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- oxigenare Hb - filtru (particule, bacterii) - eliminarea CO2 – echilibru acido-bazic
CIRCULATIA CIRCULATIA PULMONARA BRONSICA
Sange venos sange arteriala. pulmonara a. bronsiceCapilare Capilare
Vene pulmonare Vene sistemice
CIRCULATIA
PULMONARA NORMALA
PLAMANUL
Sunt fiziologic dr-stg
(pana la 30% din DC)
- bronsiectazii
- fibroza chistica
- boli congenitale
cardio-vasculare
CIRCULATIA BRONSICA
NORMALA SISTEMICE – media 20-25% din diam. vasuluiA. PULMONARE - media < 10- 5% din diam. vasuluiArteriolele pulmonare nu au tunica medie si nu contribuie
la rezistenta vasculara
VD – fluxul coronarian cel mai mare in sistola- depinde de gradientul pres. pulm. – aorta
Pres. VD creste – gradientul scade – fluxul coronar drept scade – ischemie VD
HIPERTENSIUNEA PULMONARA (HTP)
NORMALPRES. A. PULMONARA - sist. 18-25 mm Hg
- diast. 6-10 mm Hg- medie 12-16 mm Hg
PRES V. PULMONARE – 2-10 mm HgREZIST. VASC. PULM. = 1/10 din REZIST. SISTEMICA
HIPERTENSIUNEA PULMONARA (HTP)PRES. A. PULMONARA - sist. > 30-35 mm Hg
- medie > 20-25 mm Hg- diast. > 15 mm Hg
Reducerea calibrului vaselor pulmonare Cresterea fluxului
HIPERTENSIUNEA PULMONARA (HTP)
HIPOXIA VASOCONSTRICTIE PULMONARA
-histamina – receptori H1 vasculari
- endoteliu - echilibru NO – endoteline
- patrunderea Ca 2+ in celula musculara neteda
HIPOXIA CRONICA
1. Extensia musculaturii netede in peretele arterelor din periferia plamanilor
2. Ingrosarea peretilor arterelor musculare
3. Reducerea nr. arterelor – cresterea raportului alveole/artere
REACTIVITATEA VASCULARA PULMONARA
VASOCONSTRICTIEHipoxiaAcidozaProstaglandine F2α si A2
HISTAMINA – H1
SEROTONINA ?ANGIOTENSINA A2
ALTITUDINE
VASODILATATIEAlcalozaPROSTAGLANDINE I2 si EBLOCANTI αSTIMULARE β(ISOPROTERENOL)ACETILCOLINA (prin EDRF)HISTAMINA (prin H2 ?)
INDOMETACIN – creste rezistenta
pulmonara
La 10 000 m altitudine
TA pulmonara medie = 25 mm Hg in repaus
> 50 mm Hg in efort
1. HTP arteriala1.1. Idiopatica1.2. Ereditara1.3. Indusa de droguri si toxine1.4. Asociata cu:
Boli de colagenHIVHipertensiune portalaBoli cardiace congenitaleSchistosomiazaAnemie hemolitica cronica
1.5. HTP persistenta la nou nascut1’ Boala venoocluziva pulmonara si/sau hemangiomatoza capilara pulmonara
CLASIFICAREA HTPDana Point, 2008
2. HTP prin suferinta ventriculului stang
2.1. Disfunctie sistolica
2.2. Disfunctie diastolica
2.3. Boli valvulare
CLASIFICAREA HTPDana Point, 2008
3. HTP prin boli pulmonare sau hipoxie
3.1. BPOC
3.2. Boli interstitiale
3.3. Alte boli cu restrictie si obstructie
3.4. Apneea de somn
3.5. Boli cu hipoventilatie alveolara
3.6. Expunerea cronica la mare altitudine
3.7. Anomalii de dezvoltare fizica
CLASIFICAREA HTPDana Point, 2008
4. HTP prin tromboembolism
5. HTP prin factori multipli neclari
5.1. Boli hematologice: mieloproliferare, hipersplenism
5.2. Boli sistemice: sarcoidoza, histiocitoza pulmonaracu celule Langerhans
5.3. Boli metabolice: B. Gaucher, glicogenoze, disfunctiitiroidiene
5.4. Altele: obstructii tumorale, mediastinita fibrozanta,, IRC sau dializa
CLASIFICAREA HTPDana Point, 2008
In suferinta inimii stangi
PRESIUNE ATRIU STG = 7 mm Hg
scade rezistenta pulmonara (recrutare de vase)
>7 mmHg – creste presiunea in a. pulmonara (fluxul ramane constant; gradientul ramane constant)
> 25 mmHg – crestere disproportionata de presiune in a. pulmonara (gradientul creste; fluxul constant sau scade)
CATEVA MECANISME FIZIOPATOLOGICE
Variabilitatea reactivitatii vasculare pulmonare: creste presiunea venoasa – distrugere sau inchidere de cai
aeriene – hipoxie – creste presiunea in a. pulmonara creste presiunea venoasa – edem interstitial – rigidizarea
vaselor – HTP drenajul limfatic creste starea VD
normal hipertrofic insuficient miopatic (+ VS) hipoperfuzat (infarct)
