Milrinone as Compared with Dobutamine in the Treatment of Cardiogenic Shock.

BACKGROUND: Cardiogenic shock is associated with substantial morbidity and mortality. Although inotropic support is a mainstay of medical therapy for cardiogenic shock, little evidence exists to guide the selection of inotropic agents in clinical practice. METHODS: We randomly assigned patients with cardiogenic shock to receive milrinone or dobutamine in a double-blind fashion. The primary outcome was a composite of in-hospital death from any cause, resuscitated cardiac arrest, receipt of a cardiac transplant or mechanical circulatory support, nonfatal myocardial infarction, transient ischemic attack or stroke diagnosed by a neurologist, or initiation of renal replacement therapy. Secondary outcomes included the individual components of the primary composite outcome. RESULTS: A total of 192 participants (96 in each group) were enrolled. The treatment groups did not differ significantly with respect to the primary outcome; a primary outcome event occurred in 47 participants (49%) in the milrinone group and in 52 participants (54%) in the dobutamine group (relative risk, 0.90; 95% confidence interval [CI], 0.69 to 1.19; P = 0.47). There were also no significant differences between the groups with respect to secondary outcomes, including in-hospital death (37% and 43% of the participants, respectively; relative risk, 0.85; 95% CI, 0.60 to 1.21), resuscitated cardiac arrest (7% and 9%; hazard ratio, 0.78; 95% CI, 0.29 to 2.07), receipt of mechanical circulatory support (12% and 15%; hazard ratio, 0.78; 95% CI, 0.36 to 1.71), or initiation of renal replacement therapy (22% and 17%; hazard ratio, 1.39; 95% CI, 0.73 to 2.67). CONCLUSIONS: In patients with cardiogenic shock, no significant difference between milrinone and dobutamine was found with respect to the primary composite outcome or important secondary outcomes. (Funded by the Innovation Fund of the Alternative Funding Plan for the Academic Health Sciences Centres of Ontario; ClinicalTrials.gov number, NCT03207165.).

Cilostazol improves the prognosis after hepatectomy in rats with sinusoidal obstruction syndrome.

BACKGROUND AND AIM: Safe radical hepatectomy is important for patients with colorectal liver metastases complicated by sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy. This study aimed to investigate the impact of preoperative administration of cilostazol (CZ), an oral selective phosphodiesterase III inhibitor, on hepatectomy in rat SOS model. MATERIAL AND METHODS: Rats were divided into NL (normal liver), SOS (monocrotaline [MCT]-treated), and SOS + CZ (MCT + CZ-treated) groups. MCT or CZ was administered orally, and a 30% partial hepatectomy was performed 48 h after MCT administration. Postoperative survival rates were evaluated (n = 9, for each). Other rats were sacrificed on postoperative days (POD) 1 and 3 and evaluated histologically, immunohistochemically, biochemically, and using transmission electron microscopy (TEM), focusing particularly on SOS findings, liver damage, and liver sinusoidal endothelial cell (LSEC) injury. RESULTS: The cumulative 10-day postoperative survival rate was significantly higher in the SOS + CZ group than in the SOS group (88.9% vs 33.3%, P = 0.001). Total SOS scores were significantly lower in the SOS + CZ group than in the SOS group on both POD 1 and 3. Serum biochemistry and immunohistochemistry showed that CZ reduced liver damage after hepatectomy. TEM revealed that LSECs were significantly preserved morphologically in the SOS + CZ group than in the SOS group on POD 1 (86.1 ± 8.2% vs 63.8 ± 9.3%, P = 0.003). CONCLUSION: Preoperative CZ administration reduced liver injury by protecting LSECs and improved the prognosis after hepatectomy in rats with SOS.

Cilostazol Stimulates Angiogenesis and Accelerates Fracture Healing in Aged Male and Female Mice by Increasing the Expression of PI3K and RUNX2.

