Clinical Importance of Phosphodiesterase 3 Inhibitors on Outcomes in Patients With Cardiogenic Shock　― A Systematic Review ―

Abstract

Background: Inotropes play a significant role in the treatment of cardiogenic shock (CS). Phosphodiesterase 3 inhibitors (PDE3i) are being used with increasing frequency, despite limited supporting evidence.

Methods and Results: We performed a systematic review to assess the clinical importance of PDE3i in CS. The search included studies that compared the effect of ‘PDE3i with or without inotropes’ with ‘No PDE3i with or without inotropes’ in patients with cardiogenic shock. Early death, cardiac arrest, and initiation of renal replacement therapy were assessed as outcomes. We identified 2 randomized controlled trials (RCT) with a total of 224 patients who met the eligibility requirements from the PubMed, Web of Science, and CENTRAL databases, up until October 31, 2024. One RCT compared milrinone with dobutamine (DOB), and another compared enoximone with levosimendan. Meta-analysis revealed that PDE3i were neither superior nor inferior for the outcomes in the total cohort (odds ratio [OR] 1.47, 95% confidence interval [CI] 0.35–6.26 for early deaths; OR 1.14, 95% CI 0.42–3.14 for cardiac arrest; OR 1.53, 95% CI 0.80–2.92 for the initiation of renal replacement therapy).

Conclusions: The present systematic review revealed no difference in outcomes, early deaths, cardiac arrest and initiation of renal replacement therapy when using PDE3i in patients with CS treated with or without other inotropes.

Central Figure

Cardiogenic shock (CS) is associated with significant morbidity and mortality, compelling clinicians to address the CS situation and tissue hypoperfusion.¹ In parallel with cautious fluid administration and/or revascularization if indicated, administering and titrating inotropes represent the first approach to managing cardiogenic shock.² When CS persists³ despite body fluid volume optimization, primary intervention, and the use of inotropes, the introduction of mechanical circulatory support (MCS) is considered.⁴ However, not all hospitals can implement MCS promptly, and comorbidities such as infection and hemorrhage are associated with the unsafe introduction of MCS.⁵ To improve outcomes, it is also important to introduce MCS when the patient is in a stable condition.⁵ For these reasons, research should continue investigating which intravenous inotropes are recommended to treat CS.

Since the 1970s, dobutamine (DOB) has often been used as the first choice for inotropes, conceptually.⁶ If the CS condition does not improve despite DOB use, phosphodiesterase 3 inhibitors (PDE3i) become an additional inotropic option.⁷ However, there is no solid evidence in CS, and drug selection tends to rely on the choice of the facility.

PDE3i represent an interesting option to increase contractility by increasing cyclic AMP levels in the myocardium.⁸ In this respect, the combination of PDE3i with adrenergic agents is perhaps attractive.⁸ Milrinone and enoximone are PDE3i that are used in clinical situations.⁹ However, the status of systematic reviews evaluating the latest utility of PDE3i for CS remains unclear.

To address this requirement, this study aimed to investigate the existence of randomized controlled trials (RCTs) on PDE3i and clarify their utility in patients with CS.

Methods

The Japan Resuscitation Council (JRC) Cardiogenic Shock Task Force was organized by the Japanese Circulation Society and the Japanese Society of Internal Medicine. The JRC Cardiogenic Shock Task Force was established in accordance with the 2025 JRC guidelines. The JRC Cardiogenic Shock Task Force established 12 clinically relevant questions; in this article, we address the following clinical question: Does the administration of PDE3i improve clinical outcomes compared with standard of care in patients with CS treated with or without other inotropes?

The PICO criteria were as follows:

P (patients): adult patients (aged ≥18 years) admitted to hospital with CS.

I (interventions): administration of PDE3i with or without inotropes.

C (comparisons, controls): no PDE3i with or without inotropes such as dopamine, dobutamine, and levosimendan.

O (main outcomes): survival at 1 or 3 months, all-cause death, and cardiovascular death.

O (additional outcomes): length of stay in the emergency department, fatal arrhythmia, multiple organ failure, and use of mechanical circulatory support.

S (study type): RCT.

T (timeframe): all published literature up until October 31, 2024.

The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.¹⁰ The procedures followed were in accordance with the Declaration of Helsinki.

