Download heart disease in kentucky ace inhibitors beta blockers

TREATMENT OF ADVANCED
HEART FAILURE
HEART DISEASE IN
KENTUCKY
Navin Rajagopalan,
j g
MD
Assistant Professor of Medicine
University of Kentucky
Director, Congestive Heart Failure
Medical Director of Cardiac Transplantation
November 1, 2009
TOPICS FOR DISCUSSION
ACE inhibitors & BetaBeta-blockers
ACE INHIBITORS
Diuretics
Standard therapy for heart failure
Best randomized trial data for captopril,
lisinopril, and enalapril
Cardiac resynchronization
Start low dose and titrate upwards to goal
– All are now generic
i and
d cheap!
h
!
Cardiac transplantation
BETA BLOCKERS
Standard therapy for heart failure
Best randomized trial data for metoprolol succinate
(Toprol XL) and carvedilol (Coreg)
–
–
–
–
Both are now generic
g
Start low dose and titrate upwards to goal
Toprol XL: 25 mg qd to 200 mg qd
carvedilol: 3.125 mg bid to 25 mg bid
COMET trial suggested better outcomes with carvedilol
than with metoprolol (although metoprolol tartrate was
used)
– Enalapril: 2.5 mg qd
qd--bid to 10
10--20 mg bid
– Lisinopril: 2.5 mg qd to 20
20--40 mg qd
ARB can be used if ACEi intolerant
ACE INHIBITORS AND BETABETA-BLOCKERS
ACE inhibitors are commonly instituted
first
– Beneficial effects of BB were found after use
of ACE inhibitors was standardstandard-care
– BB contraindicated if patients are significantly
volume overloaded
Is this titration scheme necessary?
1
ACE INHIBITORS AND BETABETA-BLOCKERS
Sliwa et al. (2004) evaluated initiation of therapy
with carvedilol either before (n=38) or after
(n=40) perindopril therapy in newly diagnosed
NYHA IIII-III HF patients
Alternative agent was added at 6 months (target
doses: carvedilol 25 mg bid, perindopril 8 mg qd)
ACE INHIBITORS AND BETABETA-BLOCKERS
Carvedilol first group
@ 12 mo:
– Better improvement
in NYHA class
– Better
B tt improvement
i
t
in LVEF
– Lower dose of
furosemide
– Higher dose of
carvedilol (43 17
mg vs. 33 18 mg)
Endpoint: LVEF and functional class at 1 year
Sliwa et al. JACC 2004;44:1825-30
ACE INHIBITORS AND BETABETA-BLOCKERS
CIBIS III study randomized 1010 patients
with class II
II--III systolic HF to monotherapy
with bisoprolol (target dose 10 mg qd) or
enalapril (target dose 10 mg bid) for 6
months, followed by their combination for
6-24 months
Primary end
end--point: mortality or
hospitalization
ACE INHIBITORS AND BETABETA-BLOCKERS
Not necessary that ACE inhibitors be used
before betabeta-blockers
Titration of both drugs can be
accomplished at the same time
Volume status needs to be managed
before betabeta-blockers are aggressively
titrated
ACE INHIBITORS AND BETABETA-BLOCKERS
Trend towards
better survival in
bisoprolol first group
Trend towards more
HF hospitalization in
bisoprolol first group
Safe and efficacious
to initiate CHF
treatment with beta
beta-blockers
ACE INHIBITORS
IS THE DOSE IMPORTANT?
ATLAS study randomized 3164 NYHA II
II-IV systolic HF patients to low dose
lisinopril (2.5 to 5.0 mg qd) or high dose
(32 5 to 35 mg qd)
(32.5
LVEF < 30%
No BB use (trial published in 1999)
2
ACE INHIBITORS
IS THE DOSE IMPORTANT?
High-dose group
Highhad a
nonsignificant 8%
lower risk of death
(p = 0.13)
Significant 12%
lower risk of death
or hospitalization
for any reason and
24% fewer
hospitalizations for
HF in high dose
group
ACE INHIBITORS
IS THE DOSE IMPORTANT?
Using dose that is similar to that used in clinical
trials has meaningful benefit over low dose
The differences between intermediateintermediate-dose and
high-dose lisinopril is likely to be small, if present
highat all
Is the same thing true of betabeta-blockers in heart
failure?
Packer et al. Circ 1999;100:2312-2318
BETA-BLOCKERS
BETAIS THE DOSE IMPORTANT?