Fracture healing in the aged is associated with a reduced healing capacity, which often results in delayed healing or non-union formation. Many factors may contribute to this deterioration of bone regeneration, including a reduced 'angiogenic trauma response'. The phosphodiesterase-3 (PDE-3) inhibitor cilostazol has been shown to exert pro-angiogenic and pro-osteogenic effects in preclinical studies. Therefore, we herein analyzed in a stable closed femoral fracture model whether this compound also promotes fracture healing in aged mice. Forty-two aged CD-1 mice (age: 16-18 months) were daily treated with 30 mg/kg body weight cilostazol (n = 21) or vehicle (control, n = 21) by oral gavage. At 2 and 5 weeks after fracture, the femora were analyzed by X-ray, biomechanics, micro-computed tomography (µCT), histology, immunohistochemistry, and Western blotting. These analyses revealed a significantly increased bending stiffness at 2 weeks (2.2 ± 0.4 vs. 4.3 ± 0.7 N/mm) and an enhanced bone formation at 5 weeks (4.4 ± 0.7 vs. 9.1 ± 0.7 mm3) in cilostazol-treated mice when compared to controls. This was associated with a higher number of newly formed CD31-positive microvessels (3.3 ± 0.9 vs. 5.5 ± 0.7 microvessels/HPF) as well as an elevated expression of phosphoinositide-3-kinase (PI3K) (3.6 ± 0.8 vs. 17.4 ± 5.5-pixel intensity × 104) and runt-related transcription factor (RUNX)2 (6.4 ± 1.2 vs. 18.2 ± 2.7-pixel intensity × 104) within the callus tissue. These findings indicate that cilostazol accelerates fracture healing in aged mice by stimulating angiogenesis and the expression of PI3K and RUNX2. Hence, cilostazol may represent a promising compound to promote bone regeneration in geriatric patients.

Olprinone, a Selective Phosphodiesterase III Inhibitor, Has Protective Effects in a Septic Rat Model after Partial Hepatectomy and Primary Rat Hepatocyte.

Olprinone (OLP) is a selective inhibitor of phosphodiesterase III and is used clinically in patients with heart failure and those undergoing cardiac surgery; however, little is known about the effects of OLP on hepatoprotection. The purpose of this study aimed to determine whether OLP has protective effects in in vivo and in vitro rat models of endotoxin-induced liver injury after hepatectomy and to clarify the mechanisms of action of OLP. In the in vivo model, rats underwent 70% partial hepatectomy and lipopolysaccharide treatment (PH/LPS). OLP administration increased survival by 85.7% and decreased tumor necrosis factor-α, C-X-C motif chemokine ligand 1, and inducible nitric oxide synthase (iNOS) mRNA expression in the livers of rats treated with PH/LPS. OLP also suppressed nuclear translocation and/or DNA binding ability of nuclear factor kappa B (NF-κB). Pathological liver damage induced by PH/LPS was alleviated and neutrophil infiltration was reduced by OLP. Primary cultured rat hepatocytes treated with the pro-inflammatory cytokine interleukin-1ß (IL-1ß) were used as a model of in vitro liver injury. Co-treatment with OLP inhibited dose-dependently IL-1ß-stimulated iNOS induction and NF-κB activation. Our results demonstrate that OLP may partially inhibit the induction of several inflammatory mediators through the suppression of NF-κB and thus prevent liver injury induced by endotoxin after liver resection.

Post-stroke treatment with K-134, a phosphodiesterase 3 inhibitor, improves stroke outcomes in the stroke-prone spontaneously hypertensive rat model-A comparative evaluation of antiplatelet drugs.

Post-stroke antiplatelet therapy has been proved to reduce the risk of recurrent stroke; however, it may also increase the incidence of intracranial hemorrhage that could offset any benefits. Therefore, the balance between the benefits and risks of antiplatelet drugs is a critical issue to consider. In the present study, we have compared the effects of post-stroke administration of antiplatelet agents on functional outcomes in the stroke-prone spontaneously hypertensive rat (SHRSP), an established animal model that mimics human lacunar stroke and cerebral small vessel disease. We confirmed that a potent phosphodiesterase 3 (PDE3) inhibitor, K-134, significantly improved post-stroke survival rate and survival time, attenuated stroke-induced neurological deficits, and decreased the incidence of cerebral lesion caused by intracerebral hemorrhage and softening. Similarly, cilostazol showed beneficial effects, though to a lower extent with respect to the survival outcome and neurological symptoms. On the other hand, a P2Y12 inhibitor, clopidogrel significantly improved survival outcomes at the higher dose but caused massive bleeding in the brain at both low and high doses. In contrast, no hemorrhagic lesion was observed in K-134-treated SHRSPs despite its antiplatelet activity. Our findings indicate that K-134 may have a superior post-stroke therapeutic outcome in comparison to other antiplatelet drugs.

Cilostazol for Secondary Stroke Prevention: History, Evidence, Limitations, and Possibilities.

