Device Therapy in Heart Failure

1
Device Therapy in Heart Failure

Teresa M. Menendez Hood, M.D., F.A.C.C.
2
Heart Failure
Annual Incidence
Heart Failure Prevalence
Annual Mortality
5.0 million
400,000
250,000
U.S.

• Up to 30 of HF patients have an IVCD (80 with
  a LBBB) which has been linked to increases in
  mortality and morbidity.
• HF is the leading cause of hospitalizations in
  the US and uses up 5 of the health care costs
• 2 of the population and 6 of the population
  gt65
• Prevalence is on the rise.

3
Heart Failure Background
At Risk for Heart Failure Heart Failure
Stage A At high risk of HF but without structural heart disease or HF symptoms Stage C Structural heart disease with prior or current HF symptoms
Stage B Structural heart disease but without signs or symptoms of HF Stage D Refractory HF requiring specialized interventions
4
NYHA Class-evaluates the disability imposed on
the patient who already has structural heart
disease
Class I Asymptomatic heart failureejection
fraction (EF) lt40
Class II Mild symptomatic heart failure with
ordinary exertion
Class IV Symptomatic heart failure at rest
Class III Moderate symptomatic heart
failure with less than ordinary exertion
5
Stages of Heart Failure
6
Leading Causes of Death in the U.S.
Septicemia
You must combine deaths from all cancers to
outnumber the deaths from SCA each year.
Nephritis
Alzheimers Disease
Influenza/pneumonia
Diabetes
Accidents/injuries
Chronic lower respiratory diseases
Cerebrovascular disease
Other cardiac causes
Sudden cardiac arrest (SCA)
All other causes
All cancers
0
5
10
15
20
25
National Vital Statistics Report. Oct. 12,
200149(11). MMWR. State-specific mortality from
sudden cardiac death US 1999. Feb 15,
200251123-126.
7
SCD Rates in CHF Patients with LV Dysfunction
12 months
16 months
41.4 months
27 months
13 months
45 months
6 months
SCD accounts for 50 of the total deaths.
8
SCD in Heart Failure

• QRS duration is an independent predictor of
  mortality (gt140 ms)
• Other factors are age, creatinine, EF, and HR

QRS
100
Duration
(msec)
lt90
90
90
120
-
-
Cumulative Survival
80
120
170
-
-
170
220
-
-
70
gt220
60
0
60
120
180
240
300
360
Days
.
9
SCD in Heart Failure

• Degree of SCD risk by class
• Mortality in NYHA class II is 5 to 15
• 50 to 80 of the deaths are Sudden
• Mortality in NYHA class III is 20 to 50
• Up to 50 of the deaths are Sudden
• Mortality in NYHA class IV is 30 to 70
• 5 to 30 of deaths are Sudden (more deaths from
  pump failure)

10
Right Ventricular Pacing

• RV apex pacing is harmful in patients with LV
  dysfunction. Became evident in multiple pacer and
  ICD trials that it increases HF by producing a
  paced LBBB.
• Abnormal LV activation
• Reduced stroke volume

11
Detrimental RV pacing

• MADIT II (2002) had a survival benefit with the
  ICD but in a subgroup analysis, there was an
  increase in heart failure morbidity (more
  hospitalizations) felt due to forced RV pacing
  compared to controls in which no pacing was
  present.

12
MADIT II ComplicationsNew or Worsening HF

• RV pacing causes ventricular dysynchrony and may
  lead to worsening HF.
• Intrinsic ventricular activation is better for
  ICD patients with left ventricular dysfunction
  who do not need pacing.
• lt10 of ICD patients have a Class I pacing
  indication at the time of implantthey do not
  NEED pacing.
• Physicians, when appropriate, should consider
  programming of ICDs to avoid frequent RV pacing.