Search Strategy and Data Extraction

We included studies published in English that met all of the PICO criteria described above, irrespective of the study design. We identified the relevant literature indexed in PubMed, Web of Science, and CENTRAL that was related to CS and PDE3i from inception to October 31, 2024. All studies on the effects of PDE3i in patients with CS were included. Therefore, the search included studies that compared the effect of ‘PDE3i with or without inotropes’ with ‘No PDE3i with or without inotropes’ in patients with CS. Citation lists for the included studies were also reviewed, and relevant studies were included. Articles published in English and Japanese were also included. Japanese articles without English abstracts were excluded. CS is defined as inadequate tissue perfusion due to primary cardiac dysfunction. It is typically caused by conditions such as acute heart failure, myocardial infarction, valvular disease, myocarditis, or severe arrhythmia. Two investigators (M.Y., Y.H.) independently screened all identified records (titles and abstracts) and evaluated the selected full-text articles. Any disagreements regarding the selection were resolved through discussion. The exclusion criteria were duplicate studies, studies without usable data, review articles, case reports/case series, letters, animal studies, and non-English studies. We excluded incorrect populations and studies on post cardiovascular surgery.

Risk of Bias Assessment

The risk of bias in all included studies was centrally assessed by 2 reviewers (M.Y., Y.H.) using version 2 of the Cochrane Risk-of-Bias Tool for Randomized Trials (RoB 2). The risk of bias and applicability concerns were judged as low, high, or unclear.

Rating the Certainty of Evidence

The GRADEpro system was used to evaluate the quality of evidence for diagnostic studies, assessing factors such as the risk of bias, indirectness, inconsistency, imprecision, and publication bias. The certainty of evidence was categorized as high, moderate, low, or very low.^11,12

Statistical Analysis

Statistical analyses were performed using Review Manager version 5.4 (The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark). A fixed-effects meta-analysis with weighted mean differences for continuous outcomes and risk ratios for binary outcomes was performed, and 95% confidence intervals were calculated for each outcome.

Results

Search Results and Characteristics of the Included Studies

Figure 1 shows the flow diagram of the data search and selection process. A total of 3,365 articles were found in the PubMed, Web of Science, and CENTRAL databases. After evaluating the titles and abstracts, 24 articles were included in the full-text review. Finally, 2 RCTs were included in the systematic review. One RCT compared enoximone with levosimendan,¹³ and the other RCT compared milrinone with DOB.¹⁴ Milrinone and enoximone were the PDE3i studied. The detailed characteristics of the individual studies are presented in Table 1.

Figure 1.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.

Table 1.

Summary of Included Studies^13,14

Author	Year	n (%)†	Age; sex	Study design	Country	Definition of CS	Cause of CS	Early death‡
Fuhrmann et al.13	2008	Enoximon: 16 (50%) Levosimendan: 16 (50%)	Enoximon: mean 68 years; males 69% Levosimendan: mean 68 years; males 56%	Single-center, open-label RCT	Germany	(1) Deteriorating hypotension as manifested by SBP 90 mmHg, or requirement of inotropic amines and vasopressors to maintain SBP of at least 90 mmHg	Any cause (ischemic and non-ischemic)	Enoximon:10 (63%) Levosimendan: 5 (31%)
						(2) Cardiac index <2.5 L/min/m2
						(3) Pulmonary capillary occlusion pressure >18 mmHg
						(4) Clinical signs of peripheral hypoperfusion (cold skin, mental confusion, or oliguria)
Mathew et al.14	2021	Milrinone: 96 (50%) Dobutamine: 96 (50%)	Milrinone: mean 68.9 years, males 62% Dobutamine: mean 72.0 years, males 65%	Multi-center, double-blinded RCT	Canada	Meeting the SCAI definition of cardiogenic shock stage B, C, D, or E§	AMI	Miilrinone: 35 (37%) Dobutamine: 41 (43%)

^†Crude number of patients. ^‡Thirty-day death in Fuhrmann et al.¹³ and in-hospital death from any cause in Mathew et al.¹⁴ are summarized. ^§SCAI: Stage B – ‘Beginning’ (pre-shock); Stage C – ‘Classic’ cardiogenic shock; Stage D – ‘Deteriorating’; and Stage E – ‘Extremis’. AMI, acute myocardial infarction; CI, cardiac index; RCT, randomized controlled trials; SBP, systolic blood pressure below; SCAI, Society for Cardiovascular Angiography and Interventions.