Cilostazol is a PDE3 (phosphodiesterase III) inhibitor with a long track record of safety that is Food and Drug Administration and European Medicines Agency approved for the treatment of claudication in patients with peripheral arterial disease. In addition, cilostazol has been approved for secondary stroke prevention in several Asian countries based on trials that have demonstrated a reduction in stroke recurrence among patients with noncardioembolic stroke. The onset of benefit appears after 60 to 90 days of treatment, which is consistent with cilostazol's pleiotropic effects on platelet aggregation, vascular remodeling, blood flow, and plasma lipids. Cilostazol appears safe and does not increase the risk of major bleeding when given alone or in combination with aspirin or clopidogrel. Adverse effects such as headache, gastrointestinal symptoms, and palpitations, however, contributed to a 6% increase in drug discontinuation among patients randomized to cilostazol in a large secondary stroke prevention trial (CSPS.com [Cilostazol Stroke Prevention Study for Antiplatelet Combination]). Due to limitations of prior trials, such as open-label design, premature trial termination, large loss to follow-up, lack of functional or cognitive outcome data, and exclusive enrollment in Asia, the existing trials have not led to a change in clinical practice or guidelines in Western countries. These limitations could be addressed by a double-blind placebo-controlled randomized trial conducted in a broader population. If positive, it would increase the evidence in support of long-term treatment with cilostazol for secondary prevention in the millions of patients worldwide who have experienced a noncardioembolic ischemic stroke.

Literature review and meta-analysis of the efficacy of cilostazol on limb salvage rates after infrainguinal endovascular and open revascularization.

BACKGROUND: Current clinical guidelines recommend the use of cilostazol in the treatment of patients with infrainguinal peripheral artery disease (PAD) who experience intermittent claudication. However, the role of cilostazol therapy in patients with advanced PAD and critical limb ischemia (CLI) remains unclear. To conduct a meta-analysis of randomized controlled trials and cohort studies that evaluated the effect of cilostazol vs standard antiplatelet therapy on limb-related and arterial patency-related outcomes. We also reviewed literature pertinent to the effect of cilostazol on wound healing in patients with advanced PAD. METHODS: We performed a MEDLINE, EMBASE, COCHRANE (CENTRAL), SCOPUS, and US Clinical Trials database search for all trials and studies since 1999 that compared cilostazol with standard antiplatelet therapy in the setting of infrainguinal PAD revascularization procedures (endovascular or open). Aggregate data was collected from four randomized control trials and six retrospective cohort studies. The end point incidence ratios and treatment effects were generated from each study and reported as hazard ratios (HR) using a random-effect model. We also reviewed 10 studies that evaluated the effect of cilostazol on wound healing in patients with advanced PAD. RESULTS: From more than 25,000 total patients, 3136 patients met our inclusion criteria. All patients had at least lifestyle-impacting intermittent claudication, and more than 50% met the definition of CLI (Rutherford class ≥4). Patient age range was 53 to 83 years, and the majority were male (66%). The mean follow-up time averaged 2 years across all studies. Meta-analysis revealed that cilostazol treatment favored amputation-free survival (hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.69-0.91), limb salvage rate (HR, 0.42; 95% CI, 0.27-0.66), decreased repeat revascularization (risk ratio [RR], 0.44; 95% CI, 0.37-0.52), and decreased restenosis (RR, 0.68; 95% CI, 0.61-0.76). Cilostazol treatment also increased freedom from target lesion revascularization (RR, 1.35; 95% CI, 1.21-1.53) with no difference in all-cause mortality. Effective wound healing was found to be an inconsistent outcome measure in patients receiving cilostazol therapy. CONCLUSIONS: We observed that cilostazol therapy has a beneficial impact on all limb-related and arterial patency-related outcomes, but no effect on all-cause mortality in patients with advanced PAD and CLI undergoing revascularization procedures. Additional studies are needed to evaluate the effect of cilostazol therapy on wound healing in patients with advanced PAD.

PDE3-inhibitor enoximone prevented mechanical ventilation in patients with SARS-CoV-2 pneumonia.