McAlister et al. (2009)
performed a metameta-analysis
on 23 BB trials in systolic
HF to determine if the
survival benefits were
associated with BB dose
or the magnitude of heart
rate reduction
Medications: metoprolol
(5), carvedilol (9),
bisoprolol (3), bucindolol
(3), atenolol (1), and
nebivolol (2)
McAlister et al. Ann Intern Med 2009;150:784-94.
BETA BLOCKERS
IS THE DOSE IMPORTANT?
BETA-BLOCKERS
BETAIS THE DOSE IMPORTANT?
For every HR
reduction of 5
beats/min, a significant
18% reduction in the
risk of death occurred
No significant
relationship between
all--cause mortality and
all
BB dosing was
observed
McAlister et al. Ann Intern Med 2009;150:784-94.
MY OPINION
Other investigators have observed that HF patients with
higher baseline HR exhibit the greatest improvements in
LVEF with BB therapy and that greater reductions in HR
are associated with greater improvements in LVEF
If limited by BP, it is better to get a patient on
small doses of both classes of medications, as
opposed to a moderate dose of one
Optimal HR is unknown
A hi i maximal
Achieving
i ld
dose off BB iis lik
likely
l more
important than achieving maximal dose of ACE
inhibitor
If substantial HR reduction is achieved with lowlow-dose BB,
should you keep titrating?
Is there any benefit to using dosing higher than trial
doses if HR reduction is suboptimal?
If tolerated, discharge patients with both
medications, even if low dose
3
DIURETICS
Aldosterone antagonist (spironolactone)
Loop diuretics
SPIRONOLACTONE IN THE “REAL
WORLD”
Retrospective studies
have identified
inappropriate use of
spironolactone in patients
with renal insufficiencyy as
well as less than ideal
follow--up
follow
Bozkurt et al. in a
retrospective review of
104 pts reported 10%
rate of serious
hyperkalemia (K+ > 6)
SPIRONOLACTONE
RALES randomized
1663 systolic heart
failure patients (LVEF <
35%; NYHA class III/IV)
to spironolactone or
placebo
l
b
Serum Cr < 2.5, K < 5.0
Initial dose 25 mg qd,
increased to 50 mg qd if
no benefit, no side
effects
94 % on ACEi; 10% on
BB
LOOP DIURETICS
Loop diuretics (IV) are a mainstay of therapy for AHFS
– 75
75--80% in ADHERE received IV diuretics
Reduce left ventricular filling pressures
Reduce central venous pressure
40 mg furosemide = 20 mg torsemide = 1 mg
bumetanide
Bozkurt et al. JACC 2003; 41: 211-4.
PROBLEMS WITH DIURETICS
CARDIO--RENAL SYNDROME
CARDIO
Adverse neurohormonal activation
– Increased plasma renin, aldosterone, norepinephrine
Low cardiac output is not necessary
and many patients have preserved
LVEF (diastolic HF) and/or elevated
BP
In SOLVD trial, use of longlong-term diuretics was
associated with a 1
1.33
33 fold increase in risk of arrhythmic
death after correcting for other mortality risk factors
Registry of 1004 patients admitted
with CHF found worsening renal
function during hospitalization (Cr
rise > 0.3 mg/dl) in 27% which was
statistically associated with hospital
deaths and LOS > 10 days
Postdiuretic sodium rebound as a result of poor dietary
compliance
– Given short halfhalf-life of diuretics, there is a significant amount of
time where the tubular concentration of the diuretic is
subtherapeutic.
Gheorghiade et al. JACC 2009; 53: 557-73.
4
CARDIO--RENAL SYNDROME
CARDIO
CARDIO--RENAL SYNDROME
CARDIO
Animal studies have demonstrated that temporary
elevation of CVP can lead to worsened renal function via
congestion of the renal veins
Mullens et al.
al (JACC 2009) recently showed in 145
patients with AHFS that patients who developed
worsening renal function had greater CVP upon
admission as well as greater CVP following medical
therapy
– Renal function did not correlate with other hemodynamic
variables
Mullens et al. JACC 2009;53:589-96.
COMBATING DIURETIC
RESISTANCE
Addition of thiazide diuretic to a
loop diuretic results in greater
di
diuresis
i and
d naturesis
t
i than
th
increasing dose of loop diuretic
alone
COMBATING DIURETIC
RESISTANCE
Dormans et al. (JACC 1996) randomized 20 CHF patient
on high doses of oral lasix (> 250 mg/day) to intravenous
bolus therapy versus the same dose given as a
continuous infusion for 1 day
Urinary volume and urinary excretion of sodium were
both significantly greater at 8 hours and 24 hours in the
continuous infusion group (mean daily dose of 690 mg)
Less peak concentration with continuous infusion may
lessen risk of ototoxicity
Stewart JH et al. BMJ 1965; 5473: 1277-81
DOES THE CHOICE OF DIURETIC
MATTER?
