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Meta-Analysis
. 2005 Jan 25;2005(1):CD002230.
doi: 10.1002/14651858.CD002230.pub2.

Phosphodiesterase III inhibitors for heart failure

E Amsallem, C Kasparian, G Haddour, J P Boissel, P Nony
Meta-Analysis

Phosphodiesterase III inhibitors for heart failure

E Amsallem et al. Cochrane Database Syst Rev. .

Abstract

Background: In the treatment of chronic heart failure, vasodilating agents, ACE inhibitors and beta-blockers have shown an increase of life expectancy. Another strategy is to increase the inotropic state of the myocardium : phosphodiesterase inhibitors (PDIs) act by increasing intra-cellular cyclic AMP, thereby increasing the concentration of intracellular calcium, and lead to a positive inotropic effect.

Objectives: This overview on summarised data aims to review the data from all randomised controlled trials of PDIs III versus placebo in symptomatic patients with chronic heart failure. The primary endpoint is total mortality. Secondary endpoints are considered such as cause-specific mortality, worsening of heart failure (requiring intervention), myocardial infarction, arrhythmias and vertigos. We also examine whether the therapeutic effect is consistent in the subgroups based on the use of concomitant vasodilators, the severity of heart failure, and the type of PDI derivative and/or molecule. This overview updates our previous meta-analysis published in 1994.

Search strategy: Randomised trials of PDIs versus placebo in heart failure were searched using MEDLINE (1966 to 2004 January), EMBASE (1980 to 2003 December), Cochrane CENTRAL trials (The Cochrane Library Issue 1, 2004) and McMaster CVD trials registries, and through an exhaustive handsearching of international abstracting publications (abstracts published in the last 22 years in the "European Heart Journal", the "Journal of the American College of Cardiology" and "Circulation").

Selection criteria: All randomised controlled trials of PDIs versus placebo with a follow-up duration of more than three months.

Data collection and analysis: 21 trials (8408 patients) were eligible for inclusion in the review. 4 specific PDI derivatives and 8 molecules of PDIs have been considered.

Main results: As compared with placebo, treatment with PDIs was found to be associated with a significant 17% increased mortality rate (The relative risk was 1.17 (95% confidence interval 1.06 to 1.30; p<0.001). In addition, PDIs significantly increase cardiac death, sudden death, arrhythmias and vertigos. Considering mortality from all causes, the deleterious effect of PDIs appears homogeneous whatever the concomitant use (or non-use) of vasodilating agents, the severity of heart failure, the derivative or the molecule of PDI used.

Authors' conclusions: Our results confirm that PDIs are responsible for an increase in mortality rate compared with placebo in patients suffering from chronic heart failure. Currently available results do not support the hypothesis that the increased mortality rate is due to additional vasodilator treatment. Consequently, the chronic use of PDIs should be avoided in heart failure patients.

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Conflict of interest statement

None known.