BACKGROUND: Standard care in severe SARS-CoV-2 pneumonia complicated by severe dyspnea and respiratory failure, consists of symptom reduction, ultimately supported by mechanical ventilation. Patients with severe SARS-CoV-2, a prominent feature of COVID-19, show several similar symptoms to Critical Asthma Syndrome (CAS) patients, such as pulmonary edema, mucus plugging of distal airways, decreased tissue oxygenation, (emergent) exhaustion due to severe dyspnea and respiratory failure. Prior application of elective phosphodiesterase (PDE)3-inhibitors milrinone and enoximone in patients with CAS yielded rapid symptomatic relief and reverted the need for mechanical ventilation, due to their bronchodilator and anti-inflammatory properties. Based on these observations, we hypothesized that enoximone may be beneficial in the treatment of patients with severe SARS-CoV-2 pneumonia and prominent CAS-features. METHODS: In this case report enoximone was administered to four consecutive patients (1 M; 3 F; 46-70 y) with emergent respiratory failure due to SARS-CoV-2 pneumonia. Clinical outcome was compared with three controls who received standard care only. RESULTS: After an intravenous bolus of enoximone 20 mg followed by 10 mg/h via perfusor, a rapid symptomatic relief was observed: two out of four patients recovered within a few hours, the other two (with comorbid COPD GOLD II/III) responded within 24-36 h. Compared to the controls, in the enoximone-treated patients respiratory failure and further COVID-19-related deterioration was reverted and mechanical ventilation was prevented, leading to reduced hospital/ICU time. DISCUSSION: Our preliminary observations suggest that early intervention with the selective PDE3-inhibitor enoximone may help to revert respiratory failure as well as avert mechanical ventilation, and reduces ICU/hospital time in patients with severe SARS-CoV-2 pneumonia. Our findings warrant further research on the therapeutic potential of PDE3-inhibition, alone or in combination with other anti-COVID-19 strategies.

Model difference in the effect of cilostazol on the development of experimental pulmonary hypertension in rats.

BACKGROUND: Preventing pulmonary vascular remodeling is a key strategy for pulmonary hypertension (PH). Causes of PH include pulmonary vasoconstriction and inflammation. This study aimed to determine whether cilostazol (CLZ), a phosphodiesterase-3 inhibitor, prevents monocrotaline (MCT)- and chronic hypoxia (CH)-induced PH development in rats. METHODS: Fifty-one male Sprague-Dawley rats were fed rat chow with (0.3% CLZ) or without CLZ for 21 days after a single injection of MCT (60 mg/kg) or saline. Forty-eight rats were fed rat chow with and without CLZ for 14 days under ambient or hypobaric (air at 380 mmHg) CH exposure. The mean pulmonary artery pressure (mPAP), the right ventricle weight-to-left ventricle + septum weight ratio (RV/LV + S), percentages of muscularized peripheral pulmonary arteries (%Muscularization) and medial wall thickness of small muscular arteries (%MWT) were assessed. Levels of the endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (peNOS), AKT, pAKT and IκB proteins in lung tissue were measured using Western blotting. Monocyte chemotactic protein (MCP)-1 mRNA in lung tissue was also assessed. RESULTS: mPAP [35.1 ± 1.7 mmHg (MCT) (n = 9) vs. 16.6 ± 0.7 (control) (n = 9) (P < 0.05); 29.1 ± 1.5 mmHg (CH) (n = 10) vs. 17.5 ± 0.5 (control) (n = 10) (P < 0.05)], RV/LV + S [0.40 ± 0.01 (MCT) (n = 18) vs. 0.24 ± 0.01 (control) (n = 10) (P < 0.05); 0.41 ± 0.03 (CH) (n = 13) vs. 0.27 ± 0.06 (control) (n = 10) (P < 0.05)], and %Muscularization and %MWT were increased by MCT injection and CH exposure. CLZ significantly attenuated these changes in the MCT model [mPAP 25.1 ± 1.1 mmHg (n = 11) (P < 0.05), RV/LV + S 0.30 ± 0.01 (n = 14) (P < 0.05)]. In contrast, these CLZ effects were not observed in the CH model. Lung eNOS protein expression was unchanged in the MCT model and increased in the CH model. Lung protein expression of AKT, phosphorylated AKT, and IκB was downregulated by MCT, which was attenuated by CLZ; the CH model did not change these proteins. Lung MCP-1 mRNA levels were increased in MCT rats but not CH rats. CONCLUSIONS: We found model differences in the effect of CLZ on PH development. CLZ might exert a preventive effect on PH development in an inflammatory PH model but not in a vascular structural change model of PH preceded by vasoconstriction. Thus, the preventive effect of CLZ on PH development might depend on the PH etiology.