DIURETICS
Use lowest dose possible to achieve effective diuresis
Oral torsemide may be better and more reliably
absorbed than either furosemide or bumetanide, with
more consistent bioavailability
Loop + thiazide combination and consideration of
continuous infusion are options for those difficult to
diurese
Furosemide in particular has variable absorption
Worsening renal function is a not a contraindication to
diuretic therapy
Response to intravenous doses likely to be similar
5
CARDIAC RESYNCHRONIZATION
THERAPY (CRT)
Biventricular
pacemaker / ICD
Left ventricular
dyssynchrony
prevalent in systolic
HF
Indicated in:
Right Atrial
Lead
Left Ventricular
Lead
– Chronic systolic HF
on optimal medical Rx
– NYHA class III/IV
– QRS duration > 120
seconds
Right Ventricular
Lead
CARDIAC RESYNCHRONIZATION
THERAPY (CRT)
CRT alone (without
ICD) improved
survival in chronic
class III/IV HF
patients
ti t with
ith QRS >
120 ms over OMT
Benefit greater in pts
with QRS duration >
160 msec
Cleland J et al. NEJM 2005; 352:1539-49
CRT
CRT IN NYHA I/II HEART FAILURE
Can CRT be utilized in patients with less severe
heart failure?
Previous studies have suggested that CRT can
lead to positive remodeling including
improvement in left ventricular endend-systolic
volumes
MADIT-CRT was designed to determine if CRT
MADITcould improve outcomes in NYHA II-II HF
patients with QRS duration > 130 ms
Benefit of CRT driven by significant
41% reduction in HF events over 2.4
years (no difference in mortality)
Benefit confined to those with QRS
duration > 150 msec
Moss AJ et al. NEJM 2009; 361
CRT
CARDIAC TRANSPLANTATION
Future guidelines may incorporate the
latest data suggesting benefit of CRT in
class I/II HF, particularly those with QRS
duration > 150 msec
Treatment option for systolic heart failure
refractory to maximal medical therapy
Li it d b
Limited
by supply
l off d
donor organs
Procedure does have increased risk
compared to ICD alone
– 3000
3000--4000 heart transplants / year in US
Extensive patient evaluation required
Cost effectiveness?
– Medical, psychosocial, insurance, etc.
6
TRANSPLANT EVALUATION
WHEN TO REFER
Symptoms limiting quality of life
Recurrent heart failure admissions despite maximal
therapy
W
Worsening
i endend
d-organ function
f
ti (renal,
(
l h
hepatic)
ti )
– Before they become irreversible
Refractory ventricular arrhythmias
For younger patients, may be useful to be “plugged” into
the system
Mehra MR et al. Listing Criteria for Heart Transplantation. J
Heart Lung Transplant 2006;25:1024-42.
ADULT HEART RECIPIENTS
ADULT HEART TRANSPLANTATION
Functional Status of Surviving Recipients
Kaplan--Meier Survival by Era (Transplants: 1/1982 – 6/2006)
Kaplan
100
(Follow--ups: 1995 - June 2006)
(Follow
100%
Surv
vival (%)
All comparisons significant at p < 0.0001
80
80%
60
60%
1982-1991 (N=18
(N=18,854)
854)
40
1992-2001 (N=35,146)
40%
2002-6/2006 (N=12,369)
20
20%
HALF-LIFE 1982-1991: 8.8 years; 1992-2001: 10.5 years; 2002-6/2006: NA
No Activity Limitations
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Years
ISHLT
2008
J Heart Lung Transplant 2008;27: 937-983
14
15
Performs with Some Assistance
Requires Total Assistance
0%
1 Year (N = 15,388)
ISHLT
3 Years (N = 13,600) 5 Years (N = 11,698)
2008
J Heart Lung Transplant 2008;27: 937-983
CONTRAINDICATIONS
7 Years (N = 9,306)
Last updated based on data as of December 2006
VAD
Active substance abuse
Lack of social support
Severe peripheral vascular disease
Severe lung disease
Active viral hepatitis / HIV
Recent malignancy
Option for patients with
end--stage HF and who are
end
not candidates for
transplantation, or who
cannot wait for transplant
Requires major
cardiothoracic surgery with
similar contraindications as
transplant
Devices are getting smaller
and safer
Rose EA et al. NEJM 2001;345:1435-43
7
REMATCH (2001)
DESTINATION L
L--VAD
Rose EA et al. NEJM 2001;345:1435-43
129 patients with endend-stage
CHF, 80% requiring IV
inotropic therapy,
randomized to medical
therapy versus HeartMate I
LVAD (pulsatile device)
Patients were not transplant
candidates
Cause of death in LVAD
group was predominantly
sepsis, LVAD failure, and
CVA
HEARTMATE II
Continuous flow rotary
pump
External drive line still
needed
Smaller size allows for
use in smaller patients,
females
Recent studies have
shown lower adverse
events (stroke, bleeding,
infection) compared to
older, larger devices
Pagani FD et al. JACC 2009;54:312-21
HEARTMATE II
WHAT ABOUT THE COST?