Volumul sanguin pulmonar (depinde de debitul celor 2 ventriculi si de distensibilitatea vaselor pulmonare)
CATEVA MECANISME FIZIOPATOLOGICE
- Celule endoteliale capilare umflate
- Membrane bazale capilare ingrosate
- Edem interstitial
- Rupturi de membrane bazale – transudare de eritrocite –hemosideroza
- Alveole fibroase
- Destindere de limfatice
MODIFICARI ANATOMICE
Test Notable Findings
Chest x-ray Enlargement of central pulmonary arteries reflects level of PA pressure and duration.
Electrocardiography Right axis deviation and precordial T wave abnormalities are early signs.
Pulmonary function tests Elevated pulmonary artery pressure causes restrictive physiology.
Perfusion lung scan Nonsegmental perfusion abnormalities can occur from severe pulmonary vascular disease.
Chest computed tomography scan Minor interstitial changes may reflect diffuse disease; mosaic perfusion pattern indicates thromboembolism and/or left heart failure.
Echocardiography Right ventricular enlargement will parallel the severity of the pulmonary hypertension.
Contrast echocardiography Minor right to left shunting rarely produces hypoxemia.
Doppler echocardiography This is too unreliable for following serial measurements to monitor therapy.
Exercise testing This is very helpful to assess the efficacy of therapy. Severe exercise-induced hypoxemia should cause consideration of a right-to-left shunt.
TABLE 73-2 -- Clues for Interpretation of Diagnostic Tests for Pulmonary
Hypertension
Toate sunturile sistemico-pulmonare rezultand din mari defecte care duc la cresteri de presiune in VD sila inversarea suntului (pulmonar-sistemic) sau suntbidirectional cu: cianoza, eritrocitoza si multiple suferinte de organ
SINDROM EISENMENGER
GR. I : hipertrofia mediei artereor mici musculare
GR. II : + proliferarea intimei
GR. III: + fibroza concentrica cu obliterare de vase
GR. IV: “leziuni plexiforme”, dilatatii, trombi
GR. V: complexe plexiforme, leziuni angiomatoase si cavernoase si hialinizaea fibrozei intimale
GR. VI: arterita necrozanta
MODIFICARI ANATOMICE
Histopathology of endothelial cell lesions in
IPAH. A. Pulmonary artery showing medial
hypertrophy and lined by a single layer of
endothelial cells, as outlined by Factor VIII
related antigen immunostaining (arrow).
Plexiform lesion (outlined by the rim of
arrowheads) with the proximal vascular arterial
segment with marked intimal and medial
thickening by smooth muscle cells (arrow). Note
the proliferation of endothelial cells with the
outer edge (3–5 o’clock) occupied by dilated
blood vessel-like structures. C. Cross section of
a plexiform lesion, outlined by arrowheads. Note
perilesional inflammatory infiltrate (arrow). D.
High magnification histology of plexiform lesions
shown slit-like vascular channels lined by
hyperchromatic and cuboidal endothelial cells.
Cells in the core do not display distinct
cytoplamic borders. E. Low magnification
immunohistology with Factor VIII related antigen
immunohistochemistry of different endothelial
cell based vascular lesions. This area has re-
vascularized lesions (possibly an organized
thrombus), with well-formed and distinct small
capillaries/vessels (arrowhead), a plexiform
lesion (arrow), and dilated/angiomatoid lesions
(between arrowheads). F. High magnification
immunohistology of cellular plexiform lesion
stained with Factor VIII related antigen
(arrowheads). G and H. Histological
identification of plexiform and dilation lesions (G)
is markedly improved by Factor VIII related
antigen immunohistochemistry (H)
(arrowheads), while the parent vessel (arrow)
shows mild medial remodeling. I. Highlight of
vascular dilation/angiomatoid lesions with Factor
VIII related antigen immunohistochemistry. J.
