the findings of studies
appropriate?
No
10.Was the likelihood of publication bias assessed? No
11.Was the conflict of interest included? No
CA – can‘t answer.
67
The AMSTAR checklist for systematic reviews
1. Was an 'a priori' design provided?
The research question and inclusion criteria should be established before the conduct of the review.
Note: Need to refer to a protocol, ethics approval, or pre-determined/a priori published research objectives to score a “yes.”
□ Yes
□ No
□ Can't answer
□ Not applicable
2. Was there duplicate study selection and data extraction?
There should be at least two independent data extractors and a consensus procedure for disagreements should be in place.
Note: 2 people do study selection, 2 people do data extraction, consensus process or one person checks the other’s work.
□ Yes
□ No
□ Can't answer
□ Not applicable
3. Was a comprehensive literature search performed?
At least two electronic sources should be searched. The report must include years and databases used (e.g., Central,
EMBASE, and MEDLINE). Key words and/or MESH terms must be stated and where feasible the search strategy should be
provided. All searches should be supplemented by consulting current contents, reviews, textbooks, specialized registers, or
experts in the particular field of study, and by reviewing the references in the studies found.
Note: If at least 2 sources + one supplementary strategy used, select “yes” (Cochrane register/Central counts as 2 sources; a
grey literature search counts as supplementary).
□ Yes
□ No
□ Can't answer
□ Not applicable
4. Was the status of publication (i.e. grey literature) used as an inclusion
criterion?
The authors should state that they searched for reports regardless of their publication type. The authors should state whether
or not they excluded any reports (from the systematic review), based on their publication status, language etc.
Note: If review indicates that there was a search for “grey literature” or “unpublished literature,” indicate “yes.” SIGLE
database, dissertations, conference proceedings, and trial registries are all considered grey for this purpose. If searching a
source that contains both grey and non-grey, must specify that they were searching for grey/unpublished lit.
□ Yes
□ No
□ Can't answer
□ Not applicable
5. Was a list of studies (included and excluded) provided?
A list of included and excluded studies should be provided.
Note: Acceptable if the excluded studies are referenced. If there is an electronic link to the list but the link is dead, select
“no”.
□ Yes
□ No
□ Can't answer
□ Not applicable
6. Were the characteristics of the included studies provided?
In an aggregated form such as a table, data from the original studies should be provided on the participants, interventions and
outcomes. The ranges of characteristics in all the studies analyzed e.g., age, race, sex, relevant socioeconomic data, disease
status, duration, severity, or other diseases should be reported.
Note: Acceptable if not in table format as long as they are described as above.
□ Yes
□ No
68
□ Can't answer
□ Not applicable
7. Was the scientific quality of the included studies assessed and documented?
'A priori' methods of assessment should be provided (e.g., for effectiveness studies if the author(s) chose to include only
randomized, double-blind, placebo controlled studies, or allocation concealment as inclusion criteria); for other types of
studies alternative items will be relevant.
Note: Can include use of a quality scoring tool or checklist, e.g., Jadad scale, risk of bias, sensitivity analysis, etc., or a
description of quality items, with some kind of result for EACH study (“low” or “high” is fine, as long as it is clear which
studies scored “low” and which scored “high”; a summary score/range for all studies is not acceptable).
□ Yes
□ No
□ Can't answer
□ Not applicable
8. Was the scientific quality of the included studies used appropriately in formulating conclusions?
The results of the methodological rigor and scientific quality should be considered in the analysis and the conclusions of the
review, and explicitly stated in formulating recommendations.
Note: Might say something such as “the results should be interpreted with caution due to poor quality of included studies.”
Cannot score “yes” for this question if scored “no” for question 7.
□ Yes
□ No
□ Can't answer
□ Not applicable
9. Were the methods used to combine the findings of studies appropriate?
For the pooled results, a test should be done to ensure the studies were combinable, to assess their homogeneity (i.e., Chi-
squared test for homogeneity, I2). If heterogeneity exists a random effects model should be used and/or the clinical
appropriateness of combining should be taken into consideration (i.e., is it sensible to combine?).
Note: Indicate “yes” if they mention or describe heterogeneity, i.e., if they explain that they cannot pool because of
heterogeneity/variability between interventions.
□ Yes
□ No
□ Can't answer
□ Not applicable
10. Was the likelihood of publication bias assessed?
An assessment of publication bias should include a combination of graphical aids (e.g., funnel plot, other available tests)
and/or statistical tests (e.g., Egger regression test, Hedges-Olken).
Note: If no test values or funnel plot included, score “no”. Score “yes” if mentions that publication bias could not be
assessed because there were fewer than 10 included studies.
□ Yes
□ No
□ Can't answer
□ Not applicable
11. Was the conflict of interest included?
Potential sources of support should be clearly acknowledged in both the systematic review and the included studies.
Note: To get a “yes,” must indicate source of funding or support for the systematic review AND for each of the included
studies.
□ Yes
□ No
□ Can't answer
□ Not applicable
Shea et al. BMC Medical Research Methodology 2007 7:10 doi:10.1186/1471-2288-7-10
Additional notes (in italics) made by Michelle Weir, Julia Worswick, and Carolyn Wayne based on conversations with Bev
Shea and/or Jeremy Grimshaw in June and October 2008 and July and September 2010.
69
Checklist for potential ethical, organisational, social and legal aspects
1. Ethical
1.1. Does the introduction of the new technology and its potential use/nonuse instead of
the defined, existing comparator(s) give rise to any new ethical issues?
Yes
1.2. Does comparing the new technology to the defined, existing comparators point to any
differences which may be ethically relevant?
No
2. Organisational
2.1. Does the introduction of the new technology and its potential use/nonuse instead of
the defined, existing comparators require organisational changes?
Yes
2.2. Does comparing the new technology to the defined, existing comparators point to any
differences which may be organisationally relevant?
No
3. Social
3.1. Does the introduction of the new technology and its potential use/nonuse instead of
the defined, existing comparator(s) give rise to any new social issues?
No
3.2. Does comparing the new technology to the defined, existing comparators point to any
differences which may be socially relevant?
No
4. Legal
4.1. Does the introduction of the new technology and its potential use/nonuse instead of
the defined, existing comparator(s) give rise to any legal issues?
No
4.2. Does comparing the new technology to the defined, existing comparators point to any
differences which may be legally relevant?
No