Figures

1
1
Exploration of heterogeneity between PDI trials for total mortality. Relative risk, Fixed model ‐ Radial plot . The VSG 1993 trial is outside of the limits of homogeneity of the treatment effect. This illustrates the heterogeneity introduced by this trial for total mortality.
2
2
Exploration of heterogeneity between PDI trials for cardiac death. Relative risk, fixed model ‐ Radial plot. The VSG 1993 trial is outside of the limits of homogeneity of the treatment effect. This illustrates the heterogeneity introduced by this trial for cardiac death.
1.1
1.1. Analysis
Comparison 1 Phosphodiesterase inhibitor vs Placebo, Outcome 1 Total mortality.
1.2
1.2. Analysis
Comparison 1 Phosphodiesterase inhibitor vs Placebo, Outcome 2 Cardiac death.
1.3
1.3. Analysis
Comparison 1 Phosphodiesterase inhibitor vs Placebo, Outcome 3 Sudden death.
1.4
1.4. Analysis
Comparison 1 Phosphodiesterase inhibitor vs Placebo, Outcome 4 Worsening heart failure (requiring intervention).
1.5
1.5. Analysis
Comparison 1 Phosphodiesterase inhibitor vs Placebo, Outcome 5 Myocardial Infarction.
1.6
1.6. Analysis
Comparison 1 Phosphodiesterase inhibitor vs Placebo, Outcome 6 Cardiac Transplantation.
1.7
1.7. Analysis
Comparison 1 Phosphodiesterase inhibitor vs Placebo, Outcome 7 Arrhythmias.
1.8
1.8. Analysis
Comparison 1 Phosphodiesterase inhibitor vs Placebo, Outcome 8 Vertigo.
2.1
2.1. Analysis
Comparison 2 Molecule type (sub‐groups), Outcome 1 Total mortality.
2.2
2.2. Analysis
Comparison 2 Molecule type (sub‐groups), Outcome 2 Cardiac death.
2.3
2.3. Analysis
Comparison 2 Molecule type (sub‐groups), Outcome 3 Sudden death.
2.4
2.4. Analysis
Comparison 2 Molecule type (sub‐groups), Outcome 4 Worsening heart failure (requiring intervention).
2.5
2.5. Analysis
Comparison 2 Molecule type (sub‐groups), Outcome 5 Myocardial Infarction.
2.6
2.6. Analysis
Comparison 2 Molecule type (sub‐groups), Outcome 6 Cardiac Transplantation.
2.7
2.7. Analysis
Comparison 2 Molecule type (sub‐groups), Outcome 7 Arrhythmias.
2.8
2.8. Analysis
Comparison 2 Molecule type (sub‐groups), Outcome 8 Vertigo.
3.1
3.1. Analysis
Comparison 3 Derivatives type (sub‐goups), Outcome 1 Total mortality.
3.2
3.2. Analysis
Comparison 3 Derivatives type (sub‐goups), Outcome 2 Cardiac death.
3.3
3.3. Analysis
Comparison 3 Derivatives type (sub‐goups), Outcome 3 Sudden death.
3.4
3.4. Analysis
Comparison 3 Derivatives type (sub‐goups), Outcome 4 Worsening heart failure (requiring intervention).
3.5
3.5. Analysis
Comparison 3 Derivatives type (sub‐goups), Outcome 5 Myocardial Infarction.
3.6
3.6. Analysis
Comparison 3 Derivatives type (sub‐goups), Outcome 6 Cardiac Transplantation.
3.7
3.7. Analysis
Comparison 3 Derivatives type (sub‐goups), Outcome 7 Arrhythmias.
3.8
3.8. Analysis
Comparison 3 Derivatives type (sub‐goups), Outcome 8 Vertigo.
4.1
4.1. Analysis
Comparison 4 Severity of heart failure (sub‐groups), Outcome 1 Total mortality.
4.2
4.2. Analysis
Comparison 4 Severity of heart failure (sub‐groups), Outcome 2 Cardiac death.
4.3
4.3. Analysis
Comparison 4 Severity of heart failure (sub‐groups), Outcome 3 Sudden death.
4.4
4.4. Analysis
Comparison 4 Severity of heart failure (sub‐groups), Outcome 4 Worsening heart failure (requiring intervention).
4.5
4.5. Analysis
Comparison 4 Severity of heart failure (sub‐groups), Outcome 5 Myocardial Infarction.
4.6
4.6. Analysis
Comparison 4 Severity of heart failure (sub‐groups), Outcome 6 Cardiac Transplantation.
4.7
4.7. Analysis
Comparison 4 Severity of heart failure (sub‐groups), Outcome 7 Arrhythmias.
4.8
4.8. Analysis
Comparison 4 Severity of heart failure (sub‐groups), Outcome 8 Vertigo.
5.1
5.1. Analysis
Comparison 5 Vasodilators used (sub‐groups), Outcome 1 Total mortality.
5.2
5.2. Analysis
Comparison 5 Vasodilators used (sub‐groups), Outcome 2 Cardiac death.
5.3
5.3. Analysis
Comparison 5 Vasodilators used (sub‐groups), Outcome 3 Sudden death.
5.4
5.4. Analysis
Comparison 5 Vasodilators used (sub‐groups), Outcome 4 Worsening heart failure (requiring intervention).
5.5
5.5. Analysis
Comparison 5 Vasodilators used (sub‐groups), Outcome 5 Myocardial Infarction.
5.6
5.6. Analysis
Comparison 5 Vasodilators used (sub‐groups), Outcome 6 Cardiac Transplantation.
5.7
5.7. Analysis
Comparison 5 Vasodilators used (sub‐groups), Outcome 7 Arrhythmias.
5.8
5.8. Analysis
Comparison 5 Vasodilators used (sub‐groups), Outcome 8 Vertigo.
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References