Study Characteristics

Table 1 presents the characteristics of the studies included in the analysis of PDE3i in cardiogenic shock. A total of 224 patients with cardiogenic shock was assessed for the utility of PDE3i. The definition of shock varies across studies. All eligible patients were admitted to the intensive care unit and received the current recommended therapies (optimal fluid status, immediate revascularization, and inotropes). Randomization was performed using computed methods in both studies.

Outcomes

The following outcomes were set for the present study:

O (main outcomes): survival at 1 or 3 months, all-cause death, and cardiovascular death; and

O (additional outcomes): length of stay in the emergency department, fatal arrhythmia, multiple organ failure, and use of mechanical circulatory support.

However, the 2 RCTs found in this study examined the following 3 outcomes.

All-Cause Death: Early Death The 30-day deaths in 1 RCT (Fuhrmann et al.¹³) and the in-hospital deaths from any cause in another RCT (Mathew et al.¹⁴) were classified as early deaths. Figure 2A and Table 2 present the forest plot and evidence profiles of the primary outcome. PDE3i were neither superior nor inferior regarding the primary outcome in the total cohort (odds ratio [OR] 1.47; 95% confidence interval [CI] 0.35–6.26, very low certainty of evidence). There were 95 more deaths per 1,000 patients (95% CI from 243 fewer to 358 more) in the PDE3i group than in the non-PDE3i group. Regardless of the OR, considerable heterogeneity was observed among the studies (I²=72%).

Figure 2.

Forest plots for (A) early death: 30-day death in Fuhrmann et al.¹³ and in-hospital death from any case in Mathew et al.¹⁴ are summarized. (B) Cardiac arrest (VT/VF): VT or VF in Fuhrmann et al.¹³ and cardiac arrest in Mathew et al.¹⁴ are summarized. (C) Initiation of renal replacement therapy. CI, confidence interval; PDE3i, phosphodiesterase 3 inhibitors; VF, ventricular fibrillation; VT, ventricular tachycardia.

Table 2.

Evidence Profile

No. studies	Certainty assessment						No. patients		Effect		Certainty	Importance
	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	CQ7	[Placebo]	Relative (95% CI)	Absolute (95% CI)
All-cause death: early death
2	Randomised trials	Not serious	Serious	Serious	Serious	None	57/112 (50.9%)	57/112 (50.9%)	OR 1.47 (0.35 to 6.26)	95 more per 1,000 (from 243 fewer to 358 more)	⊕○○○ Very low	Critical
Cardiac arrest (VT/VF)
2	Randomised trials	Not serious	Serious	Serious	Serious	None	59/112 (52.7%)	52/112 (46.4%)	OR 1.14 (0.42 to 3.14)	62 more per 1,000 (from 67 fewer to 190 more)	⊕○○○ Very low	Critical
Initiation of renal replacement therapy
2	Randomised trials	Not serious	Not serious	Not serious	Serious	None	94/112 (83.9%)	90/112 (80.4%)	OR 1.53 (0.80 to 2.92)	43 more per 1,000 (from 83 fewer to 119 more)	⊕⊕⊕○ Moderate	Important

⊕: indicates the certainty of evidence. Higher number of ⊕ symbols signifying greater evidence quality. CI, confidence interval; MD, mean difference; OR, odds ratio; VF, ventricular fibrillation; VT, ventricular tachycardia.

Additional Outcome: Cardiac Arrest (VT/VF) Ventricular tachycardia (VT) and ventricular fibrillation (VF) in Fuhrmann et al.¹³ and cardiac arrest in Mathew et al.¹⁴ were summarized as cardiac arrest (VT/VF). Figure 2B and Table 2 show the forest plot and evidence profile of cardiac arrest (VT/VF). PDE3i were neither superior nor inferior regarding the outcome of cardiac arrest (VT/VF) in the total cohort (OR 1.14; 95% CI 0.42–3.14, very low certainty of evidence). There were 62 more cardiac arrests per 1,000 patients (95% CI from 67 fewer to 190 more) in the PDE3i group than in the non-PDE3i group. Regardless of the OR, moderate heterogeneity was observed among the studies (I²=28%).

Additional Outcome: Initiation of Renal Replacement Therapy Figure 2C and Table 2 show the forest plot and evidence profile for the initiation of renal replacement therapy. PDE3i were neither superior nor inferior regarding the outcome of this additional outcome (OR 1.53; 95% CI 0.80–2.92, moderate certainty of evidence). There were 43 more patients requiring renal replacement therapy per 1,000 patients (95% CI from 83 fewer to 119 more) in the PDE3i group than in the non-PDE3i group. Regardless of the OR, minimal heterogeneity was observed between the studies (I²=0%).

