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Oral Levosimendan Increases Cerebral Blood Flow Velocities in Patients with a History of Stroke or Transient Ischemic Attack: A Pilot Safety Study.

ABSTRACT: Intravenous levosimendan is indicated for acute heart failure. The compound has shown promising beneficial effects in ischemic stroke models.We evaluated the efficacy and safety of oral levosimendan in patients with a history of cerebral ischemia.In a randomized, double-blind, placebo-controlled, parallel-group study, 16 patients with a history of ischemic stroke/transient ischemic attack received oral levosimendan in 5 escalating doses from 0.125 to 2.0 mg daily for 18-day intervals of each dose; 5 patients received placebo. Twenty-four-hour ambulatory ECG and cerebral blood flow velocities using transcranial Doppler ultrasound were recorded at baseline and at the end of each dosing period. Vasomotor reactivity was assessed via the breath holding index. In addition, plasma levels of N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP) and the metabolites of levosimendan were determined.Levosimendan induced an increase in cerebral blood flow velocities and a decrease in NT-pro-BNP compared with placebo. There was no significant effect on breath holding index. Doses ?0.5 mg increased heart rate by 5 to 9 beats/min. The dose level of 2.0 mg exceeded the preset safety margin of ventricular extrasystoles per hour (ie, upper 90% CI of the ratio of levosimendan to placebo above 2) with an estimate of 3.10 (90% CI, 0.95-10.07).Oral levosimendan increases cerebral blood flow velocities and diminishes NT-pro-BNP levels in patients with earlier ischemic cerebrovascular event. Daily doses up to 1.0 mg were well tolerated, whereas the 2.0 mg dose level induced an increase in ventricular extrasystoles. ClinicalTrials.gov identifier: NCT00698763.

SUBMITTER: Kivikko M

PROVIDER: S-EPMC4461857 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Oral Levosimendan Increases Cerebral Blood Flow Velocities in Patients with a History of Stroke or Transient Ischemic Attack: A Pilot Safety Study.

Kivikko Matti M Kuoppamäki Mikko M Soinne Lauri L Sundberg Stig S Pohjanjousi Pasi P Ellmen Juha J Roine Risto O RO

Current therapeutic research, clinical and experimental 20150129

<h4>Background</h4>Intravenous levosimendan is indicated for acute heart failure. The compound has shown promising beneficial effects in ischemic stroke models.<h4>Objective</h4>We evaluated the efficacy and safety of oral levosimendan in patients with a history of cerebral ischemia.<h4>Methods</h4>In a randomized, double-blind, placebo-controlled, parallel-group study, 16 patients with a history of ischemic stroke/transient ischemic attack received oral levosimendan in 5 escalating doses from 0 ...[more]

PMID: 26082815

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Project description:BackgroundPatients with ischemic stroke or transient ischemic attack (TIA) are at increased risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease.MethodsIn this multicenter, double-blind trial, we randomly assigned 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo. Eligible patients did not have diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index. The primary outcome was fatal or nonfatal stroke or myocardial infarction.ResultsBy 4.8 years, a primary outcome had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group (hazard ratio in the pioglitazone group, 0.76; 95% confidence interval [CI], 0.62 to 0.93; P=0.007). Diabetes developed in 73 patients (3.8%) and 149 patients (7.7%), respectively (hazard ratio, 0.48; 95% CI, 0.33 to 0.69; P<0.001). There was no significant between-group difference in all-cause mortality (hazard ratio, 0.93; 95% CI, 0.73 to 1.17; P=0.52). Pioglitazone was associated with a greater frequency of weight gain exceeding 4.5 kg than was placebo (52.2% vs. 33.7%, P<0.001), edema (35.6% vs. 24.9%, P<0.001), and bone fracture requiring surgery or hospitalization (5.1% vs. 3.2%, P=0.003).ConclusionsIn this trial involving patients without diabetes who had insulin resistance along with a recent history of ischemic stroke or TIA, the risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo. Pioglitazone was also associated with a lower risk of diabetes but with higher risks of weight gain, edema, and fracture. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00091949.).

Project description:Background and Purpose- Studies of causes of cerebral small vessel disease (SVD) should fully adjust for blood pressure (BP), but most etiological studies use a single BP measurement or history of hypertension, which might underestimate the role of hypertension. In patients with transient ischemic attack and ischemic stroke, we therefore compared the associations of baseline and long-term premorbid BP with measures of SVD on magnetic resonance imaging brain. Methods- We studied 1009 transient ischemic attack/ischemic stroke patients who had a brain magnetic resonance imaging, in the population-based OXVASC (Oxford Vascular Study), and related baseline and 20-year premorbid BP (median: 15 readings/patient) to the total SVD score on imaging. Results- SVD score was associated with increasing mean baseline systolic BP (SBP; odds ratio of top versus bottom BP quartile: 2.28; [95% CI, 1.62-3.21]; P<0.0001) and with prior hypertension (2.53; [95% CI, 2.01-3.20]; P<0.0001), but the association was much stronger with mean premorbid SBP (6.09; [95% CI, 4.34-8.55]; P<0.0001). Mean diastolic BP at baseline was negatively associated with SVD score (0.71; [95% CI, 0.51-1.00]; P=0.050), and a positive association was only evident for diastolic BP 10 to 20 years previously (3.35; [95% CI, 2.33-4.84]; both P<0.0001). Relationships between overall mean premorbid BP and SVD burden were strongest in patients age <70 (SBP: 6.99; 4.11-11.86; diastolic BP: 3.13; 1.95-5.07; both P<0.0001) versus ?70 years (2.37; 1.42-3.94; P=0.001; and 1.16; 0.74-1.84; P=0.52). Conclusions- Mean premorbid SBP is more strongly associated with SVD burden than baseline SBP or history of hypertension, and baseline diastolic BP yields a misleading estimate of the likely etiological importance of midlife hypertension for the subsequent development of SVD. Studies of novel potential etiological factors for SVD should aim to adjust for long-term prior BP, and trials of BP lowering with only a few years of follow-up may underestimate the overall impact on SVD.

Dataset Information

Oral Levosimendan Increases Cerebral Blood Flow Velocities in Patients with a History of Stroke or Transient Ischemic Attack: A Pilot Safety Study.

Publications

Oral Levosimendan Increases Cerebral Blood Flow Velocities in Patients with a History of Stroke or Transient Ischemic Attack: A Pilot Safety Study.

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