References to studies included in this review

AMTG 1985 {published data only}
    1. Massie B, Bourassa M, Dibianco R, Hess M, Konstam M, Lifoff M et al for the Amrinone Multicenter Trial Group. Long‐term oral administration of amrinone for congestive heart failure: lack of efficacy in a muticenter controlled trial. Circulation 1985;71:963‐71. - PubMed
    1. Massie B, Bourassa M, Dibianco R, Hess M, Krebs C, Lifoff M et al for the Amrinone Multicenter Study Group. Multicenter controlled trial of oral amrinone in congestive heart failure : lack of benefit compared to placebo. Journal of the American College of Cardiology 1985;5:514 (abstr).
Bergler‐Klein 1992 {published data only}
    1. Bergler‐Klein J, Globits S, Stefenelli T, Mayr H, Porenta G, Sochor H, et al. Pimobendan (UDCG 115 BS) in long‐term therapy of chronic heart failure [Pimobendan (UDCG 115 BS) in der Langzeittherapie der chronischen Herzinsuffizienz]. Zeitschrift fur Kardiologie 1992;81(10):546‐52. - PubMed
Cowley 1993 {published data only}
    1. Cowley AJ, McEntegart DJ. Placebo‐controlled trial of flosequinan in moderate heart failure. The possible importance of aetiology and method of analysis in the interpretation of the results of heart failure trials. International Journal of Cardiology 1993;38(2):167‐75. - PubMed
Cowley 1994 {published data only}
    1. Cowley AJ, Skene AM. Treatment of severe heart failure: quantity or quality of life? A trial of enoximone. Enoximone Investigators. British Heart Journal 1994;72(3):226‐30. - PMC - PubMed
Dies 1989 {published data only}
    1. Dies F, Mcnay JL, Andrejasich CM, Burke PJ, Enas NH. Indolidan (a new phosphodiesterase inhibitor) in chronic heart failure. Circulation 1989;80(suppl II):II‐175 (abstr 0698).
EMTG 1990 {published data only}
    1. Uretsky BF, Jessup M, Konstam MA, Benotti JR, Sandberg JA, Dec GW et al for the Enoximone Study Group. Multicenter trial of oral enoximone in patients with moderately severe congestive heart failure: lack of benefit compared to placebo. Circulation 1989;80(suppl II):II‐174 (abstr 0694). - PubMed
    1. Uretsky BF, Jessup M, Konstam MA, Dec GW, Leier CV, Benotti J et al for the Enoximone Multicenter Trial Group. Multicenter trial of oral enoximone in patients with moderate to moderately severe congestive heart failure. Circulation 1990;82:774‐780. - PubMed
EPOCH 2002 {published data only}
    1. The EPOCH Study Group. Effects of pimobendan on adverse cardiac events and physical activities in patients with mild to moderate chronic heart failure: the effects of pimobendan on chronic heart failure study (EPOCH study). Circulation Journal 2002;66(2):149‐57. - PubMed
ESG 2000 {published data only}
    1. Lowes BD, Higginbotham M, Petrovich L, DeWood MA, Greenberg MA, Rahko PS, et al. Low‐dose enoximone improves exercise capacity in chronic heart failure. Enoximone Study Group. American Journal of Cardiology 2000;36(2):501‐8. - PubMed
    1. Schleman MM, for the enoximone study group. Double‐blind placebo‐controlled 12 week trial of low dose enoximone in patients with mild to moderate congestive heart failure. Circulation 1991;84(suppl II):II‐243 (abstr 0967).
FACET 1993 {published data only}
    1. Massie BM, Berk MR, Brozena SC, Elkayam U, Plehn JF, Kukin ML, et al. Can further benefit be achieved by adding flosequinan to patients with congestive heart failure who remain symptomatic on diuretic, digoxin, and an angiotensin converting enzyme inhibitor? Results of the flosequinan‐ACE inhibitor trial (FACET). Circulation 1993;88(2):492‐501. - PubMed
IRG 1991 {published data only}
    1. Goldberg AD, Nicklas J, Goldstein S. Effectiveness of imazodan for treatment of chronic congestive heart failure. The Imazodan Research Group. The American Journal of Cardiology 1991;68(6):631‐6. - PubMed
    1. Goldberg AD, Nicklas J, Goldstein S, Ford H. Multicenter trial of imazodan in patients with chronic congestive heart failure. European Heart Journal 1990;11:132 (abstr 677).
    1. Golderg AD, Goldstein S, Nicklas J. Mulicenter trial of imazadan in patients with chronic congestive heart failure. Circulation 1990;82(suppl III):III‐673 (abstr 2673).
Lardoux 1987 {published data only}
    1. Lardoux H, Trimarco B, Granier G, Marcadet O, Dubois‐Rande JL, Tarral A. Multicentric, double blind and controlled study of oral enoximone (MDL 17043) in chronic heart failure. Circulation 1987;76(suppl IV):IV‐179 (abstr 0711).
MMTG 1989 {published data only}
    1. Bianco R, Shabetai R, Kostuk W, Moran J, Schlant R, Wright R. Oral milrinone and digoxin in heart failure: results of a placebo‐controlled, prospective trial of each agent and the combination. Circulation 1987;76(suppl IV):IV‐256 (abstr 1020).
    1. DiBianco R, Shabetai R, Kostuk W, Moran J, Schlant RC, Wright R. A comparison of oral milrinone, digoxin, and their combination in the treatment of patients with chronic heart failure. New England Journal of Medicine 1989;320(11):677‐83. - PubMed