Assessment of Risk of Bias

Figure 2 shows the results of the ROB2 quality assessment of the included studies. Quality assessment of the included studies indicated a generally low risk of bias and applicability concerns across most domains. In Fuhrmann et al.,¹³ no comments on selective reporting (reporting bias) were found in the paper, and therefore selective reporting (reporting bias) was assessed as unclear in their study. Overall, the 2 studies demonstrated reliable methodological quality in almost all domains.

Table 2 summarizes the findings regarding the clinical questions and the assessment of evidence quality using the GRADEpro system. Regarding ‘all-cause death: early death’, inconsistency was downgraded because of the high I² level (I²=72%) and because the direction of the effect was not consistent between the 2 RCTs. In terms of ‘cardiac arrest (VT/VF)’, although the I² level was not high (I²=28%), the direction of the effect was not consistent between the 2 RCTs. Therefore, we also downgraded the inconsistency regarding ‘cardiac arrest (VT/VF)’. Regarding the ‘initiation of renal replacement therapy’, we judged that the inconsistency was not serious because I²=0%, and the direction of the effect was consistent between the 2 RCTs. We summarized 30-day death in Fuhrmann et al.¹³ and in-hospital death from any cause in Mathew et al.¹⁴ as ‘all-cause death: early death’, and VT or VF in Fuhrmann et al.¹³ and cardiac arrest in Mathew et al.¹⁴ as ‘cardiac arrest (VT/VF)’, so we downgraded the grade regarding indirectness in the 2 outcomes. Regarding the evaluation of imprecision, as the CI crossed the null region and the number of events was small, we determined that the imprecision was serious for all 3 outcomes.

Discussion

In the present study, we were unable to determine whether PDE3i and/or other inotropes were more effective in CS.

Shock is a clinical manifestation of circulatory failure that results in inadequate cellular oxygen utilization. Early adequate hemodynamic support of patients in shock is crucial to prevent the worsening of organ dysfunction and poor prognosis. Once shock situations have been identified, the investigation of pathophysiological mechanisms and cause stabilization must be corrected rapidly⁹ (e.g., control of bleeding and hypovolemia, percutaneous coronary intervention for coronary syndromes,^15,16 thrombolysis or embolectomy for massive pulmonary embolism, and administration of antibiotics and source control for septic shock). Fluid therapy to improve microvascular blood flow and increase cardiac output is an essential part of the treatment of any form of shock, including patients with CS.¹⁷ In routine practice, standard parameters such as decreased serum lactate levels,¹⁸ elevation of mixed venous oxygen blood saturation,¹⁹ improved urinary output,²⁰ and other biomarkers and monitors are used. If it is difficult to achieve resolution of the shock situation, and the shock is judged to be cardiogenic, we should consider inotropes and MCS.^9,21 However, it is not possible to introduce MCS promptly at every facility.

The early use of inotrope is stated for targeted hemodynamics, but the type and sequence of inotrope use is not mentioned as there is a lack of evidence.⁹ Therefore, solid evidence for the use of intravenous inotropic drugs in CS is required. Moreover, PDE3i are often used in clinical practice as an add-on to DOB, and its usefulness is unclear.

DOB is often used in CS situations because of its strong inotropic effect (β₁ stimulating). As a β₁-adrenergic agonist, DOB primarily stimulates β₁-receptors in the heart, which enhances the force of contraction and increases heart rate.²² This leads to improved perfusion and may help reverse the low-output state of CS. Additionally, DOB has mild vasodilatory effects due to β₂-receptor stimulation, which can reduce systemic vascular resistance and improve forward flow.²²

PDE3i, such as milrinone²³ and enoximone,²⁴ are used to enhance cardiac contractility and promote vasodilation. These drugs inhibit PDE3, leading to an increase in intracellular cyclic adenosine monophosphate (cAMP) levels in cardiac and vascular smooth muscle cells.²⁵ In the heart, elevated cAMP enhances calcium availability, resulting in a positive inotropic effect.²⁵ In the vasculature, it causes vasodilation, which reduces afterload and preload, thereby improving cardiac output and tissue perfusion.²⁵ Because PDE3i are expected to provide inotropic action that differs from DOB, PDE3i are often expected to be effective when used as an add-on to DOB.