Endothelial cells in plexiform lesion is
highlighted by CD34 immunohisochemistry
(arrowheads). Proximal pulmonary artery with
marked intima and medial thickening is
highlighted by the arrow. K and I. Endothelial
cells are highlighted by CD31
immunohistochemistyr (arrowheads). Note that
capillary endothelial cells express CD31 as well
(arrow in I),
A. Fibrotic, relatively paucicellular
intima thickening (outlined by
arrowheads) in a pulmonary artery
with the media highlighted with the
arrow. B. Marked intima remodeling
with almost complete obliteration by
fibrous tissue with a marked
intravascular and perivascular
inflammatory infiltrate (arrows). C.
Smooth muscle cell hypertrophy, with
prominent thickening of medial layer
(arrow). D. Highlight of medial
hypertrophy with smooth muscle α
actin immunohistochemistry. E.
Markedly remodeled pulmonary artery
with endothelial cell layer highlighted
by Factor VIII related antigen
immunohistochemistry. Note that the
intima and medial smooth muscle
cells are negative for Factor VIII
related antigen reactivity. F. Ingrowth
of smooth muscle cells in a plexiform
lesions, highlighted by smooth
muscle cell α actin
immunohistochemistry (arrow).
Veno-occlusive PH. A. Low-power histological view of thickened pulmonary veins running into the lung parenchyma from the
pleural surface (left edge) (arrows). Note marked vein wall thickening and decreased lumen. Adjacent alveoli are filled with blood
and show septal thickening with engorged capillaries (arrowhead). B. Marked vein thickening with intimal projection probably
representing organized thrombus (arrow). Alveolar hemorrhage and septal thickening are highlighted with arrowhead. C and D.
Movat stained pulmonary vein showing arterialization pattern with internal and external elastic layers (arrow). The vein shows
marked intima thickening with organized thrombus (arrowheads).
Normal Flux crescut in lobii inferiori
Gravitatie
Presiuni diferite intra –alveolare
Raport A/B = 1,2 : 1
CRESTEREA FLUXULUI PULMONARFLUX - Φ VASE x 8 (rezerva) +
Φ vase - flux + presiune
- presiune
Creste Φ venos
Rx – 1/3 ext. vascularizata
- Circ. Inf = circ. sup.
N – Φ a. pulm. desc. dr. = 10-15 mm la barbati si 9-14 mm la femei
Rx în HTP
HTP arteriala
- vasoconstrictie periferica
- vasospasm
- ingrosarea peretelui vascular
Rx- scade circulatia (creste transparenta) in 1/3 ext.
- vasele centrale elastice se largesc
- calcificari ale vaselor centrale
Rx în HTP
HTP de origine venoasa
P venoasa > 8 – 12 mm Hg
fluxul pulmonar este redistribuit spre lobii superiori
Rx – inversare a aspectului normal (cefalizarea fluxului arterial si venos)
P venoasa > 25 mm Hg Edem pulmonar
Rx în HTP
Mecanisme Sechestrarea de lichid interstitial in lobii inferiori
↓ Presiunea interstitiala ↑
↓ Complianta pulmonara ↓
↓ Fluxul spre lobii inferiori ↓
+ Spasm arterial
Fluxul este redistribuit spre lobii superiori
Rx în HTP
ETIOLOGIE Embolism pulmonar recurent, asimptomatic
Embolism amniotic
Tromboza in situ, tulburari de coagulare si fibrinoliza , contraceptive
Vasoconstrictie cronica → necroza fibrinoida → leziuni plexiforme
Vasculita generala cu fenomen Raynaud
Hipersensibilitate la droguri
Ingestia de fumarat de aminorex (anorexigen)
Hormoni feminini
HTP IDIOPATICA
MODIFICARI HISTOLOGICE Ingrosarea intimala a a. mici si arteriole cu fibroza in