Comparing the effects of milrinone and olprinone in patients with congestive heart failure.

Phosphodiesterase-3 (PDE3) inhibitors are widely used among patients with congestive heart failure (CHF). However, no studies have compared the cardiovascular outcomes between different PDE3 inhibitors in CHF management. In this report, we retrospectively compared the clinical benefits of two PDE3 inhibitors, milrinone and olprinone, to determine which better controls the progression of CHF. A total of 288 hospitalized patients who received PDE3 inhibitors [(milrinone; n = 77 and olprinone; n = 211, respectively)] for CHF were retrospectively enrolled. The primary endpoint was defined as having a major adverse cardiovascular and cerebrovascular event (MACCE) or cardiac death by day 60. Kaplan-Meier curves and multivariate Cox proportional models were used to compare the outcomes for patients treated with milrinone and olprinone. We found no significant differences in the baseline characteristics between the two groups. In patients treated with milrinone, a greater incidence of a MACCE or cardiac death was observed (log rank; P = 0.005 and P = 0.01, respectively). Milrinone-treated patients with ischemic heart disease and chronic kidney disease (CKD) at stage ≥ 4 presented with greater incidence of MACCE (log rank; P < 0.001 and P = 0.006, respectively). Similarly, these patients were significantly more likely to succumb to cardiac death (log rank; P < 0.001 and P = 0.02). Multivariate Cox proportional hazard models demonstrated that milrinone treatment was an independent predictor of MACCE [hazard ratio (HR) 3.17; 95% CI 1.64-6.10] and cardiac death (HR 2.64; 95% CI 1.42-4.91). Oral administration of a ß-blocker at discharge occurred more often in the olprinone-treated patients than in the milrinone-treated patients (63% vs. 29%, P = 0.004). We compared the outcomes of milrinone and olprinone treatment in patients with CHF. Those treated with milrinone were more likely to succumb to a MACCE or cardiac death within 60 days of treatment, which was especially true for patients with ischemic heart disease or CKD.

Is Milrinone Effective for Infants with Mild-to-Moderate Congenital Diaphragmatic Hernia?

OBJECTIVE: Pulmonary hypertension with left ventricular dysfunction commonly occurs in congenital diaphragmatic hernia (CDH). Milrinone, a phosphodiesterase-III inhibitor with lusitropic and vasodilator effects, is used in up to 30% of CDH infants across the United States. No randomized trials have tested the efficacy or safety of milrinone in CDH neonates. STUDY DESIGN: We performed a paired retrospective analysis of CDH infants to assess the efficacy of milrinone treatment (N = 24 pairs). Efficacy was assessed by change in oxygenation index (OI) and calculated pulmonary artery pressure (PAP). We evaluated safety on the basis of risks factors such as nonoperative bleeding, dysrhythmia, hypokalemia, and thrombocytopenia. RESULTS: The median age of milrinone initiation was 18 hours (interquartile range [IQR]: 9-38) and the median duration was 127 hours (IQR: 95-194). PAP did not change from the baseline of 49 ± 11 mm Hg (milrinone) and 53 ± 11 mm Hg (no milrinone; p = 0.327). Baseline OI was 9.6 ± 6.5. There was a similar decrease in OI (median [IQR]; milrinone: 58% [16-74]; vs. no milrinone: 65% [50-71]; p = 0.221 between groups; p < 0.005 within groups). Baseline left ventricle measurements were similar. Both groups showed significant improvement over time. No adverse events were noted. CONCLUSION: In OI-matched untreated neonates with mild-to-moderate CDH, milrinone use was associated with neither improved OI, PAP, or left ventricular measurements, nor adverse events. Study limitations warrant prospective randomized controlled trials.

Low-Dose Phosphodiesterase III Inhibitor Reduces the Vascular Amyloid Burden in Amyloid-ß Protein Precursor Transgenic Mice.