13

DAVID Dual Chamber and VVI Implantable
Defibrillator Trial 2002

• ICD indication but no indication for a pacemaker
• EF lt 40
• DDDR _at_ 70BPM versus VVI 40 BPM

14
Search AV Extension and Managed Ventricular
Pacing for Promoting Atrioventricular Conduction
(SAVE PACe) Trial 2007

• 1065 patients with sinus-node disease, intact AV
  conduction and normal QRS interval
• Randomized to conventional dual-chamber pacing
  (n535) or dual-chamber minimal ventricular
  pacing (n530)
• ? study tests new pacing algorithm that avoids
  ventricular pacing except during periods of
  high-grade AV block
• With dual-chamber pacing, ? frequency RV pacing
  (9.1 vs. 99 plt0.001) and 40 relative risk ?
  in incidence of persistent AF

15
The Concept

• In most patients with an IVCD (QRS gt 130 ms) ,
  the presence of atrial-biventricular (RV LV)
  pacing will provide early stimulation to an
  otherwise late segment of electrical activation
  in the LV.
• This should translate into an increase in the EF,
  decrease of the LV dimension, improvement in the
  QOL and NYHA class.
• This may translate into an decrease in CHF
  exacerbations , hospitalizations and a decrease
  in mortality.

16
The Proof

• 1994 1997 Mechanistic and both short and longer
  term observational studies. Studies initially
  used epicardial leads placed by thoracotomy or
  thorascope.
• The first BiV pacer was implanted in 1994
• 1998 1999 Randomized, controlled studies to
  assess exercise capacity, functional status, and
  quality of life.
• There was development of transvenous leads via
  the coronary sinus in to get to the LV.

Cohen TJ, Klein J. J Inva20021448-53.
17
The Proof

• 2000 2006 Randomized, controlled trials to
  assess combined mortality and CHF
  hospitalization. Also evaluated the combined
  benefit of ICDs with CRT.
• 2006-2008 Trials to identify patients who will
  benefit from CRT. This uses echocardiographic
  markers of dyssynchrony and the QRS measurement.
• 20 of patients do not respond to therapy in
  clinical trials with a wide QRS and 50 patients
  with a narrow QRS/CHF have dyssynchrony on echo
  and may benefit from this therapy.
• If the QRS is lt 150 ms, then the chance of
  responding to BiVP is 5. It will be in this
  patient group of QRS of 120-150 ms where
  preselection of responders would be most
  valuable.

18
The Cardiac Resynchronization Clinical Trials

• PATH-CHF, MUSTIC, MIRACLE, COMPANION, and
  CARE-HF
• This is not a complete list of all the CRT
  trials and the dates given are when the trial
  results were published.

19
Cumulative Enrollment in Cardiac
Resynchronization Randomized Trials
20
PATH-CHF 1999
Pacing Therapy for Congestive Heart Failure

• This was the first multicenter trial and used the
  standard endocardial RV lead and an epicardial LV
  lead via thoracotomy or thorascope
• Single blinded RCT
• 53 centers in Europe
• 41 patients

21
PATH-CHF

• Primary endpoints
• Peak VO2
• Six-minute walk distance
• Secondary endpoints
• Minnesota Living with Heart Failure score (QOL)
• NYHA class
• EF
• Trend towards decrease in Hospitalizations
• Acute hemodynamic testing revealed that the
  lateral and posterolateral walls were the best
  target sites.
• The best responders were those with QRSgt150 ,
  long PR and dP/dt lt 700 mm Hg/s

22
MUSTIC 2001Multicenter Stimulation in CM

• European study with 67 patients
• QRSgt150, CHF, EF lt35
• BiVP versus backup VVI pacing at 40 BPM
• Increase in 6 minute walk time , QOL and Peak
  VO2 with BiVP and persisted for up to 12 months
• 60 decrease in CHF hospitalizations
• First to use endocardial LV leads via the CS
• No significant change in mortality, but a trend
  towards an improvement.
• Acute hemodynamic studies showed the mid lateral
  wall to be the best site

23
MIRACLE2002Multi-center In Sync Randomized
Clinical Evaluation Trial

• Double blinded RCT
• First US trial
• Class 3 or 4, on OPT, QRS gt130 ms, EFlt35
• Enrollment of 453 patients

24
MIRACLE
25
MIRACLE
Nonresponders older, ischemic CM, no MR,
QRSlt150 Responders had shorter duration on CHF
and longer QRSgt155
26
MIRACLE

• There was a decrease in hospitalizations of 50
  at 6 months and a trend towards a decrease in
  mortality.
• All other primary and secondary endpoints were
  met 6 minute walk time, peak Vo2, QOL, EF , NYHA
  class, LVEDD
• Magnitude of improvement not influenced by
  degree of QRS shortening with BiVP (average in
  all was 20msec)

27
FDA Approval

• The first CRT device was approved by the FDA in
  September 2001 .
• The first CRT with an ICD was approved by the FDA
  in
• May 2002 .