OPC‐8212 MRG 1990 {published data only}
    1. OPC‐8212 Multicenter Research Group. A placebo‐controlled, randomized, double‐blind study of OPC‐8212 in patients with mild chronic heart failure. Cardiovascular Drugs and Thearpy 1990;4:419‐26. - PubMed
PICO 1996 {published data only}
    1. Just H, Hjalmarsson AC, Remme WJ, Heinrich‐Nols J, Dumont JM, Seed P et al on behalf of the pimobendan in congestive heart failure (PICO) investigators. Pimobendan in congestive heart failure : results of the PICO trial. Circulation 1995;92(Suppl I):I‐722 (abstr 3469).
    1. Lubsen J, Just H, Hjalmarsson AC, Framboise D, Remme WJ, Heinrich‐Nols J, et al. Effect of pimobendan on exercise capacity in patients with heart failure: main results from the Pimobendan in Congestive Heart Failure (PICO) trial. Heart 1996;76(3):223‐31. - PMC - PubMed
PMRG 1992 {published data only}
    1. Gollub SB, Kubo SH. Beneficial effects of pimobendan in patients with chronic heart failure: results of a multicenter trial. Circulation 1991;84(suppl II):II‐312 (abstr 1241). - PubMed
    1. Kubo SH, Gollub S, Bourge R, Rahko P, Cobb F, Jessup M et al for the Pimobendan Multicenter Research Group. Beneficial effects of pimobendan on exercise tolerance and quality of life in patients with heart failure. Results of a multicenter trial. Circulation 1992;85:942‐9. - PubMed
    1. Rector TS, Cohn JN. Assessment of patient outcome with the Minnesota Living with Heart Failure questionnaire: eliability and validity during a randomized, double placebo‐controlled trial of pimobendan. Pimobendan Multicenter Research Group. American Heart Journal 1992;124(4):1017‐25. - PubMed
PROMISE 1991 {published data only}
    1. Eichhorn EJ, Tandon PK, DiBianco R, Timmis GC, Fenster PE, Shannon J, et al. Clinical and prognostic significance of serum magnesium concentration in patients with severe chronic congestive heart failure: the PROMISE Study. Journal of the American College of Cardiology 1993;21(3):634‐40. - PubMed
    1. Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM et al for the PROMISE Study Research Group. Effect of oral milrinone on mortality in severe chronic heart failure. New England Journal of Medicine 1991;325:1468‐75. - PubMed
    1. Packer M, Francis GS, Abrams J, Cobb FR, Eichhorn EJ, Giles TD et al and the PROMISE investigators and coordinators. Oral milrinone increases the risk of sudden death in severe chronic heart failure : the PROMISE trial. Circulation 1991;84(suppl II):II‐310 (abstr 12434).
    1. Teerlink JR, Jalaluddin M, Anderson S, Kukin ML, Eichhorn EJ, Francis G, et al. Ambulatory ventricular arrhythmias in patients with heart failure do not specifically predict an increased risk of sudden death. PROMISE (Prospective Randomized Milrinone Survival Evaluation) Investigators. Circulation 2000;101(1):40‐6. - PubMed
REFLECT 1993 {published data only}
    1. Binkley PF, Nunziata E, Cody RJ. Influence of flosequinan on autonomic tone in congestive heart failure: implications for the mechanism of the positive chronotropic effect and survival influence of long‐term vasodilator administration. American Heart Journal 1994;128:1147‐56. - PubMed
    1. Packer M, Narahara KA, Elkayam U, Sullivan JM, Pearle DL, Massie BM, et al. Double‐blind, placebo‐controlled study of the efficacy of flosequinan in patients with chronic heart failure. Principal Investigators of the REFLECT Study. Journal of the American College of Cardiology 1993;22(1):65‐72. - PubMed
REFLECT II 1991 {published data only}
    1. Pitt B, on behalf of the REFLECT II Study Group. A randomized, multicenter, double‐blind placebo controlled study of the efficacy of Flosequinan in patients with chronic heart failure. Circulation 1991;84(suppl II):II‐311 (abstr 1238).
VEST 1998 {published data only}
    1. Cohn JN, Goldstein SO, Greenberg BH, Lorell BH, Bourge RC, Jaski BE, et al. A dose‐dependent increase in mortality with vesnarinone among patients with severe heart failure. Vesnarinone Trial Investigators. New England Journal of Medicine 1998;339(25):1810‐6. - PubMed
VSG 1993 {published data only}
    1. Carson PE, Colucci WS, Deedwania PC, Uresky BF, Bristow MR, Feldman AM, et al. Lack of proarrhythmia reduction by vesnarinone in advanced heart failure. Circulation 1993;88(suppl I):I‐602 (abstr 3240).
    1. Feldman AM, Bristow MR, Parmley WW, Carson PE, Pepine CJ, Gilbert EM et al for the vesnarinone study group. Effects of vesnarinone on morbidity and mortality in patients with heart failure. New England Journal of Medicine 1993;329:149‐55. - PubMed
WESG 1991 {published data only}
    1. Narahara KA, and the Western Enoximone Study Group. Enoximone versus placebo: a double‐blind trial in chronic congestive heart failure. Circulation 1989;80(suppl II):II‐175 (abstr 0695).
    1. Narahara KA, and the Western Enoximone Study Group. Oral enoximone therapy in chronic heart failure: a placebo‐controlled randomized trial. AmericanHeart Journal 1991;121:1471‐9. - PubMed