“foi de ceapa”
Ingrosarea mediei a. musculare si muscularizarea arteriolelor
Arterita necrozanta cu necroza fibrinoida
Leziuni plexiforme → arteriopatie pulmonara plexogenica → umbre vasculare → reducerea patului vascular
HTP IDIOPATICA
HIPOXIE → raspuns anormal → disfunctie endoteliala
Modificarea raportului EDRF - endoteline
Distrugeri de endoteliu
Tromboza
Vasoconstrictie → necroza fibrinoida
Leziuni plexiforme
HTP IDIOPATICA
ASPECTE CLINICE
Femei tinere4 simptome principale
Dispnee de efort Accentuarea zgomotului II Modificari Rx – cardiomegalie
- a. pulmonara proeminenta Modificari ECG : - HVD
- deviatie axiala dr.- HAD
Mai rar:- Ameteli si sincope de efort- Dureri toracice de efort- Edeme
- Fenomene Raynaud- Ciroza hepatica- Istoric de tromboflebita superficiala
HTP IDIOPATICA
PROGNOSTIC
Prost (supravietuire peste 5 ani – 21%) Anticoagulantele imbunatatesc prognosticul
MOARTEA Insuficienta cardiaca congestiva Pneumonie Moarte subita Moarte la cateterism Disectie de a pulmonara
HEMOPTIZIA IN STADII TARDIVE Ruptura de leziuni plexiforme Tromboze in situ Embolism pulmonar
DUREREA TORACICA Ischemia subendocardului VD Distensia a pulmonare
HTP IDIOPATICA
SEMNE CLINICE Zgomot II intarit la pulmonara Suflu sistolic la pulmonara Semne de insuficienta cardiaca dreapta Semne de regurgitare triscuspidiana Cianoza - tardiv prin deschidere de foramen ovale Paralizie de recurent (rara)
HTP IDIOPATICA
LABORATOR - Uneori defecte de coagulare si fibrinoliza
ECG: HVD, HAD
Rx: largirea a pulmonare; marirea atriului si ventriculului dr
CT – Φ a pulmonare
TESTE FUNCTIONALE - Disfunctie restrictiva
ECHOCARDIOGRAFIAMarirea atriului si ventriculului dreptCavitati stangi normaleIngrosarea septuluiRegurgitare tricuspidiana si prolaps de valva mitrala secundare dilatatiei
de VD
HTP IDIOPATICA
SCINTIGRAFIA PULMONARA - normala
In stadii avansate poate fi daunatoare – trasorul legat de albumina –procoagulant
CATETERISMUL CARDIAC SI ANGIOGRAFIA RISCANTE
Presiunea in VD egala sau chiar mai mare decit presiunea sistemica
Rezistenta vasculara pulmonara depaseste uneori pe cea sistemica
Uneori foramen ovale este patent
Presiunile stg. sunt normale sau mici, dar uneori greu de determinat
BIOPSIA PULMONARA
HTP IDIOPATICA
HTP IDIOPATICA
DIAGNOSTIC DIFERENTIALHTP secundara (mai benigna si mai tratabila)
In sala de cateterism cardiac
PAPm dupa administrarea de NO inhalator (sau adenozina iv, epoprostenol iv sau inhalator)
Test + = reducerea cu 20% a PAPm sau a rezistentei vasculare pulmonare – bolnavul va primi vasodilatator indelungat
TESTUL VASODILATATOR
Supravietuirea medie in HTP netratata = 2,8 aniFactori de prognostic:Varsta < 14 ani sau 65 ani – prognostic prostClasa NYHA: I – II: supravietuire 6 ani in medie
III: supravietuire 2,5 ani in medieIV: supravietuire 0,5 ani in medie
Scaderea capacitatii de efortSincopaHemoptizieSemne de insuficienta ventriculara dreaptaO2 in a pulmonara > 63 – 55% supravietuire la 5 ani
< 63 – 17% supravietuire la 5 aniIndexul cardiac < 2,1 l/min/m2 supravietuire medie 17 luniPresiunea in AD < 10 mmHg - supravietuire 4 ani in medie
> 20 mmHg - supravietuire medie o lunaTest de vasodilatatie negativ
PROGNOSTICUL
1. Anticoagulantele
Warfarina dubleaza supravietuirea in HPP
Indicatiile anticoagularii permanente: toti pacientii cu HTPI
