Terapia farmacologica Lo scompenso cardiaco: certezze, incertezze e sfide.

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Terapia farmacologicaLo scompenso cardiaco
certezze, incertezze e sfide.

• Francesco Cosentino

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PATHOPHYSIOLOGY OF HEART FAILURE AND POLYPHARMACY
INOTROPIC AGENTS
ACE INHIBITORS - ARBs
Renal Perfusion ?
Cardiac Output ?
Neuro-hormonal Activation
Renin, angiotensin II ?
SNS Activation
Aldosterone
VASODILATATORS
Apoptosis, inflammation, hypertrophy, fibrosis
Vasocostrition
Retention of sodium and water
VENTRICULAR FUNCTION ?
Pre-load ? Increase of O2 consumption
DIURETICS
BETA BLOCKERS
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Effect of ACE Inhibitors on Mortality Reduction
in Patients With Heart Failure
Mortality
Trial
ACEI
Controls
RR (95 CI)
Chronic CHF
CONSENSUS I
39
54
0.56 (0.340.91)
SOLVD (Treatment)
40
35
0.82 (0.700.97)
SOLVD (Prevention)
15
16
0.92 (0.791.08)
Post-MI
SAVE
25
20
0.81 (0.680.97)
AIRE
17
23
0.73 (0.600.89)
TRACE
0.78 (0.670.91)
35
42
Average
23
27
Data shown from individual trialsnot direct
comparison data. Garg R et al. JAMA.
199527314501456. Pfeffer MA et al. N Engl J
Med. 1992327669677. The AIRE Study
Investigators. Lancet. 1993342821828. Køber L
et al. N Engl J Med. 199533316701676. The
SOLVD Investigators. N Engl J Med.
1992327685691.
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ACE Inhibitor Recommendations

• Recommended for all patients with current or
  prior symptoms of HF and reduced LVEF, unless
  contraindicated
• Indicated in all patients with a recent or remote
  history of MI regardless of LVEF or presence of
  HF
• Should be used in patients with a reduced LVEF
  and no symptoms of HF, even if they have not
  experienced an MI

Underlining represents changes from 2001
guidelines. Hunt SA, et al. ACC/AHA 2005
Practice Guidelines. Available at
http//www.acc.org.
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ARB Recommendations

• ARBs approved for the treatment of HF are
  recommended in patients with current or prior
  symptoms of HF and reduced LVEF who are
  ACEI-intolerant
• An ARB should be administered to post-MI patients
  without HF who are ACEI-intolerant and have a low
  LVEF
• Are reasonable to use as alternatives to ACEIs as
  first-line therapy for patients with mild to
  moderate HF and reduced LVEF, especially for
  patients already taking ARBs for other
  indications
• Can be beneficial in patients with low LVEF and
  no symptoms of HF who are ACEI-intolerant
• Addition of an ARB may be considered in
  persistently symptomatic patients with reduced
  LVEF who are already being treated with
  conventional therapy

Underlining represents changes from 2001
guidelines.Hunt SA, et al. ACC/AHA 2005 Practice
Guidelines. Available at http//www.acc.org.
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Combined All-cause Mortality and Morbidity
n5010
Event-free probability
100
95
90
85
13.3 risk reduction
80
75
Valsartan
Placebo
70
p0.009
65
0
0
3
6
9
12
15
18
21
24
27
Months
Cohn et al, N Engl J Med 2001
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VALIANT All-Cause Mortality
0.3
Captopril
Valsartan
0.25
Valsartan Captopril
0.2
0.15
Probability of Event
0.1
0.05
0
0
6
12
18
24
30
36
Months
Number at risk

Captopril 4,909 4,428 4,241 4,018 2,635 1,432 364
Valsartan 4,909 4,464 4,272 4,007 2,648 1,437 357
Val Cap 4,885 4,414 4,265 3,994 2,648 1,435 382
Valsartan vs captopril hazard ratio (HR)1.00
P.98. Valsartan captopril vs captopril
HR0.98 P.73. Pfeffer MA, et al. N Engl J Med.
20033491893-1906.
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CHARM-Alternative Primary Endpoint
CV death or HF hospitalization ()
50
Placebo
406 (40.0)
40
334 (33.0)
30
Candesartan cilexetil
20
HR 0.77, P0.0004
10
0
0
1
2
3
3.5
Time (years)
Number at risk Candesartan cil. Placebo
1013 1015
929 887
831 798
434 427
122 126
Granger CB, McMurray JJ, Yusuf S et al. Lancet
2003362(9386)772-6
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CHARM-Added Primary Endpoint
CV death or HF hospitalization ()
50
Placebo
538 (42.3)
40
483 (37.9)
30
Candesartan cilexetil
20
10
HR 0.85, P0.011
0
0
1
2
3
3.5
Time (years)
Number at risk Candesartan cil. Placebo
1276 1272
1176 1136
1063 1013
948 906
457 422
McMurray JJV, Ostergren J, Swedberg K et al.
Lancet. 2003362(9386)767-71
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Relative risk (RR) of adverse effects associated
with combined ACE-inhibitor/ARB therapy
Phillips CO et al. Arch Intern Med 2007
1671930-1936.
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?-Blocker Recommendations

• Use of 1 of the 3 proven to reduce mortality (ie,
  bisoprolol, carvedilol, and sustained release
  metoprolol succinate) is recommended for all
  stable patients with current or prior symptoms of
  HF and reduced LVEF, unless contraindicated
• Indicated in all patients with a recent or remote
  history of MI regardless of LVEF or presence of
  HF
• Indicated in all patients without a history of MI
  who have a reduced LVEF with no HF symptoms