References to studies excluded from this review

Assmann 1991 {published data only}
    1. Assmann I, Kassel P, Duck HG, Fiehring H, Morgan P, Schmidt PKH, et al. Akut‐und langzeiteffekte von pimobendan (UD‐DG 115) bei herzinsuffizienz NYHA II und III. Ergebnisse einer randomisierten multizentrischen doppelblindstudie. Zeitschrift fur Kardiologie 1991;80:687‐94. - PubMed
Banning 1996 {published data only}
    1. Banning AP, Ramsey MW, Jones EA, Evans W, Carolan G, Jones CH, et al. Flosequinan in chronic heart failure: how is exercise capacity improved?. European Journal of Clinical Pharmacology 1996;51:133‐8. - PubMed
Binkley 1989 {published data only}
    1. Binkley PF, Shaffer PB, Ryan JM, Leier CV. Augmentation of diastolic function with phosphodiesterase inhibition in congestive heart failure. The Journal of Laboratory and Clinical Medicine 1989;114(3):266‐71. - PubMed
Corder 1992 {published data only}
    1. Corder CN, Puls A, Wilson M. Clinical effect of indolidan in congestive heart failure. International Journal of Clinical Pharmacology, Therapy, and Toxicology 1992;30:405‐9. - PubMed
Cowley 1989 {published data only}
    1. Cowley AJ, Fullwood L, Stainer K, Hampton JR. Exercise tolerence in patients with heart failure ‐ how should it be measured?. International Journal of Cardiology 1989;24(3):311‐6.
Cowley 1991 {published data only}
    1. Cowley AJ, Fullwood L, Stainer K, Hampton JR. Exercise tolerance in patients with heart failure ‐ how should it be measured?. European Heart Journal 1991;12(1):50‐4. - PubMed
Crawford 1989 {published data only}
    1. Crawford MH, Deedwania P, Massie B, Rogers W, Smith G, Dae M, et al. Comparative efficacy of enoximone versus captopril in moderate heart failure. Circulation 1989;80(suppl II):II‐175 (abstr 0695).
DiBianco 1983 {published data only}
    1. Dibianco R, Shabetai R, Silverman B, Leier C, Benotti J, Silverman ME, et al. Oral amrinone for congestive heart failure : preliminary results of a multicenter double blind and placebo controlled withdrawal. Journal of the American College of Cardiology 1983;1:675 (abstr). - PubMed
DiBianco 1984 {published data only}
    1. DiBianco R, Shabetai R, Silverman BD, Leier CV, Benotti JR, with the Amrinone Multicenter Study Investigators. Oral amrinone for the treatment of chronic congestive heart failure: results of a multicenter randomized double‐blind and placebo‐controlled withdrawal study. Journal of the American College of Cardiology 1984;4:855‐66. - PubMed
Dickstein 1990 {published data only}
    1. Dickstein K, Gauthier DF, Hartley LH, Colucci WS. Effect of IV milrinone on submaximal exercise endurance in heart failure. Circulation 1990;82(suppl III):III‐324 (abstr 1285).
DuBourg 1990 {published data only}
    1. Dubourg O, Delorme G, Hardy A, Beauchet A, Tarral A, Bourdarias JP. Placebo‐controlled trial of oral enoximone in end‐stage congestive heart failure refractory to optimal treatment. International Journal of Cardiology 1990;28(suppl 1):S33‐42. - PubMed
Elborn 1989 {published data only}
    1. Elborn JS, Stanford CF, Nicholls DP. Effect of flosequinan on exercise capacity and symptoms in severe heart failure. British Heart Journal 1989;61(4):331‐5. - PMC - PubMed
Elborn 1990 {published data only}
    1. Elborn JS, Riley M, Stanford CF, Nicholls DP. The effects of flosequinan on submaximal exercise in patients with chronic cardiac failure. British Journal of Clinical Pharmacology 1990;29(5):519‐24. - PMC - PubMed
Evans 1984 {published data only}
    1. Evans JR, Pacht K, Huss P, Unverferth DV, Bashore TM, Leier CV. Chronic oral amrinone therapy in congestive heart failure: a double‐blind placebo‐controlled withdrawal study. International Journal of Clinical Pharmacology Research 1984;4(1):9‐18. - PubMed
Feldman 1991 {published data only}
    1. Feldman AM, Baughman KL, Lee WK, Gottlieb SH, Weiss JL, Becker LC, et al. Usefulness of OPC‐8212, a quinolinone derivative, for chronic congestive heart failure in patients with ischemic heart disease or idiopathic dilated cardiomyopathy. The American Journal of Cardiology 1991;68:1203‐10. - PubMed
Galinier 1989 {published data only}
    1. Galinier M, Massabuau P, Fourcade J, Rochiccioli JP, Puel J, Bounhoure JP. Hemodynamics effects of enoximone in severe congestive heart failure with low cardiac output. European Heart Journal 1989;10:76 (abstr P365).
Gilbert 1991 {published data only}
    1. Gilbert E. Double‐blind, placebo‐controlled (P), comparison of enoximone (E) and dobutamine (D) infusions in moderate to severe congestive heart failure patients (NYHA III‐IV). Journal of the American College of Cardiology 1991;17:274A (abstr 245). - PubMed
Haas 1990 {published data only}
    1. Haas GJ, Binkley PE, Leier CV. Chronic vasodilator therapy with flosequinan in congestive heart failure. Clinical Cardiology 1990;13(6):414‐20. - PubMed
Hori 1992 {published data only}
    1. Hori M, Sato H, Ozaki H, Inoue M, Naka M, Fukunami M, et al. Effect of flosequinan on exercise capacity and cardiac function in patients with chronic mild heart failure: a double‐blind placebo‐controlled study. Heart Vessels 1992;7(3):133‐40. - PubMed
Huanqlong 2000 {published data only}
    1. Huanqlong Z, Shan W, Dejla H, Xingbin L, Yuan F. Response to milrinone treatment in patients with chronic congestive heart failure. J WCUMS 2000;31:246‐7. - PubMed
Jondeau 1993 {published data only}
    1. Jondeau G, Dubourg O, Delorme G, Chikli F, Dumas C, Bock F, et al. Is there any indication for oral phosphodiesterase inhibitor today?. Journal of the American College of Cardiology 1993;21:377A (abstr 800‐2).