A previous study reported that relatively high-dose cilostazol (0.3%) promoted the drainage of cerebrovascular amyloid-ß (Aß) protein in Aß Precursor Protein (APP) transgenic mice overexpressing vasculotropic Aß. We investigated whether lower-dose cilostazol can decrease micro-hemorrhages and Aß deposition in the brain using APP transgenic mice. At baseline, 14-month-old female Tg2576 mice were randomly assigned to a control group (vehicle), aspirin group (0.01% aspirin), or cilostazol group (0.01% cilostazol). The severity of cerebral micro-hemorrhages (i.e., number), area of senile plaque, and severity of vascular amyloid burden (quantified with cerebral amyloid angiopathy (CAA) score (=number of Aß-positive vessels × severity of amyloid burden of Aß-positive vessels) were evaluated in the brain of mice aged 15 and 21-23 months. At 15 months, no differences were shown in each pathological change among the three groups. At 21-23 months, there were no differences in the severity of cerebral micro-hemorrhages or area of senile plaque among the three groups. However, the CAA score was significantly lower in the cilostazol compared to the control group (p = 0.046, Mann-Whitney U test), although no difference was seen between the control and aspirin group. Our study showed that lower-dose cilostazol could reduce the vascular amyloid burden without increasing cerebral micro-hemorrhages in APP transgenic mice.

Comparative effects of lipid lowering, hypoglycemic, antihypertensive and antiplatelet medications on carotid artery intima-media thickness progression: a network meta-analysis.

BACKGROUND: Carotid artery intima-media thickness (cIMT) progression is a surrogate marker of atherosclerosis with a high predictive value for future CVD risk. This study evaluates the comparative efficacies of lipid lowering, hypoglycemic, antihypertensive and antiplatelet medications on cIMT progression. METHODS: We conducted a network meta-analysis (NMA) to evaluate the relative efficacies of several drug classes in modifying cIMT progression. After a literature search in several electronic databases, studies were selected by following predetermined eligibility criteria. An inverse variance-heterogeneity model was used for NMA. Sensitivity analyses were performed to check the reliability of the overall NMA, and transitivity analyses were performed to examine the effects of modifiers on the NMA outcomes. RESULTS: Data were taken from 47 studies (15,721 patients; age: 60.2 years [95% confidence interval (CI) 58.8, 61.6]; BMI: 27.2 kg/m2 [95% CI 26.4, 28.0]; and gender: 58.3% males [95% CI 48.3, 68.3]). Treatment duration was 25.8 months [95% CI 22.9, 28.7]. Of the 13 drug classes in the network, treatment with phosphodiesterase III inhibitors was the most effective in retarding annual mean cIMT against network placebo (weighted mean difference (WMD) - 0.059 mm [95% CI - 0.099, - 0.020) followed by the calcium channel blockers (WMD - 0.055 mm [95% CI - 0.099, 0.001]) and platelet adenosine diphosphate inhibitors (WMD - 0.033 mm [95% CI - 0.058, 0.008]). These 3 drug classes also attained the same positions when the NMA was conducted by using first-year changes in mean cIMT. In transitivity analyses, longer treatment duration, higher body mass index (BMI), and a higher baseline cIMT were found to be independently associated with a lesser reduction in annual mean cIMT. However, in a multivariate analysis with these 3 modifiers, none of these factors was significantly associated with annual change in mean cIMT. In the placebo group, age was inversely associated with annual change in mean cIMT independently. CONCLUSION: Phosphodiesterase III inhibitors and calcium channel blockers are found more effective than other drug classes in retarding cIMT progression. Age, BMI, and baseline cIMT may have some impact on these outcomes.

Oral levosimendan in amyotrophic lateral sclerosis: a phase II multicentre, randomised, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of oral levosimendan in patients with amyotrophic lateral sclerosis (ALS). This phase II, randomised, double-blind, placebo-controlled, crossover, three-period study with 6 months open-label follow-up enrolled adults with ALS and sitting slow vital capacity (SVC) 60%-90 % of predicted from 11 sites in four countries. METHODS: Patients received levosimendan 1 mg daily, 1 mg two times a day or placebo during three 14-day crossover periods and levosimendan 1-2 mg daily during open-label follow-up. Primary endpoint was sitting SVC; secondary endpoints included supine SVC, ALS Functional Rating Scale-Revised (ALSFRS-R), tolerability and safety. RESULTS: Of 66 patients randomised, 59 contributed to the double-blind results and 50 entered open-label follow-up. Sitting SVC was not significantly different between the treatments. In post hoc analysis using period-wise baselines, supine SVC favoured levosimendan over placebo, estimated mean differences from baseline being -3.62% on placebo, +0.77% on levosimendan 1 mg daily (p=0.018) and +2.38% on 1 mg two times a day (p=0.001). Headache occurred in 16.7% of patients during levosimendan 1 mg daily (p=0.030), 28.6% during 1 mg two times a day (p=0.002) and 3.3% during placebo. The respective frequencies for increased heart rate were 5.1% (p=0.337), 18.5% (p=0.018) and 1.7%. No significant differences between the treatments were seen for other adverse events. CONCLUSIONS: Levosimendan did not achieve the primary endpoint of improving sitting SVC in ALS. Headache and increased heart rate were increased on levosimendan, although it was otherwise well tolerated. A phase III study to evaluate the longer term effects of oral levosimendan in ALS is ongoing.