C
Underlining represents changes from 2001
guidelines. Hunt SA, et al. ACC/AHA 2005 Practice
Guidelines. Available at http//www.acc.org.
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Addition of ?-Blockade to ACE Inhibition
Reduces Mortality in Heart Failure
US Carvedilol Trials
MERIT-HF
1.0
20
34 ?
Carvedilol (n696)
Placebo (n2,001)
P.0062 (adjusted)
15
0.9
Probability of Survival
Placebo(n398)
10
Cumulative Mortality ()
0.8
65 ?
Metoprolol CR/XL (n1,990)
Plt.001
5
0.7
0.0
0
0
100
200
300
400
600
0
400
300
200
100
500
Days
Days
COPERNICUS
CIBIS-II
100
Bisoprolol (n1,327)
90
Carvedilol (n1,156)
34 ?
80
35 ?
Placebo(n1,320)
Survival ()
Placebo (n1,133)
Survival
Plt.0001
70
P.0014 (adjusted)
60
0
18
0
12
9
6
3
15
21
Days
Months
Packer M, et al. N Engl J Med. 19963341349-1355.
MERIT-HF Study Group. Lancet. 19992532001-2007.
CIBIS-II Investigators. Lancet. 19993539-13.
Packer M, et al. N Engl J Med. 20013441651-1658.
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MOCHA Dose response study (carvedilol)
Ejection Fraction

Plt.001


??LVEF (EF units)
Placebo
25 mg bid
6.25 mg bid
12.5 mg bid
Carvedilol
P?.05 vs placebo.
Bristow et al. Circulation, 1996.
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MERIT-HF Achieved b-blocker dose vs outcomes
Wikstrand J, et al. Circulation. 2001
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LVESVI in REVERT reverse remodeling
Colucci WS et al Circulation 2007
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Aldosterone Blockade in Heart Failure
RALES Randomized Aldactone Evaluation Study
Spironolactone
100
Placebo
80
60
Probability of Survival ()
RR 0.70 (0.600.82)
40
Plt.001
20
0
0
10
20
30
36
Follow-up (months)
1663 pts NYHA II, III, and IV, average age 65 and
LVEF ?.35, on ACEI, loop diuretic, digoxin
randomized to spironolactone 25 mg PO qd vs
placebo.

Pitt B et al. N Engl J Med. 1999341709717.
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EPHESUS Relative Risk of Total Mortality
22
20
18
16
14
Placebo Eplerenone
Cumulative Incidence ()
12
10
RR 0.85 (95 CI, 0.75-0.96) P 0.008
8
6
4
2
0
36
33
30
27
24
21
18
15
12
9
6
3
0
Months Since Randomization
0
0
2
99
323
709
1213
1801
2418
2830
2983
3064
3313
Placebo
Eplerenone
0
0
0
110
336
728
1260
1857
2463
2896
3044
3125
3319
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Aldosterone Antagonist Recommendations

• Reasonable in selected patients with moderately
  severe to severe symptoms of HF and reduced LVEF
  who can be carefully monitored for preserved
  renal function and normal potassium
  concentration. Under circumstances where
  monitoring for hyperkalemia and renal dysfunction
  is not anticipated to be feasible, the risks may
  outweigh the benefits

Creatinine 2.5 mg/dL in men or 2.0 mg/dL in
women and K lt5.0 mEq/L.Underlining represents
changes from 2001 guidelines.Hunt SA, et al.
ACC/AHA 2005 Practice Guidelines. Available at
http//www.acc.org.
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Risk Factors for Hyperkalemia with the Useof
Drugs That Interfere with the ReninAngiotensinAl
dosterone System.

• Drugs used concomitantly that interfere in renal
  K excretion
• NSAIDs
• Beta-blockers
• cyclosporine, tacrolimus
• Heparin
• Ketoconazole
• Potassium supplements, including salt substitutes

• Chronic kidney disease
• Diabetes mellitus
• Decompensated CHF
• Volume depletion
• Advanced age

The risk is inversely related to the glomerular
filtration rate and increases substantially when
the rate is less than 30 ml per minute.
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Therapy of symptomatic chronic heart failure due
to systolic left ventricular dysfunction

• ARBs can be considered
• in combination with ACE-inhibitors in patients
  who remain symptomatic, to reduce mortality (B,
  IIa) and hospital admissions for HF (A, I)
• Aldosterone receptor antagonist is recommended
• in addition to ACE-inhibition, beta-blockers and
  diuretics in advanced HF (NYHA III-IV) to improve
  survival and morbidity (B,I)
• Is recommended in addition to ACE-inhibition and
  beta-blockade in HF after myocardial infarction
  with LVSD and signs of HF to reduce mortality and
  morbidity (B,I)
• Swedberg et al. ESC Guidelines for the diagnosis
  and treatment of chronic heart failure,
• Eur Heart J 2005

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Beneficial effects of aldosterone inhibition
override adverse effects

• Aldosterone inhibition may be associated to
  serious adverse effects ONLY when used
  inappropriately
• In patients with or at risk of hyperkalemia/renal
  failure
• Beyond approved indications
• Without proper monitoring
• At doses exceeding the safe dose range
• Combination of an ACE inhibitor/ARB and an
  aldosterone-receptor blocker should be avoided
  when the glomerular filtration rate is lt30 ml/min

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Cumulative Impact of Heart Failure Therapies
Relative-Risk 2 Year Mortality None - - 35 ACE
Inhibitor 23 27 Aldosterone Ant 30 19 Beta-Blo
cker 35 12 CRT /- ICD 36 8
Cumulative risk reduction if all four therapies
are used 77 Absolute risk reduction 27, NNT
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Updated from Fonarow GC. Rev Cardiovasc Med. 2000
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