Karlsberg 1992 {published data only}
    1. Karlsberg RP. Milrinone is superior to dobutamine in heart failure complicating myocardial infarction. Circulation 1992;86(suppl I):I‐808 (abstr 3214).
Katz 1987 {published data only}
    1. Katz SD, Forman R, Giustino SR, Sonnenblick EH, Jemtel TH. Double‐blind, randomized evaluation of pimobendan, a new inotrope and vasodilator agent for refractory heart failure. Circulation 1987;76(supll IV):IV‐178 (abstr 0707).
Katz 1992 {published data only}
    1. Katz SD, Kubo SH, Jessup M, Brozena S, Troha JM, Wahl J, et al. A multicenter, randomized, double‐blind, placebo‐controlled trial of pimobendan, a new cardiotonic and vasodilator agent, in patients with severe congestive heart failure. American Heart Journal 1992;123(1):95‐103. - PubMed
Khalife 1987 {published data only}
    1. Khalife K, Zannad F, Brunotte F, Belhadj K, Juilliere Y, Iannascoli F, et al. Placebo‐controlled study of oral enoximone in congestive heart failure with initial and final intravenous hemodynamic evaluation. American Journal of Cardiology 1987;60(5):75C‐79C. - PubMed
Kneissl 1990 {published data only}
    1. Kneissl GD, Scholz M, Dieterich HA, Bubmann WD. Efficacy of enoximone in comparison with captopril in congestive heart failure. European Heart Journal 1990;11:20 (abstr 117).
Konstam 1985 {published data only}
    1. Konstam MA, Benotti JR, Biddle T, Creager MA, Faxon DP, Firth BG, et al. Multicenter comparison of milrinone and dobutamine in congestive heart failure. Circulation 1985;72(supll III):III‐201 (abstr 803).
Leier 1987 {published data only}
    1. Leier CV, Meiller SEL, Binkley PF, Unverferth DV. Regional hemodynamic effects of enoximone in congestive heart failure. Circulation 1987;76(suppl IV):IV‐255 (abstr 1017).
Leier 1988 {published data only}
    1. Leier CV, Lima JJ, Meiler SE, Unverferth DV. Central and regional hemodynamic effects of oral enoximone in congestive heart failure: a double‐blind, placebo‐controlled study. American Heart Journal 1988;115(5):1051‐9. - PubMed
Leier 1989 {published data only}
    1. Leier CV, Binkley PF, Starling RC, Huss‐Randolph P. Disparity between improvement in left ventricular function and changes in clinical status and exercise capacity during chronic enoximone therapy. American Heart Journal 1989;117(5):1092‐8. - PubMed
Likoff 1985 {published data only}
    1. Likoff MJ, Weber KT, Andrews V, Janicki JS, Wilson H, Rocci ML Jr. Milrinone in the treatment of chronic cardiac failure: a controlled trial. American Heart Journal 1985;110(5):1035‐42. - PubMed
Orie 1989 {published data only}
    1. Orie JE, Rahko PS, Brookfield L, Gorwit J, McKiernan T. A double blind comparison of enoximone (Enox) and Captopril (Cap) in CHF. Circulation 1989;80(suppl II):II‐175 (abstr 0686).
Pilcher 1985 {published data only}
    1. Pilcher J, Choraria SK, Taylor DN. Enoximone (MDL 17043) and left ventricular function. A placebo controlled trial. Circulation 1985;72(suppl III):III‐404 (abstr 1616).
Raw 1989 {published data only}
    1. Raw K, Patel J, Mitha A, Chun R, Baragwanath JD. Amrinone vs dobutamine in congestive heart failure due to dilated cardiomyopathy ‐ differences in hemodynamic effects and therapeutic implications. European Heart Journal 1989;10:386 (abstr P2124).
Remme 1992 {published data only}
    1. Remme MW, Krayenbuhl HP, Frick H, Haehl M, Nehmiz G for the European Pimobendan‐Enalapril study group. Discordant hemodynamic and clinical efficacy of enalapril in moderate heart failure. Is pimobendan superior?. European Heart Journal 1992;13:345 (abstr P 1896).
Rettig 1986 {published data only}
    1. Rettig G, Sen S, Frohlig G, Schieffer H, Bette L. Withdrawal of long‐term amrinone therapy in patients with congestive heart failure: a placebo controlled trial. European Heart Journal 1986;7:628‐631. - PubMed
Ruegg 1987 {published data only}
    1. Ruegg PC, Salzmann R, Alther S. Assessment of a new inotropic agent, DPN 205‐734, by means of systolic time intervals (STIs) in healthy volunteers. European Heart Journal 1987;8(suppl 2):abstr 184.
Schoeller 1986 {published data only}
    1. Schoeller R, Bruggemann T, Vohringer H, Nothel T, Opitz C, Schroder K, et al. Long‐term oral administration of milrinone for dilated cardiomyopathy. Journal of the American College of Cardiology 1986;7:108A.
Sridhara 1994 {published data only}
    1. Sridhara BS, Senior R, Anagnostou E, Kinsey C, Lahiri A. Saterinone, a dual‐action drug ofr the management of congestive heart failure. European Heart Journal 1994:36 (abstr 393).
Voelker 1989 {published data only}
    1. Voelker W, Mauser M, Preisack M, Karsch KR. Acute hemodynamic effects of abidendan, a new phosphodiesteras inhibitor, in patients with severe heart failure. European Heart Journal 1989;10:387 (abstr 2126). - PubMed
Weber 1990 {published data only}
    1. Weber PW, Kupper W, Hamm CW, Heitmann NB, Heitmann NB, Bleifeld W. Acute hemodynamic effects of saterinone in patients with severe chronic heart failure. European Heart Journal 1990;11:19 (abstr 113).
Yoshikawa 2000 {published data only}
    1. Yoshikawa T, Baba A, Suzuki M, Yokozuka H, Okada Y, Nagami K, et al. Effectiveness of carvedilol alone versus carvedilol + pimobendan for severe congestive heart failure. For the Keio Interhospital Cardiology Study (KICS) Group. The American Journal of Cardiology 2000;85(12):1495‐7 (A7). - PubMed
Zipperle 1987 {published data only}
    1. Zipperle G, Butzer F, Dieterich HA, Heinrich F. A double‐blind dose response comparison of oral enoximone and placebo for congestive heart failure. The American Journal of Cardiology 1987;60(5):72C‐74C. - PubMed

