Novel role of phosphodiesterase inhibitors in the management of end-stage heart failure

Table 1 Clinical studies evaluating phosphodiesterase III inhibitors in heart failure

Ref.	Aim of study	Background beta blocker therapy	Study size n (total)	HF symptoms	Trial duration	Major findings/conclusion	Impact of therapy on LVEF	Complications/adverse events	Inotrope weaning rate
Packer et al[29], 1991	Effect of oral milrinone on mortality of pts with symptomatic chronic HF on conventional therapy	No	1088	100% NYHA III-IV 42% NYHA IV	Median F/U duration 6.1 mo (stopped early due to adverse effects)	28% increased mortality with milrinone (30% vs 24%)	Not reported	Syncope palpitations hypotension headache blurry vision	Not reported
Böhm et al[16], 1997	Metoprolol restores the reduction of the inotropic effect of the cAMP-phosphodiesterase inhibitor milrinone, independent of beta-adrenoceptor	Yes (100%)	15	NYHA II or III	6 mo	Treatment with metoprolol increased LVEF, fractional shortening and submaximal exercise tolerance and reduced heart rate, plasma norepinephrine concentrations	Addition of metoprolol improved EF (%) from 24.6 ± 1.5 to 40.3 ± 3.6	Not reported	Not reported
						After metoprolol treatment, milrinone increased fractional shortening but had no effect before beta-blocker treatment
						Effect of dobutamine was completely antagonized by treatment with metoprolol
Shakar et al[12], 1998	Clinical impact of combined therapy with enoximone and beta blocker	Yes (80%)	30	NYHA IV	Mean duration of combination therapy was 9.4 ± 1.8 mo; mean length of F/U was 20.9 ± 3.9 mo	Combination therapy with enoximone and beta blocker improved EF and functional status in severe HF	LVEF increased from 17.7 ± 1.6% to 27.6 ± 3.4% (P = 0.01) NYHA improved from 4 to 2.8 (P = 0.0001)	2 sudden deaths	48% were weaned off enoximone
Yamani et al[67], 2001	Clinical outcome and economic cost of dobutamine-based and milrinone-based therapy in patients with ADHF	Yes 20% (18% milrinone grp)	329 (60 milrinone grp)	100% NYHA IV	Retrospective review of ADHF admissions	No difference in the in-hospital mortality rate or clinical outcomes	Not reported	No difference in adverse effects between the grps (20% pts in milrinone grp with either NSVT or VT)	Not reported
Lowes et al[32], 2001	Efficacy of milrinone vs dobutamine in patients with decompensated heart failure on chronic carvedilol therapy	Yes (100%)	20	100% NYHA II-IV	Acute therapy	Dobutamine has less favorable hemodynamic effects in patients treated chronically with carvedilol	Not reported	Not reported	Not reported
Kumar et al[33], 2001	Carvedilol titration in NYHA class IIIb/IV on milrinone therapy as compared to class II/IIIa CHF without milrinone	Yes (90%)	32	Class II-IV	Mean: 24 wk	Successful carvediolol uptitration in NYHA III-b/IV can be achieved at similar rates as in NYHA II/IIIa in the presence of stable chronic milrinone therapy	Not reported	No statistical difference in adverse events among the two grps	53% patients were weaned off milrinone infusions in a mean of 8.4 ± 8.4 wk
Metra et al[13], 2002	Hemodynamic effects of dobutamine and enoximone before and after 9-12 mo of beta-blocker therapy with metoprolol or carvedilol in chronic HF	Yes (100%)	34	NYHA II-IV	9-12 mo	Beta blockers significantly inhibit the favorable hemodynamic response to dobutamine. No attenuation occurred with beta blockers and enoximone	Not reported	Not reported	Not reported
Cuffe et al[68], 2002	Short-term milrinone in addition to standard therapy to improve outcomes in pts with ADHF	Yes (22%)	949	93% NYHA III-IV	Treatment for up to 72 h, 60 d F/U	Milrinone was associated with higher rate of treatment failure at 48 h due to AE (12.6% vs 2.1%)	Not reported	Hypotension, (SBP < 80 mmHg); 10.7% with milrinone Significant atrial arrhythmias during index hospitalization; 4.6%	Not reported
Felker et al[30], 2003	To assess the interaction between HF etiology and response to milrinone in ADHF	Yes (23%)	949	93% NYHA III-IV	Treatment up to 72 h with 60 d F/U	In ischemic HF, milrinone was associated with worse outcomes: 60 d mortality or hospitalization: 42% vs 36% placebo; in-hospital mortality 5% vs 1.6% placebo	Not reported	No difference in atrial or ventricular arrhythmias and hypotension in both grps	Not reported
						In nonischemic HF, benefit was derived from milrinone:
						60 d mortality or hospitalization: 28% vs 35% placebo; in-hospital mortality 2.6% vs 3.1% placebo
Aranda et al[23], 2003	Clinical outcomes and costs associated dobutamine vs milrinone in hospitalized pts awaiting cardiac transplantation	Yes (41% in dobutamine grp; 74% in milrinone grp)	36	Not reported presumably NYHA III-IV	Enrollment 17 mo	No difference between milrinone and dobutamine with respect to clinical outcomes or hemodynamic measures	Not reported	No difference in death of length of hospital stay	Not reported
						Beta blocker use in dobutamine grp was associated with worsened pulmonary pressures and PCWP
Brozena et al[22], 2004	Feasibility and safety of continuous IV milrinone therapy administered at home in pts listed as status IB for heart transplant	Yes (73%)	60	NYHA II-III Peak VO2 11.4 mL/kg per minute	43 mo F/U	88.3% of pts underwent OHT 3.2% died before transplant	Not reported	8% hospitalized for IV line infection	1 pt weaned off based on clinical improvement
Abraham et al[69], 2005	In-hospital mortality in ADHF pts receiving treatment with 1 of 4 vasoactive meds (NTG, nesiritide, milrinone, dobutamine)	Yes (56% milrinone grp)	2021 (milrinone)	100% NYHA IV	10/01-7/03	Worse inpatient mortality and longer LOS with IV inotropes	N/A	N/A	N/A
Feldman et al[70], 2007	Whether low-dose oral enoximone could wean pts with end-stage HF from IV inotropic support	Yes (40%)	201	100% NYHA III-IV	26 wk	30 d after weaning, 51% of placebo pts and 61.40% enoximone pts were alive and free of IV inotropic therapy	Not reported	Dyspnea, 5% enoximone vs 0% placebo, P < 0.05
						At 60 d, the wean rate was 30% in placebo grp and 46.5% in enoximone grp Kaplan-Meier curves demonstrated a trend towards decreased in time to death or reinitiation of IV inotropic therapy over the 182-d study period and a reduction at 60 d and 90 d after weaning in the enoximone grp
Elkayam et al[71], 2007	Six month risks of all-cause mortality and all-cause mortality plus rehospitalization associated with the use of vasodilators, inotropes, and their combinations	Yes (62%)	433; 75 (vasodilator); 133 (IV inotrope); 47 (both); 178 (neither inotrope/vasodilator)	Mean peak VO2 10.0	N/A	Worse 6 mo mortality and either mortality/re-hospitalization with inotropes (whether alone or with vasodilator)	Not reported	N/A	N/A
Gorodeski et al[27], 2009	Relationship between choice of dobutamine or milrinone and mortality in inotrope dependent stage D HF pts	Yes [5% (dob) vs 34% (mil)]	112	Not reported presumably NYHA III-IV	Median F/U of 130 d	Higher mortality in the dobutamine grp; No difference in mortality between inotrope type in propensity matched cohort	Not reported	Not reported	Not reported
Metra et al[37], 2009	Effects of low dose enoximone on symptoms, exercise capacity, and major clinical outcomes in pts with advanced HF who were also treated with beta blockers and other guideline recommended background therapy	ESSENTIALI Yes (83%) ESSENTIALII Yes (90%)	ESSENTIALI: 904 ESSENTIALII: 950	100% NYHA III-IV	Median F/U duration 16.6 mo	No difference in first co-primary endpoints: All cause mortality, all-cause mortality and CV hospitalizations	Not reported	Palpitations 8% enoximone vs 5% placebo, P = 0.01	N/A