Tromboembolismul pulmonar (INR = 2-3)
HTP secundare, daca nu exista contraindicatii
2. OxigenoterapiaSe recomanda monitorizarea Sat O2 nocturna, Sat O2 < 90% in aerul atmosferic corectabila la administrarea de O2, indica oxigenoterapia nocturna
3. Tratamentul insuficientei ventriculare drepte:- Diuretice
- Digoxinul creste DC in administrarea acuta in HTPI, efectul sau in administrarea cronica este discutabil
TRATAMENTUL MEDICAL
4. Tratamentul vasodilatatorAntagonistii de Ca (diltiazem sau nifedipina):
HTP de tip arterial cu test vasodilatator pozitiv
CI in : HTP venoasa (precipita EPA)
HTP hipoxica din bolile cronice pulmonare cu Sat O2 in sangele venos < 63% (agraveaza hipoxemia)
PAD > 10 mm Hg
Index cardiac < 2,1 l/min/m2
TRATAMENTUL MEDICAL
Responders: Ca.-blockers
(if bradicardic)
Nifedipine :120 -240 mg
(if tahicardic)
Diltiazem 240-720 mg
Begin low dosage , increase weekly
Less than ½ of pts tolerate maximum dosage
5. Prostaglandinele – efectele pozitive ale tratamentului indelungat (min 3 luni)Reducerea rezistentei vasculare pulmonare
Cresterea indexului cardiac
Dublarea supravietuirii la 5 ani
Reducerea riscului si ameliorarea evolutiei dupa transplantul pulmonar
TRATAMENTUL MEDICAL (PG)
Indicatii
Bolnavii cu ICC cl III – IV, index cardiac < 2,1 l/min/m2 si/sau Sat O2 in artera pulmonara < 63% si/sau PAD > 10 mmHg, indiferent de testul vasodilatator
Toti bolnavii care nu raspund la tratamentul medical conventional, in asteptarea transplantului pulmonar
TRATAMENTUL MEDICAL
Efecte adverse:
Diaree, dureri abdominale, cefalee, flush, artralgii, dureri musculare
Ascita, edem pumonar (prin cresterea permeabilitatii vasculare)
Toleranta ce necesita cresterea dozelor
Rebound al HTP la intreruperea brusca a tratamentului
Infectii de cateter
TRATAMENTUL MEDICAL (PG)
Preparate folosite:
Epoprostenol = PGI2 iv. Se incepe cu 2 ng/kc/min in pev continua si se creste doza dupa o saptamana pana la doza maxima tolerata de pacient
Iloprost = analog al epoprostenolului, mai puternic iv (pev continua) sau in aerosoli, 6-9 inhalatii/zi (50 -200 μg/zi)
Trepostenil (UT – 15) este analog de PGI2. Doza initiala este de 1,25 ng/kc/min si se creste cu 1,25 ng/kc/min la 7 zile pana la 9,3 ng/kc/min
TRATAMENTUL MEDICAL (PG)
Beraprost: derivat stabil de PGI2, poate fi adminisrat p.o. 1 tb = 20μg. Se incepe cu 1 tb/zi si dupa 6 saptamani de titrare, se ajunge la 6 tb/zi (studiul ALPHABET). Rezultate bune in HTPI, neconcludente in HTP sec. Se pare ca nu este eficient in stadiile avansate de boala.
TRATAMENTUL MEDICAL (PG)
Prostanoid analogues
CTD= boala de tesut conjunctiv
Epoprostenolshort HL, temp.-dependent , i- v (infusion pump ) , local facilities
2-4ng/kg/min ..20-40 ( tolerance , rebound , adverse reactions: common)
>100.000 $ /year
Rubin LJ Ann. Intern.Med. 1990;112:485-92
Barst RJ N.Engl. J Med 1996;334:296-304
Badesch DB Ann. Intern.Med. 2000;132:425-34
3 month results: indic. surv/altern
Conversion to oral agents ??
Treprostenilsufficient chemical stability to be
administered at ambient temperature
allow iv / subcutaneous /oral ( bid )
and inhalatory adm.(6-9 d )
Beraprost
Orally :40-80microg qid/zi
efficacy does not appear to be sustained
with extended duration of therapy
Iloprost
Inhalations 6-12 times/d
(20-40 microg/d.)