28
The Primary ICD Prevention Trials

• MADIT 1 1996 required a positive EP
  studyischemics
• MUSTT 1999 required a positive EP study
  ischemics EFlt40
• MADIT 2 2002 prior MI (ischemic cardiomyopathy)
  and EFlt30 (no EP study required) 60 had CHF
  and 50 had QRS gt 120 ms resulted in a 31
  decrease risk of death and halted prematurely due
  to the positive effect of the ICD resulted in
  the FDA approving the ICD for primary prevention
  this patient population, but only those with a
  QRS gt 120 ms.

29
The Primary ICD Prevention Trials

• SCD-Heft - 2005 The SCD-Heft trial resulted in
  FDA approval of the ICD January 2005 in patients
  with CHF and EFlt35 that included both ischemic
  and nonischemic cardiomyopathy for primary
  prevention without a positive EP study or
  ventricular ectopy . No QRS cutoff was required.

30
COMPANION2004
Comparison of Medical Therapy, Pacing and
Defibrillation in Heart Failure
31
COMPANION

• Enrolled 1520 patients class 3 and 4, QRS gt120ms
• Primary endpoint death or hospitalization for
  any cause
• CRT met the primary endpoints and the CRT /- ICD
  significantly reduces mortality
• This was the first to show mortality benefit
  from CRT alone
• Showed that patients with CRT also benefit from
  ICD therapy
• OPT had SCD in 36, 23 in CRT and 3 in CRTICD

32
COMPANION

• CRT arm had 20 reduction in mortality and
  hospitalization over OPT arm but it was not
  statistically significant
• Significant reduction in CRT-ICD arm of 40 for
  mortality over OPT arm (19 in OPT and 11 in
  CRT-ICD group)
• Study was halted prematurely due to its positive
  benefit.
• Mean follow up was 16 months

33
CARE-HFCArdiac REsynchronization in Heart
Failure 2005

• The effect of cardiac resynchronization on
  morbidity and mortality in heart failure in 813
  patients in Europe ( prospective multicenter RCT)
  with completed enrollment by 2002
• Large patient size and length of trial (average
  follow up of 29 months) allowed ability to asses
  effects of CRT
• Looked at CRT alone (no ICD)
• Patients with class 3 or 4, EF lt 35, QRS gt120 ms
• There was a 37 reduced mortality or first
  hospitalization for a cardiac cause compared to
  OPT

34
CARE-HF

• All endpoints were met EF, NYHA, QOL, BNP, Echo
  and hemodynamic parameters
• 33 of the deaths in the CRT group were due to
  SCD
• For every 9 devices, one death and 3
  hospitalizations were prevented
• Echo criteria in patients with QRS 120-149ms to
  look for dyssynchrony (had to have 2 of 3)the
  gray area group
• Aortic pre-ejection delay of gt 140 ms ( onset of
  QRS to Aortic ejection)
• Interventricular mechanical delay of gt40 ms (
  RV-LV)
• Delayed activation of the postero-lateral LV wall
  (gt50ms)

35
Primary Endpoint(All-cause Mortality or
Unplanned Hosp. for Major CVS Event)
CRT 159 pts (39)
36
Conclusions

• Conclusive results from CARE-HF demonstrate that
  CRT should be considered as part of routine
  therapy for patients with moderate to severe HF
  due to LVSD with evidence (ECG supported by Echo)
  of cardiac dyssynchrony to
• Improve cardiac function and efficiency
• Improve symptoms and QoL
• Reduce morbidity
• Prolong survival
• These benefits are in addition to those of
  optimal pharmacological therapy (OPT)

37
The Resynchronization Therapy in Normal QRS
(RethinQ) Study2007
38
Background

• Currently, indications for cardiac
  resynchronization therapy (CRT) include QRS
  duration gt 120ms, LVEF lt 35 and NYHA
• Class III-IV.
• 20-30 of patients do not respond to CRT despite
  application of established selection criteria.
• Patients with normal conduction or a slightly
  prolonged QRS duration also exhibit mechanical
  abnormalities due to intraventricular
  dyssynchrony.
• Myocardial Tissue Doppler Imaging (TDI) allows
  both the velocity and timing of regional
  longitudinal motion to be measured.
• LV dyssynchrony may also be useful in predicting
  the benefit of CRT before implantation of the
  pulse generator.