References to studies awaiting assessment

Goldberg 1990 {published data only}
    1. Golderg AD, Goldstein S, Nicklas J, for the Imazodan Study Group. Multicenter trial of imazadan in patients with chronic congestive heart failure. Circulation 1990;82(suppl III):III‐673 (abstr 2673)a.
Japanese's Studies {published data only}
    1. Kato K, Yasuda K, Isuka M, Sukimoto T, Kimata S, Taniguchi K, et al. Evaluation of the efficacy and safety of pimobendan (UD‐CG 115 BS) in treatment of chronic heart failure. A multicenter placebo‐controlled, double‐blind study. Rinsho Iyaku 1992;8:1311‐51b.
    1. Kato K, Yasuda K, Kawai C, Kumada T, Sugimoto T, Kimata S, et al. Clinical efficacy of pimobendan for patients with chronic heart failure. A dose‐finding study by a multicenter double‐blind comparison trial. Rinsho Iyaku 1991;7:2643‐9a.
MIL 1077‐1078 {published data only}
    1. Colucci WS, Sonnenblick EH, Adams KF, Berk M, Brozena SC, Cowley AJ, et al. Efficacy of phosphodiesterase inhibition with milrinone in combination with converting enzyme inhibitors in patients with heart failure. The Milrinone Multicenter Trials Investigators. Journal of the American College of Cardiology 1993;22(4 suppl A):113A‐8Aa. - PubMed
    1. Colucci WS, Sonnenblick EH, for the milrinone multicenter trials investigators. Oral milrinone as adjunctive therapy for CHF. Circulation 1991;84(suppl II):II‐243a.
PROFILE 1993 {published data only}
    1. Hansen MS, Stanton EB, Gaward Y, Packer M, Pitt B, Swedberg K et al for the Canadian PROFILE Investigators. Relation of circulating cardiac myosin light chain 1 isoform in stable severe congestive heart failure to survival and treatment with flosequinan. The American Journal of Cardiology 2002;90:969‐73. - PubMed
    1. Moe GW, Rouleau JL, Charbonneau L, Proulx G, Arnold JM, Hall C, et al. Neurohormonal activation in severe heart failure: relations to patient death and the effect of treatment with flosequinan. American Heart Journal 2000;139(4):587‐95. - PubMed
    1. Packer M, Rouleau J, Swedberg K, Pitt B, Fisher L, Klepper M and the PROFILE investigators & Coordinators. Effect of flosequinan on survival in chronic heart failure: preliminary results of the PROFILE study. Circulation 1993;88(suppl I):I‐301 (abstr 1612).