Advant: selective to pulm.circ.
J Am CollCardiol. 2003 Jun 18;41(12): 2119–25
6. Antagonistii receptorilor de endotelinaBosentan (ET1RA) po. Doze: 62,5 mg de 2 ori/zi, pana la 125 mg de 2 ori/zi, timp de 16 saptamani.
TRATAMENTUL MEDICAL (ARE)
Endothelin receptor antagonists
Type A receptor :
vasoconstriction, proliferation, fibrosis.
Type B receptor (endotelial):
increases the synthesis of nitric oxide
( vasodilation )
Type B receptor (SMC):
activates aldosterone,
thromboxane, norepinephrine.
( vasoconstriction )
Bosentan ( Tracleer ) available in Romaniadual ETA and ETB-receptor antagonist
125 mg bid BREATHE-1BREATHE-3 (children )
10% liver enzimes > BREATHE -5 EARLY
Sitaxsentan6500 times greater affinity for the ETA STRIDE I and II
Chest , 2008; 134(4): 775 - 782.100-300 mg od 2004 : Level of evidence : BIncl .HTP in congenitals/CTD aproved in EuropeWarfarine interference
Ambrisentan ARIES-2 . Am J Respir Cirt Care Med. 2006;173: lower incidence of liver enzyme abnormality Ann. Pharmacother, 2008; 42(11): 1653 absence of significant drug interactions -
2004 : Level of evidence : C
7. Inhibitori de fosfodiesteraza (Sildenafil)
TRATAMENTUL MEDICAL (IFD)
Phosphodiesterase inhibitors
Sildenafil ( REVATIO )
25 mg t.i.d.
Available in Romania
Humbert M N Engl J Med 2004;351: 1425–36.
Type 5 Phosphodiesterase inhibitors
Vardenafil HCL ( Levitra ) Br J Pharmacol., 154(4):787-96. 2008 Apr 21
Tadalafil ( Cialis )longer half-life (17.50 hours )marketing approval began in late 2008
J Am Coll Cardiol, 2004; 44:1488-1496 Circulation. 2004;110:3149-3155
The three PDE5 inhibitors differ markedly in :
kinetics of pulmonary vasorelaxation (most rapid effect by vardenafil) selectivity for the pulmonary circulation (sildenafil and tadalafil, but
not vardenafil),
impact on arterial oxygenation (improvement with sildenafil only).
Septostomie atriala. Procedeu paleativ ce scade presiunea
in inima dreapta.
Indicatii: HTP severa, care nu raspunde la prostaglandine
Se exclud pacientii cu Insuf Ventr dr severa, disfunctie de VS sau in stare critica
Trombendarterectomie
Transplant pulmonar
TRATAMENTE CHIRURGICALE
Indicatii transplant
HTPI simptomatica, progresiva in ciuda tratamentului medical optim, cu test de mers de 6 min < 400 m, cu index cardiac < 2,1 l/min/m2 si/sau Sat O2 in artera pulmonara < 63% si/sau PAD > 10 mm Hg sau PAP m > 55 mmHg
TRATAMENTE CHIRURGICALE
Test vasodilatator acut
Raspuns +
Sv O2>63%, IC > 2,1
Raspuns -
NYHA I/II, Sv O2>63%,
IC > 2,1
NYHA III/IV, Sv O2<63%,
IC < 2,1
Blocanti de CaNu raspund la tratament
Prostaglandine
+/- transplant
Warfarina + diuretic + digoxin
Frequently asked questions
At which level of pulm .pressure should we begin pharmacological treatment in sec. PHT ?Adapted to etiology ! Unknown borderline !
Is it harmful to use CCB in nonresponders ?Yes , at least for high doses
ACCP Gd.: Level of evidence: expert opinion; benefit: substantial;
grade of recommendation: E/A.
Would it be better to use the more active drugsfor responders also ?
Probably yes , but economically unwise
Frequently asked questions
How useful is multiple drug therapy
Which order of introduction /doses ?
BREATHE -2
Is atrial septostomy an option ?
Rarely (bridge to… ) ; 5-15% mortality
CONCLUSIONS
PPHT pts to be treated in dedicated centers
New therapies available ; debate on results
Combination therapy in developpement
Rapid change of recomandations /guidelines
Cost –effectiveness analysis vital
Hard end points-including mortality may be influenced