39
Hypothesis

• We hypothesized that patients with NYHA class
  III, left ventricular ejection fraction less than
  or equal to 35, narrow QRS duration lt 130 ms,
  and evidence of mechanical dyssynchrony on
  echocardiography may benefit from cardiac
  resynchronization therapy.

40
Echo Criteria for LV Dyssynchrony

• Mechanical dyssynchrony considered present if
  either
• M-Mode
• - Septal posterior wall mechanical delay
  (SPWMD) 130 ms
• OR
• Tissue Doppler Imaging (TDI) of the basal
  ventricular
• segments in apical 4/2/3 chamber views
• 
  
• - Septal to lateral delay 65ms
• OR
• - Antero-septal to posterior delay 65ms

41
SummaryRethinQ

• This prospective, multi-center, randomized trial
  was designed to evaluate the effectiveness of CRT
  therapy in a HF population with narrow QRS
  duration and evidence of mechanical dyssynchrony.
• There was no statistical significant difference
  in the change in Peak VO2 between the treatment
  and control group during cardiopulmonary exercise
  testing.
• No improvement in other objective parameters
  including 6-minute walk test, LV reverse
  remodeling, and secondary endpoint - quality of
  life score .

42
ConclusionRethinQ

• CRT did not improve Peak VO2 during exercise in
  patients with NYHA Class III heart failure, QRS
  duration lt130ms, EF 35 and mechanical
  dyssynchrony as specified in this trial.
• While there was a statistically significant
  improvement of NYHA class, a secondary endpoint,
  there was no improvement in quality-of-life,
  6-minute walking test, or echocardiographic
  measures of reverse LV remodeling
• A subgroup of patients with QRS duration between
• 120 ms and 130 ms demonstrated an improvement
  from CRT, however patients with QRS duration lt
  120 ms did not demonstrate improvement
• The subgroup of patients stratified on the basis
  of cardiomyopathy etiology did not demonstrate an
  improvement in peak VO2.

43
PROSPECT TRIAL 5/2008

• Predictors of response to CRT
• 53 centers worldwide, 426 patients
• Patients had standard CRT indications (OMT, EF lt
  35, Class III-IV, QRS gt 130)
• 12 ECHO parameters of dyssynchrony
• 69 of patients clinically improved and 56
  showed a decrease in LVESV of gt15
• No single ECHO measure of dyssynchrony could help
  select responders to CRT

44
RAO is best to distinguish BASE position from
APEX
45
ANTERIOR
Anterior
LAO is best to distinguish LATERAL position
from SEPTAL
LATERAL
SEPTAL
Posterior Lateral
INFERIOR
46
LAO
47
The 3 levels of Dyssynchrony

1. Intraventricular dyssynchrony is best treated by
   placing the LV lead in the best anatomic
   location-usually the lateral or posterolateral
   (proven my multiple studies). Get the LV working.
2. Interventricular dyssynchrony is dealt with by
   adjusting the V-V interval. Get the RV and the LV
   to work together.
3. A-V dyssynchrony is dealt with by adjusting the
   A-V interval. Get the atria and the ventricles
   working together.

48
Posterolateral or Lateral walls are the best
with LBBB where the septum contracts first and
then the lateral wall last.
Paced at most mechanically delayed LV site
Paced at any other LV site
0
10
P0.04
-5
9
8
-9.2
-10
6
Improvement
-15
4
-20
2
-25
-28.4
P0.04
2
-30
0
Change in LV End-systolic Volume ml
Change in LVEF
49
CRT and Tissue Doppler Imaging -a measure of
intraventricular delay

• Measures dyssynchronous (delayed) contraction
  patterns _at_ different areas of the ventricle
• Measure from the onset of the QRS to the peak
  systolic shortening of that segment
• Defined as a segment with gt 50 ms delay this
  indicates intraventricular delay or asynchrony by
  ECHO criteria
• Colors green-yellow-red (the longest delay of
  gt300 ms)

50
V-V Timing synchronize the RV and the LV

• The best V-V setting by measuring the RVOT and
  LVOT via PW Doppler
• V-V above gt 40 ms is considered abnormal
• In normals, the RV will contract before the LV
  in the heart by -20 ms
• LV and RV have different outputs in the newer
  devices that allow sequential instead of
  simultaneous delivery of output and thus allow
  for this to be programmable.