HM II device appears to be safe for bridge to
transplant and an improvement over older
pulsatile devices
No randomized study versus transplant
Learning curve is present
Outcomes not assessed after transplant –
does VAD prior to transplant constitute a risk
factor for poor outcome?
Hernandez et al. (JAMA, 2008) examined Medicare
data for patients who underwent VAD implant
between 2/2000 and 6/2006
Mean 11-year Medicare payments for inpatient care
was $178714 in the primary device group and
$111769 in the post
post--cardiotomy group
CONCLUSION
QUESTIONS?
– Primary device group (n = 1476)
– Post cardiotomy (n =1467)
1 year survival was 51.6% in the primary device
group and 30.8% in post
post--cardiotomy group
Advanced heart failure is a severe,
debilitating illness that requires a
multidisciplinary approach
Evidence based therapy is still underutilized
Referral for transplantation should be
considered in acceptable candidates
Navin Rajagopalan
Email: [email protected]
Phone: 800800-888888-5533 (UK MD)
Cell: 859859-317317-0775
8
For each of the following
medications used in chronic HF,
specify if they improve mortality,
worsen mortality, or are neutral
A.
B.
C.
D.
E.
Enalapril
Digoxin
Amlodipine
Dobutamine
Nesiritide
IMPROVE
NEUTRAL
NEUTRAL
WORSEN
????????
ACE INHIBITORS AND BETABETA-BLOCKERS
Which of the following statements is true about management of chronic
HF?
A.
B.
C.
D.
E.
DIURETICS IN HEART FAILURE
DEVICE THERAPY
48 year old female presents with progressive SOB
following mild viral illness
Subsequent echo shows dilated LV (LVEDD 6.8 cm) and
EF 20%
ECG shows LBBB which is old (p
(patient has known of
LBBB since age 25). QRS duration 150 msec
LHC showed no CAD
Started on carvedilol and lisinopril and medications are
titrated upwards
Symptoms improve and patient is back to baseline,
exercising, in NYHA class I
Repeat echo in 3 months shows LVEF 25%
Which of the following has proven mortality benefit
in patients with systolic heart failure?
A. Furosemide
B. Spironolactone
C. Torsemide
D. Chlortalidone
E. None of the above
DEVICE THERAPY
Patient is referred to Electrophysiology.
What device is recommended by the
current heart failure guidelines?
A. No device
ACE inhibitors should be started before beta blockers
Carvedilol is the only FDA approved betabeta-blocker for
heart failure
ACE inhibitors are contraindicated in HF patients with
serum creatinine > 2.0
Despite benefits seen with hydralazine / nitrates in
African Americans, African Americans with HF should
still be started on ACE inhibitors first
If a HF patient develops cough from ACE inhibitor, it is
advisable not to switch to an angiotensin receptor
blocker (ARB) given the lack of data using ARBs in
heart failure
CARDIAC TRANSPLANTATION
All of the following statements are true, except:
A.
Following cardiac transplantation, 5 year survival is 75% and 10
year survival is 50%
B
B.
History of drug abuse including smoking is a contraindication for
cardiac transplantation
C.
For patients who unable to receive a heart transplant in time, left
ventricular assist devices (VAD) can be utilized as a “bridge” to
transplantation
D.
Referral for heart transplantation should be considered if a patient
remains significantly limited despite optimal medical therapy
B. Dual chamber pacemaker
C. Biventricular pacemaker / ICD (i.e CRT)
D. Dual chamber ICD
9