Effect of cilostazol, a phosphodiesterase-3 inhibitor, on coronary artery stenosis and plaque characteristics in patients with type 2 diabetes: ESCAPE study.

AIM: To perform a prospective study to evaluate the effect of cilostazol (CTZ) compared with aspirin (acetylsalicylic acid; ASA) in Korean people with diabetes and subclinical coronary atherosclerosis. MATERIALS AND METHODS: A total of 100 people with diabetes who had mild to moderate coronary atherosclerosis, assessed by coronary computed tomographic angiography (CCTA), were randomly assigned to either 200 mg/d CTZ or 100 mg/d ASA (n = 50 each group). The primary outcome was change in coronary artery stenosis assessed by CCTA after 12 months of treatment. Secondary outcomes included changes in plaque composition, coronary artery calcium score and cardiac markers. RESULTS: The mean age, body mass index and glycated haemoglobin concentration were 61.5 years, 25.0 kg/m2 and 56.8 mmol/mol, respectively, and were well matched between the two groups. Coronary artery stenosis decreased in the CTZ group (from 44.0 ± 2.1% to 40.4 ± 2.5%) but remained unchanged in the ASA group (from 38.9 ± 2.1% to 40.6 ± 2.1%). In the CTZ group, the non-calcified portion of plaques decreased significantly (from 20.6 ± 3.0 to 17.3 ± 3.0 mm3 ), whereas it did not change significantly in the ASA group (15.2 ± 2.8 vs 16.6 ± 2.9 mm3 ). Increases in HDL cholesterol, decreases in triglycerides, liver enzyme and high-sensitivity C-reactive protein levels, and reductions in abdominal visceral fat area and insulin resistance were observed only in the CTZ group. CONCLUSION: CTZ treatment for 12 months decreased coronary artery stenosis and the non-calcified plaque component. These results suggest that CTZ treatment may be an option for preventing the progression of coronary atherosclerosis in people with diabetes.

Safety of cilostazol in peripheral artery disease: a cohort from a primary healthcare electronic database.

BACKGROUND: Cilostazol has been associated with spontaneous reports of cardiovascular adverse events and serious bleeding. The objective of this study is to determine the relative risk of cardiovascular adverse events or haemorrhages in patients with peripheral artery disease treated with cilostazol in comparison to pentoxifylline users. METHODS: Population-based cohort study including all individuals older than 40 who initiated cilostazol or pentoxifylline during 2009-2011 in SIDIAP database. The two treatment groups were matched through propensity score (PS). RESULTS: Nine thousand one hundred twenty-nine patients met inclusion criteria and after PS matching, there were 2905 patients in each group. 76% of patients were men, with similar mean ages in both groups (68.8 for cilostazol and 69.4 for pentoxifylline). There were no differences in bleeding, cerebrovascular and cardiovascular events between both groups. CONCLUSIONS: Patients treated with cilostazol were different from those treated with pentoxifylline at baseline, so they were matched through PS. We did not find differences between treatment groups in the incidence of bleeding or cardiovascular and cerebrovascular events. Cilostazol should be used with precaution in elderly polymedicated patients.

Cilostazol Improves Wound Healing in Patients Undergoing Open Bypass for Ischemic Tissue Loss: A Propensity Score Matching Analysis.