51
AV Delay Optimization Methods

• Electrocardiographic
• COMPANION trial method
• Echocardiographic (combined)
• Aortic velocity time integral (VTI) methods
• Mitral velocity Doppler methodsE and A waves
• Ritter formula
• Hemodynamic measurements
• Pulse pressure method
• dP/dtmax method

52
Cardiac Resynchronization Therapy in Patients
With Severe Systolic Heart Failure2008 Guidelines

• For patients who have left ventricular ejection
  fraction (LVEF) less than or equal to 35, a QRS
  duration greater than or equal to 0.12 seconds,
  and sinus rhythm, cardiac resynchronization
  therapy (CRT) with or without an ICD is indicated
  for the treatment of New York Heart Association
  (NYHA) functional Class III or ambulatory Class
  IV heart failure symptoms on optimal recommended
  medical therapy.
• For patients who have LVEF less than or equal to
  35, a QRS duration greater than or equal to 0.12
  seconds, and AF, CRT with or without an ICD is
  reasonable for the treatment of NYHA functional
  Class III or ambulatory Class IV heart failure
  symptoms on optimal recommended medical therapy.
• For patients with LVEF less than or equal to 35
  with NYHA functional Class III or ambulatory
  Class IV symptoms who are receiving optimal
  recommended medical therapy and who have frequent
  dependence on ventricular pacing, CRT is
  reasonable.

53
Cardiac Resynchronization Therapy in Patients
With Severe Systolic Heart Failure 2008
Guidelines

• For patients with LVEF less than or equal to 35
  with NYHA functional Class I or II symptoms who
  are receiving optimal recommended medical therapy
  and who are undergoing implantation of a
  permanent pacemaker and/or ICD with anticipated
  frequent ventricular pacing, CRT may be
  considered.
• CRT is not indicated for asymptomatic patients
  with reduced LVEF in the absence of other
  indications for pacing.
• CRT is not indicated for patients whose
  functional status and life expectancy are limited
  predominantly by chronic noncardiac conditions.

54

• Indications for ICD Therapy
• 2008

55
Implantable Cardioverter-Defibrillators

• ICD therapy is indicated in patients who are
  survivors of cardiac arrest due to ventricular
  fibrillation or hemodynamically unstable
  sustained VT after evaluation to define the cause
  of the event and to exclude any completely
  reversible causes.
• ICD therapy is indicated in patients with
  structural heart disease and spontaneous
  sustained VT, whether hemodynamically stable or
  unstable.
• ICD therapy is indicated in patients with
  syncope of undetermined origin with clinically
  relevant, hemodynamically significant sustained
  VT or VF induced at electrophysiological study.

All primary SCD prevention ICD recommendations
apply only to patients who are receiving optimal
medical therapy and have reasonable expectation
of survival with good functional capacity for
more than 1 year.
56
Implantable Cardioverter-Defibrillators

• ICD therapy is indicated in patients with LVEF
  less than or equal to 35 due to prior MI who are
  at least 40 days post-MI and are in NYHA
  functional Class II or III.
• ICD therapy is indicated in patients with
  nonischemic DCM who have an LVEF less than or
  equal to 35 and who are in NYHA functional Class
  II or III.
• ICD therapy is indicated in patients with LV
  dysfunction due to prior MI who are at least 40
  days post-MI, have an LVEF less than or equal to
  30, and are in NYHA functional Class I.
• ICD therapy is indicated in patients with
  nonsustained VT due to prior MI, LVEF less than
  or equal to 40, and inducible VF or sustained VT
  at electrophysiological study.

All primary SCD prevention ICD recommendations
apply only to patients who are receiving optimal
medical therapy and have reasonable expectation
of survival with good functional capacity for
more than 1 year.
57
Implantable Cardioverter-Defibrillators

• ICD implantation is reasonable for patients with
  unexplained syncope, significant LV dysfunction,
  and nonischemic DCM.
• ICD implantation is reasonable for patients with
  sustained VT and normal or near-normal
  ventricular function.
• ICD implantation is reasonable for patients with
  HCM who have 1 or more major risk factors for
  SCD.
• ICD implantation is reasonable for the
  prevention of SCD in patients with arrhythmogenic
  right ventricular dysplasia/cardiomyopathy
  (ARVD/C) who have 1 or more risk factors for SCD.
  
