Review
Copyright ©The Author(s) 2016.
World J Cardiol. Jul 26, 2016; 8(7): 401-412
Published online Jul 26, 2016. doi: 10.4330/wjc.v8.i7.401
Table 1 Clinical studies evaluating phosphodiesterase III inhibitors in heart failure
Ref.Aim of studyBackground beta blocker therapyStudy size n (total)HF symptomsTrial durationMajor findings/conclusionImpact of therapy on LVEFComplications/adverse eventsInotrope weaning rate
Packer et al[29], 1991Effect of oral milrinone on mortality of pts with symptomatic chronic HF on conventional therapyNo1088100% NYHA III-IV 42% NYHA IVMedian F/U duration 6.1 mo (stopped early due to adverse effects)28% increased mortality with milrinone (30% vs 24%)Not reportedSyncope palpitations hypotension headache blurry visionNot reported
Böhm et al[16], 1997Metoprolol restores the reduction of the inotropic effect of the cAMP-phosphodiesterase inhibitor milrinone, independent of beta-adrenoceptorYes (100%)15NYHA II or III6 moTreatment with metoprolol increased LVEF, fractional shortening and submaximal exercise tolerance and reduced heart rate, plasma norepinephrine concentrationsAddition of metoprolol improved EF (%) from 24.6 ± 1.5 to 40.3 ± 3.6Not reportedNot 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], 1998Clinical impact of combined therapy with enoximone and beta blockerYes (80%)30NYHA IVMean duration of combination therapy was 9.4 ± 1.8 mo; mean length of F/U was 20.9 ± 3.9 moCombination therapy with enoximone and beta blocker improved EF and functional status in severe HFLVEF 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 deaths48% were weaned off enoximone
Yamani et al[67], 2001Clinical outcome and economic cost of dobutamine-based and milrinone-based therapy in patients with ADHFYes 20% (18% milrinone grp)329 (60 milrinone grp)100% NYHA IVRetrospective review of ADHF admissionsNo difference in the in-hospital mortality rate or clinical outcomesNot reportedNo difference in adverse effects between the grps (20% pts in milrinone grp with either NSVT or VT)Not reported
Lowes et al[32], 2001Efficacy of milrinone vs dobutamine in patients with decompensated heart failure on chronic carvedilol therapyYes (100%)20100% NYHA II-IVAcute therapyDobutamine has less favorable hemodynamic effects in patients treated chronically with carvedilolNot reportedNot reportedNot reported
Kumar et al[33], 2001Carvedilol titration in NYHA class IIIb/IV on milrinone therapy as compared to class II/IIIa CHF without milrinoneYes (90%)32Class II-IVMean: 24 wkSuccessful 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 therapyNot reportedNo statistical difference in adverse events among the two grps53% patients were weaned off milrinone infusions in a mean of 8.4 ± 8.4 wk
Metra et al[13], 2002Hemodynamic effects of dobutamine and enoximone before and after 9-12 mo of beta-blocker therapy with metoprolol or carvedilol in chronic HFYes (100%)34NYHA II-IV9-12 moBeta blockers significantly inhibit the favorable hemodynamic response to dobutamine. No attenuation occurred with beta blockers and enoximoneNot reportedNot reportedNot reported
Cuffe et al[68], 2002Short-term milrinone in addition to standard therapy to improve outcomes in pts with ADHFYes (22%)94993% NYHA III-IVTreatment for up to 72 h, 60 d F/UMilrinone was associated with higher rate of treatment failure at 48 h due to AE (12.6% vs 2.1%)Not reportedHypotension, (SBP < 80 mmHg); 10.7% with milrinone Significant atrial arrhythmias during index hospitalization; 4.6%Not reported
Felker et al[30], 2003To assess the interaction between HF etiology and response to milrinone in ADHFYes (23%)94993% NYHA III-IVTreatment up to 72 h with 60 d F/UIn ischemic HF, milrinone was associated with worse outcomes: 60 d mortality or hospitalization: 42% vs 36% placebo; in-hospital mortality 5% vs 1.6% placeboNot reportedNo difference in atrial or ventricular arrhythmias and hypotension in both grpsNot 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], 2003Clinical outcomes and costs associated dobutamine vs milrinone in hospitalized pts awaiting cardiac transplantationYes (41% in dobutamine grp; 74% in milrinone grp)36Not reported presumably NYHA III-IVEnrollment 17 moNo difference between milrinone and dobutamine with respect to clinical outcomes or hemodynamic measuresNot reportedNo difference in death of length of hospital stayNot reported
Beta blocker use in dobutamine grp was associated with worsened pulmonary pressures and PCWP
Brozena et al[22], 2004Feasibility and safety of continuous IV milrinone therapy administered at home in pts listed as status IB for heart transplantYes (73%)60NYHA II-III Peak VO2 11.4 mL/kg per minute43 mo F/U88.3% of pts underwent OHT 3.2% died before transplantNot reported8% hospitalized for IV line infection1 pt weaned off based on clinical improvement
Abraham et al[69], 2005In-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 IV10/01-7/03Worse inpatient mortality and longer LOS with IV inotropesN/AN/AN/A
Feldman et al[70], 2007Whether low-dose oral enoximone could wean pts with end-stage HF from IV inotropic supportYes (40%)201100% NYHA III-IV26 wk30 d after weaning, 51% of placebo pts and 61.40% enoximone pts were alive and free of IV inotropic therapyNot reportedDyspnea, 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], 2007Six month risks of all-cause mortality and all-cause mortality plus rehospitalization associated with the use of vasodilators, inotropes, and their combinationsYes (62%)433; 75 (vasodilator); 133 (IV inotrope); 47 (both); 178 (neither inotrope/vasodilator)Mean peak VO2 10.0N/AWorse 6 mo mortality and either mortality/re-hospitalization with inotropes (whether alone or with vasodilator)Not reportedN/AN/A
Gorodeski et al[27], 2009Relationship between choice of dobutamine or milrinone and mortality in inotrope dependent stage D HF ptsYes [5% (dob) vs 34% (mil)]112Not reported presumably NYHA III-IVMedian F/U of 130 dHigher mortality in the dobutamine grp; No difference in mortality between inotrope type in propensity matched cohortNot reportedNot reportedNot reported
Metra et al[37], 2009Effects 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 therapyESSENTIALI Yes (83%) ESSENTIALII Yes (90%)ESSENTIALI: 904 ESSENTIALII: 950100% NYHA III-IVMedian F/U duration 16.6 moNo difference in first co-primary endpoints: All cause mortality, all-cause mortality and CV hospitalizationsNot reportedPalpitations 8% enoximone vs 5% placebo, P = 0.01N/A
Table 2 Hemodynamic parameters at baseline and after milrinone loading
Hemodynamic parametersPatient 1
Patient 2
Reference values
BaselinePost-milrinone loadingBaselinePost-milrinone loading
RA (mmHg)15155-7
RV (mmHg)54/15Dec-5815-30/1-5
PA (mmHg)53/33 (40)56/21 (34)61/37 (45)15-30/4-10; mean < 20
PA O2 saturation49.50%57%60%-80%
PCWP (mmHg)291530< 12
Cardiac output (L/min)5.17.13.364-8
Cardiac index (L/min per meter squared)2.12.951.643.032.6-4.2
PVR (WU)2.682.164.54< 3 WU
Hemoglobin (g/dL)10.210.211.713.5-17.5