References to ongoing studies

EMOTE {published and unpublished data}
    1. EMOTE. http://investor.myogen.com/news/20040429‐134186.cfm Accessed November 2004.
    1. EMOTE. http://www.uihealthcare.com/depts/uiheartcare/clinicaltrials.html#emote [accessed on 04‐03‐2003].
ESSENTIAL {published and unpublished data}
    1. ESSENTIAL. http://clinicaltrials.gov/ct/gui/show/NCT00051285;jsessionid=9722D918B06... [accessed on 04‐03‐2003].

Additional references

Baptista 1977
    1. Baptista J, Pike MC. Exact two‐sided confidence limits for the odds ratio in a 2 x 2 table. Algorithm AS 115. Applied statistics 1977;26:214‐20.
Boissel 1989
    1. Boissel JP, Blanchard J, Panak E, Peyrieux JC, Sacks H. Considerations for the meta‐analysis of randomized clinical trials. Summary of a panel discussion. Controlled Clinical Trials 1989;10:254‐81. - PubMed
Braunwald 1991
    1. Braunwald E. ACE inhibitors ‐ a cornerstone of the treatment of heart failure. New England Journal of Medicine 1991;325:351‐3. - PubMed
Chatterjee 1980
    1. Chatterjee K, Parmley WW. Vasodilator therapy for chronic heart failure. Annual Review of Pharmacology and Toxicology 1980;20:475‐80. - PubMed
Chesebro 1988
    1. Chesebro JH, Browne KF, Fenster PE, Garland WT, Konstam MA, for the Milrinone Research Group. The hemodynamic effects of chronic oral milrinone therapy: a multicenter controlled trial. Journal of the American College of Cardiology 1988;11:144A.
CIBIS II 1999
    1. Dargie HJ, Lechat P. The Cardiac Insufficiency Bisoprolol Study II (CIBIS‐II): a randomised trial. Lancet 1999;353:9‐13. - PubMed
Cochran 1954
    1. Cochran WG. The combination of estimates from different experiments. Biometrics 1954;10:101‐29.
Cohn 1973
    1. Cohn JN. Vasodilator therapy for heart failure. The influence of impedance on left ventricular performance. Circulation 1973;48:5‐8. - PubMed
Cohn 1977
    1. Cohn JN, Franciosa JA. Vasodilatator therapy of cardiac failure. New England Journal of Medcine 1977;297:254‐7. - PubMed
Cohn 1986
    1. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. New England Journal of Medicine 1986;314:1547‐52. - PubMed
Cohn 1991
    1. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, et al. A comparison of enalapril with hydralazine‐isosorbide dinitrate in the treatment of chronic congestive heart failure. New England Journal of Medicine 1991;325:303‐10. - PubMed
Colucci 1991
    1. Colucci WS. Cardiovascular effects of milrinone. American Heart Journal 1991;121:1945‐7. - PubMed
CONSENSUS 1987
    1. The CONSENSUS Trial Study Group. Effects of Enalapril on mortality in severe congestive heart failure. New England Journal of Medicine 1987;316:1429‐35. - PubMed
Curfman 1991
    1. Curfman GD. Inotropic therapy for heart failure ‐ an unfulfilled promise. New England Journal of Medicine 1991;325:1509‐10. - PubMed
Der Simonian 1986
    1. Simonian R, Laird N. Meta‐analysis in clinical trials. Controlled Clinical Trials 1986;7:177‐88. - PubMed
DiBianco 1991
    1. DiBianco R. Acute positic inotropic intervention: the phosphoesterase inhibitors. American Heart Journal 1991;121:1871‐5. - PubMed
Egger 1997
    1. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta‐analysis detected by a simple, graphical test. BMJ 1997;315:629‐34. - PMC - PubMed
Feldman 1987
    1. Feldman MD, Copelas L, Gwathmey JK, Philips P, Warrn SE. Deficient production of cyclic AMP: pharmacologic evidence of an important cause of contractile dysfunction in patients with end‐stage heart failure. Circulation 1987;75:331‐9. - PubMed
Fleiss 1973
    1. Fleiss J. Statistical methods for rates and proportions. New York: Wiley, 1973.
Furberg 1988
    1. Furberg CD, Yusuf S. Effect of drug therapy on survival in chronic congestive heart failure. American Journal of Cardiology 1988;62:41A‐5A. - PubMed
Galbraith 1988
    1. Galbraith RF. A note on graphical presentation of estimated odds ratios from several clinical trials. Statistics in Medicine 1988;7(8):889‐94. - PubMed
Garg 1995
    1. Garg R, Yusuf S. Overview of randomized trials of angiotensin‐converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA 1995;273:1450‐6. - PubMed
Gilfrich 1991
    1. Gilfrich HJ, Dieterich HA. Tolerance of enoximone in patients with heart failure. Zeitschrift fur Kardiologie 1991;80(suppl 4):93‐7. - PubMed
Hood 1989
    1. Hood WB. Controlled and uncontrolled studies of phosphodiesterase III inhibitors in contemporary cardiovascular medicine. American Journal of Cardiology 1989;63:46A‐53A. - PubMed
Katz 1990
    1. Katz AM. Cardiomyopathy of overload : a major determinant of prognosis in congestive heart failure. New England Journal of Medicine 1990;322:100‐10. - PubMed
LeJemtel 1980
    1. LeJemtel TH, Keung E, Ribner HS, Wexler J, Blaufox MD, Sonnenblick EH. Sustained beneficial effects of oral amrinone on cardiac and renal function in patients with severe congestive heart failure. American Journal of Cardiology 1980;45:123‐9. - PubMed
Ludmer 1986
    1. Ludmer PL, Wright RF, Arnold JML, Ganz P, Braunwald E, Colucci WS. Separation of the direct myocardial and vasodilator actions of milrinone administered by an intracoronary infusion technique. Circulation 1986;73:130‐7. - PubMed
Mancini 1985
    1. Mancini D, LeJemtel T, Sonnenblick E. Intravenous use of amrinone for the treatment of the failing heart. American Journal of Cardiology 1985;56:8B‐15B. - PubMed
Mantel 1959
    1. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. Journal of the National Cancer Institute 1959;22:719‐48. - PubMed
MERIT‐HF 1999
    1. Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT‐HF). Effect of metoprolol CR/XL in chronic heart failure. Lancet 1999;353:2001‐7. - PubMed
Mikulic 1977
    1. Mikulic E, Cohn JN, Franciosa JA. Comparative hemodynamic effects of inotropic and vasodilator drugs in severe heart failure. Circulation 1977;56:528‐33. - PubMed
Mulrow 1988
    1. Mulrow CD, Mulrow JP, Linn WD, Aguilar C, Ramirez G. Relative efficacy of vasodilator therapy in chronic congestive heart failure. Implications of randomized trials. JAMA 1988;259:3422‐6. - PubMed
Nony 1995
    1. Nony P, Boissel JP, Lievre M, Cucherat M, Haugh MC, Dayoub G. Introduction à la méthodologie méta‐analytique. Revue de Medecine Interne 1995;16:536‐46. - PubMed
Nony 1997
    1. Nony P, Cucherat M, Haugh MC, Boissel JP. Standardization of terminology in meta‐analysis: a proposal for working definitions. Fundamental & Clinical Pharmacology 1997;11:481‐93. - PubMed
Nony 1999
    1. Nony P, Cucherat M, Boissel JP. Implication of evidence‐based medicine in prescription guidelines taught to French medical students: current status in the cardiovascular field. Clinical pharmacology and Therapeutics 1999;66:173‐84. - PubMed
Packer 1984
    1. Packer M, Medina N, Yushak M. Hemodynamic and clinical limitations of long‐term inotropic therapy with amrinone in patients with severe chronic heart failure. Circulation 1984;70:1038‐47. - PubMed
Packer 1988a
    1. Packer M. Effect of vasodilator and inotropic drugs on clinical symptoms and long‐term survival in chronic congestive heart failure. European Heart Journal 1988;9(suppl h):105‐8. - PubMed
Packer 1988b
    1. Packer M. Vasodilator and inotropic drugs for chronic heart failure: distinguishing hype from hope. The American Journal of Cardiology 1988;12:1299‐317. - PubMed
Packer 2001
    1. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, et al. Effect of carvedilol on survival in severe chronic heart failure. New England Journal of Medicine 2001;344:1651‐8. - PubMed
Peto 1978
    1. Peto R. Clinical trial methodology. Biomedicine 1978;28:24‐36. - PubMed
Rosenthal 1979
    1. Rosenthal R. The "file drawer" problem and tolerance for null results. Psychol Bull 1979;86:638‐41.
Simonton 1985
    1. Simonton CA, Chatterjee K, Cody RJ, Kubo SH, Leonard D, Daly P, et al. Milrinone in congestive heart failure : acute and chronic hemodynamic and clinical evaluation. Journal of the American College of Cardiology 1985;6:453‐9. - PubMed
SOLVD 1991
    1. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. New England Journal of Medicine 1991;325:293‐302. - PubMed
Storstein 1988
    1. Storstein L. Non‐receptor‐mediated inotropic drugs. European Heart Journal 1988;9:91‐3. - PubMed
Tukey 1977
    1. Tukey JW. Some thoughts on clinical trials, especially problems of multiplicity. Science 1977;198:679‐84. - PubMed
Weber 1987
    1. Weber KT, Gill SK, Janicki JS, Maskin CS, Jain MC. Newer positive inotropic agents in the treatment of chronic cardiac failure. Current status and future directions. Drugs 1987;33:503‐19. - PubMed
Wilmshurst 1984
    1. Wilmshurst PT, Walker JM, Fry CH, Mounsey JP, Twort CHC, Williams BT, et al. Inotropic and vasodilator effects of amrinone on isolated human tissue. Cardiovascular Research 1984;18:302‐9. - PubMed
Wood 1989
    1. Wood MA, Hess ML. Review: long‐term oral therapy of congestive heart failure with phosphodiesterase inhibitors. The American Journal of the Medical Sciences 1989;297:105‐13. - PubMed
Yusuf 1987
    1. Yusuf S, Simon R, Ellenberg S. Proceedings of "Methodological Issues in Overviews of Randomized Clinical Trials". Statistical Medicine 1987;6:217‐409.
Yusuf 1990
    1. Yusuf S, Teo K. Inotropic agents increase mortality in patients with congestive heart failure. Circulation 1990;82(suppl III):III‐673(abstr 2675).

References to other published versions of this review

Nony 1994
    1. Nony P, Boissel JP, Lievre M, Leizorovicz A, Haugh MC, Fareh S, et al. Evaluation of the effect of phosphodiesterase inhibitors on mortality in chronic heart failure patients: a meta‐analysis. European Journal of Clinical Pharmacology 1994;46:191‐6. - PubMed

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