• ICD implantation is reasonable to reduce SCD in
  patients with long-QT syndrome who are
  experiencing syncope and/or VT while receiving
  beta blockers.

All primary SCD prevention ICD recommendations
apply only to patients who are receiving optimal
medical therapy and have reasonable expectation
of survival with good functional capacity for
more than 1 year. See Section 3.2.4,
Hypertrophic Cardiomyopathy, in the full-text
guidelines for definition of major risk factors.
58
Implantable Cardioverter-Defibrillators

• ICD implantation is reasonable for
  nonhospitalized patients awaiting
  transplantation.
• ICD implantation is reasonable for patients with
  Brugada syndrome who have had syncope.
• ICD implantation is reasonable for patients with
  Brugada syndrome who have documented VT that has
  not resulted in cardiac arrest.
• ICD implantation is reasonable for patients with
  catecholaminergic polymorphic VT who have syncope
  and/or documented sustained VT while receiving
  beta blockers.
• ICD implantation is reasonable for patients with
  cardiac sarcoidosis, giant cell myocarditis, or
  Chagas disease.

All primary SCD prevention ICD recommendations
apply only to patients who are receiving optimal
medical therapy and have reasonable expectation
of survival with good functional capacity for
more than 1 year.
59
Implantable Cardioverter-Defibrillators

• ICD therapy may be considered in patients with
  nonischemic heart disease who have an LVEF of
  less than or equal to 35 and who are in NYHA
  functional Class I.
• ICD therapy may be considered for patients with
  long-QT syndrome and risk factors for SCD.
• ICD therapy may be considered in patients with
  syncope and advanced structural heart disease in
  whom thorough invasive and noninvasive
  investigations have failed to define a cause.
• ICD therapy may be considered in patients with a
  familial cardiomyopathy associated with sudden
  death.
• ICD therapy may be considered in patients with LV
  noncompaction.

All primary SCD prevention ICD recommendations
apply only to patients who are receiving optimal
medical therapy and have reasonable expectation
of survival with good functional capacity for
more than 1 year.
60
Implantable Cardioverter-Defibrillators

• ICD therapy is not indicated for patients who do
  not have a reasonable expectation of survival
  with an acceptable functional status for at least
  1 year, even if they meet ICD implantation
  criteria specified in the Class I, IIa, and IIb
  recommendations above.
• ICD therapy is not indicated for patients with
  incessant VT or VF.
• ICD therapy is not indicated in patients with
  significant psychiatric illnesses that may be
  aggravated by device implantation or that may
  preclude systematic follow-up.
• ICD therapy is not indicated for NYHA Class IV
  patients with drug-refractory congestive heart
  failure who are not candidates for cardiac
  transplantation or cardiac resynchronization
  therapy defibrillators (CRT-D).

All primary SCD prevention ICD recommendations
apply only to patients who are receiving optimal
medical therapy and have reasonable expectation
of survival with good functional capacity for
more than 1 year.
61
Implantable Cardioverter-Defibrillators

• ICD therapy is not indicated for syncope of
  undetermined cause in a patient without inducible
  ventricular tachyarrhythmias and without
  structural heart disease.
• ICD therapy is not indicated when VF or VT is
  amenable to surgical or catheter ablation (e.g.,
  atrial arrhythmias associated with the
  Wolff-Parkinson-White syndrome, RV or LV outflow
  tract VT, idiopathic VT, or fascicular VT in the
  absence of structural heart disease).
• ICD therapy is not indicated for patients with
  ventricular tachyarrhythmias due to a completely
  reversible disorder in the absence of structural
  heart disease (e.g., electrolyte imbalance,
  drugs, or trauma).

All primary SCD prevention ICD recommendations
apply only to patients who are receiving optimal
medical therapy and have reasonable expectation
of survival with good functional capacity for
more than 1 year.
62
Summary

• Large number of patients studied in multiple
  RCTs.
• CRT improves quality of life, exercise capacity,
  functional capacity, EF, peak VO2.
• CRT reduces the risk of mortality, worsening HF,
  and hospitalizations for CHF.
• CRT ICD significantly reduces risk of mortality.