BACKGROUND: Few reports have described the effects of medication on the wound healing of ischemic ulcers after revascularization. This study was conducted to investigate the effects of cilostazol on wound healing in patients who underwent infrainguinal bypass for ischemic tissue loss. METHODS: Two hundred sixty-three limbs undergoing de novo infrainguinal bypass for tissue loss from January 2004 to December 2015 were divided into 2 groups based on whether or not cilostazol was administered after surgery. The end point was wound healing. The 1-year outcomes of the groups were analyzed using the Kaplan-Meier method, and a propensity score matching analysis was performed to examine the effects of cilostazol on wound healing. In addition, the significant predictors were determined using a Cox proportional hazards regression analysis. RESULTS: Sixty-one and 202 limbs were included in the cilostazol and non-cilostazol group, respectively. The cilostazol group showed superior wound healing to the non-cilostazol group (cilostazol versus non-cilostazol, 1-year wound healing rate: 92% vs. 81%; median wound healing time: 45 vs. 78 days, P = 0.002). The results of the cilostazol group remained superior after a propensity score matching (cilostazol versus non-cilostazol, 1-year wound healing rate: 95% vs. 83%; median wound healing time: 45.5 vs. 57 days, P = 0.048). A Cox proportional hazards regression analysis indicated that foot infection, Rutherford classification, diabetes mellitus, coronary artery disease, angiosome, the administration of cilostazol, and graft patency were significant factors that influenced wound healing. CONCLUSIONS: The postoperative use of cilostazol help to promote wound healing after open surgery.

Prognostic factors of ulcer healing and amputation-free survival in patients with critical limb ischemia.

OBJECTIVE: A multidisciplinary approach is required to treat critical limb ischemia. We determined the poor prognostic factors of ischemic ulcer healing after optimal arterial revascularization, and assessed the efficacy of the medication therapy using cilostazol, which is a selective inhibitor of phosphodiesterase 3. METHODS: In this retrospective, single-center, cohort study, 129 limbs that underwent infrainguinal arterial revascularization for Rutherford class 5 critical limb ischemia were reviewed. The primary end point was the ulcer healing time after arterial revascularization. The secondary end point was the amputation-free survival rate. RESULTS: Of the 129 limbs, endovascular therapy was performed in 69 limbs, and surgical reconstructive procedures were performed in 60 limbs for initial therapy. Complete ulcer healing was achieved in 95 limbs (74%). The median ulcer healing time was 90 days. In multivariate analysis, no cilostazol use significantly inhibited ulcer healing ( p = 0.0114). A white blood cell count >10,000 ( p = 0.0185), a major defect after debridement ( p = 0.0215), and endovascular therapy ( p = 0.0308) were significant poor prognostic factors for ulcer healing. Additionally, ischemic heart disease ( p < 0.0001), albumin levels <3 g/dl ( p = 0.0016), no cilostazol use ( p = 0.0078), and a major defect after debridement ( p = 0.0208) were significant poor prognostic factors for amputation-free survival rate. CONCLUSIONS: Ulcer healing within 90 days after arterial revascularization is impaired by no cilostazol use, a white blood cell count >10,000, a major defect after debridement, and endovascular therapy. Furthermore, cilostazol improves amputation-free survival rate in patients with critical limb ischemia.

Efficacy of Cilostazol in Prevention of Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage: A Meta-Analysis.

OBJECTIVES: Cilostazol, a selective inhibitor of phosphodiesterase 3, may reduce symptomatic vasospasm and improve outcome in patients with aneurysmal subarachnoid hemorrhage considering its anti-platelet and vasodilatory effects. We aimed to analyze the effects of cilostazol on symptomatic vasospasm and clinical outcome among patients with aneurysmal subarachnoid hemorrhage (aSAH). PATIENTS AND METHODS: We searched PubMed and Embase databases to identify 1) prospective randomized trials, and 2) retrospective trials, between May 2009 and May 2017, that investigated the effect of cilostazol in patients with aneurysmal aSAH. All patients were enrolled after repair of a ruptured aneurysm by clipping or endovascular coiling within 72hours of aSAH. fixed-effect models were used to pool data. We used the I2 statistic to measure heterogeneity between trials. RESULTS: Five studies were included in our meta-analysis, comprised of 543 patients with aSAH (cilostazol [n=271]; placebo [n=272], mean age, 61.5years [SD, 13.1]; women, 64.0%). Overall, cilostazol was associated with a decreased risk of symptomatic vasospasm (0.31, 95% CI 0.20 to 0.48; P<0.001), cerebral infarction (0.32, 95% CI 0.20 to 0.52; P <0.001) and poor outcome (0.40, 95% CI 0.25 to 0.62; P<0.001). We observed no evidence for publication bias. Statistical heterogeneity was not present in any analysis. CONCLUSION: Cilostazol is associated with a decreased risk of symptomatic vasospasm and may be clinically useful in the treatment of delayed cerebral vasospasm in patients with aSAH. Our results highlight the need for a large multi-center trial to confirm the observed association.