AE: Adverse event; dob: Dobutamine; F/U: Follow-up; grp: Group; HF: Heart failure; mil: Milrinone; NYHA: New York Heart Association; OPTIME-CHF: The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure study; OHT: Orthotopic heart transplant; PCWP: Pulmonary capillary wedge pressure; pts: Patients; SBP: Systolic blood pressure; IV: Intravenous; cAMP: Cyclic adenosine monophosphate; ADHF: Acute decompensated heart failure; CV: Cardiovascular; LVEF: Left ventricular ejection fraction; LOS: Length of stay; EF: Ejection fraction; NSVT: Non sustained ventricular tachyarrhythmia; NTG: Nitroglycerin; VT: Ventricular tachyarrhythmia; VO₂: Peak oxygen consumption; ADHERE: The Acute Decompensated Heart Failure National Registry; EMOTE: The EnoxiMone in intravenous inOTropE-dependent subjects study.

Table 2 Hemodynamic parameters at baseline and after milrinone loading

Hemodynamic parameters	Patient 1		Patient 2		Reference values
	Baseline	Post-milrinone loading	Baseline	Post-milrinone loading
RA (mmHg)	15		15		5-7
RV (mmHg)	54/15		Dec-58		15-30/1-5
PA (mmHg)	53/33 (40)	56/21 (34)	61/37 (45)		15-30/4-10; mean < 20
PA O2 saturation	49.50%		57%		60%-80%
PCWP (mmHg)	29	15	30		< 12
Cardiac output (L/min)	5.1	7.1	3.3	6	4-8
Cardiac index (L/min per meter squared)	2.1	2.95	1.64	3.03	2.6-4.2
PVR (WU)	2.68	2.16	4.54		< 3 WU
Hemoglobin (g/dL)	10.2	10.2	11.7		13.5-17.5

PA: Pulmonary artery; PCWP: Pulmonary capillary wedge pressure; PVR: Pulmonary vascular resistance; RA: Right atrial; RV: Right ventricle; WU: Wood units.