The most important study comparing DOB with the PDE3i milrinone was the DOREMI trial.¹⁴ In this study, patients with cardiogenic shock were randomly assigned to receive milrinone or DOB in a double-blind style. The treatment groups did not differ significantly with respect to the primary outcome: composite of in-hospital death from any cause, resuscitated cardiac arrest, receipt of cardiac transplant or mechanical circulatory support, non-fatal myocardial infarction, transient ischemic attack or stroke diagnosed by a neurologist, or initiation of renal replacement therapy; a primary outcome event occurred in 47 (49%) participants in the milrinone group and in 52 (54%) participants in the DOB group (relative risk [RR] 0.90; 95% CI 0.69–1.19; P=0.47).

In contrast, there was only 1 small, single-center study comparing levosimendan with enoximone, which is one of the PDE3i.¹³ Levosimendan, which is not used in Japan, acts as a calcium sensitizer by stabilizing the calcium-bound conformation of troponin C, thereby enhancing myocardial contractility (positive inotropy) without increasing intracellular calcium levels.^26,27 The study by Fuhrmann et al.¹³ enrolled 32 participants investigating levosimendan compared with enoximone in people with CS induced by AMI. There were 5 (31.3%) deaths out of 16 participants in the intervention arm with levosimendan compared with 10 (62.5%) deaths out of 16 participants in the control group treated with enoximone (P=0.023 log rank test).

In the present study, we were unable to determine whether PDE3i or other inotropes were more effective in CS. In the present meta-analysis, we integrated different treatment interventions and outcomes and judged that there was a serious risk of bias in terms of indirectness.

In the ‘Heart Failure Clinical Practice Guidelines Revised 2025’, ‘Consider PDE3i for pulmonary congestion in patients with nonischemic low cardiac output and tissue hypoperfusion’ is a class IIa recommendation.²⁸ There are some previous reports of PDE3i improving hemodynamics in wet and cold patients²⁹ and being considered for use in patients on β-blockers.³⁰ However, in the present analysis, PDE3i were neither superior nor inferior regarding the outcome of the initiation of renal replacement therapy; PDE3i have been reported to induce renal dysfunction.²⁸ Further evidence must be generated and disseminated to consider use of PDE3i for a variety of situations.

Study Limitations

The present study has some limitations. First, our analysis included only 2 studies, which were insufficient to provide definitive evidence to support our findings. In the present research, we compared the effect of ‘PDE3i with or without inotropes’ with ‘no PDE3i with or without inotropes’, being conscious of the clinical expectations that PDE3i might be effective as an addition to DOB. Contrary to our speculation, we could not find RCTs comparing ‘PDE3i with DOB’ vs. ‘DOB alone’. Second, 1 study compared PDE3i with DOB, and another study compared PDE3i with levosimendan. In the 2 studies, the drugs used in the control groups differed. In addition, levosimendan has not yet been approved for use in Japan. Third, there were many differences between the 2 studies, such as the era in which the study was performed, diagnostic methods for CS, and whether they were multicenter or single-center studies. These differences may have influenced the results. We should consider the risk of bias and the quality of evidence. According to the GRADEpro system (Table 2), certainty was very low for ‘all-cause death: early death’ and ‘cardiac arrest (VT/VF)’. The study by Fuhrmann et al.¹³ was open-label. It should be noted that the 2 RCTs (Fuhrmann et al.¹³ and Mathew et al.¹⁴) could not be weighted to the same degree. More in-depth RCTs are needed to determine how PDE3i work in CS.

Conclusions

The present systematic review revealed little to no differences in outcomes, early deaths, cardiac arrest and the initiation of renal replacement therapy using PDE3i in patients with CS treated with or without other inotropes.

Acknowledgments

The authors thank Mr. Shunya Suzuki and Ms. Tomoko Nagaoka, librarians at the Dokkyo Medical University, Tochigi, Japan, for their support in the literature search. This work was supported by the Japan Resuscitation Council, Japanese Circulation Society, and JSPS KAKENHI (Grant no. JP23K08454).

Sources of Funding

None.

Disclosures

T.M. and K.T. are members of Editorial Team for Circulation Reports’. The authors have no relevant financial relationships to disclose and declare there are no conflicts of interest.

IRB Information

Not applicable.

Data Availability

All data used in this analysis are available from PubMed, Web of Science Core Collection (Science Citation Index - Expanded Since 1973), and Cochrane Library (CENTRAL) databases.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circrep.CR-25-0152

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