Low-dose carvedilol reduces transmural heterogeneity of ventricular repolarization in congestive heart failure

ObjectivesTo investigate the influence of vasodilator drugs on the occurrence of features depending on myocardial ischaemia/fibrosis (ventricular arrhythmias, Q waves, cardiac blocks, pacemaker implantation, left ventricular ejection fraction (LVEF) <55%, and/or congestive heart failure and sudden cardiac death) in systemic sclerosis (SSc).Methods601 patients with SSc were enrolled from 1 December 2012 to 30 November 2015 and had a second visit 0.5–4 years apart. 153 received no vasodilators; 448 received vasodilator therapy (ie, calcium channel blockers and/or ACE inhibitors or angiotensin II receptor blockers or combinations of them), 89 of them being also treated with either endothelin receptor antagonists or PDE5 inhibitors or prostanoids. Associations between the occurrence of myocardial disease manifestations and any demographic, disease and therapeutic aspect were investigated by Cox regression analysis. A Cox frailty survival model with centre of enrolment as random effect was performed.ResultsDuring 914 follow-up patient-years, 12 ventricular arrhythmias, 5 Q waves, 40 cardiac blocks, 6 pacemaker implantations and 19 reduced LVEF and/or congestive heart failure (CHF) occurred. In multivariate Cox regression analysis, vasodilator therapy was associated with a lower incidence of ventricular arrhythmias (p=0.03); low-dose acetylsalicylic acid (ASA) with a lower incidence of cardiac blocks and/or Q waves and/or pacemaker implantation (p=0.02); active disease with a higher incidence of LVEF <55% and/or CHF and cardiac blocks and/or Q waves and/or pacemaker implantation (p=0.05).ConclusionsThe present study might suggest a preventative effect on the occurrence of distinct myocardial manifestations by vasodilator therapy and low-dose ASA.

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Short and long-term effects of treatment with low dose captopril in patients with severe congestive heart failure.

British Journal of Clinical Pharmacology ◽

10.1111/j.1365-2125.1982.tb02082.x ◽

1982 ◽

Vol 14 (S2) ◽

pp. 231S-235S ◽

Cited By ~ 5

Author(s):

U Dahlstrom ◽

BE Karlberg

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Low Dose ◽

Severe Congestive Heart Failure ◽

Long Term Effects ◽

Short And Long Term

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Decitabine Improves Clinical Outcomes in Severely Ill Sickle Cell Disease Patients Who Have Exhausted Standard of Care Options.

Blood ◽

10.1182/blood.v110.11.3792.3792 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3792-3792

Author(s):

Yogenthiran Saunthararajah ◽

Robert Molokie ◽

Seema Sidhwani ◽

Santosh Saraf ◽

Stephen Vara ◽

...

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Clinical Trials ◽

Low Dose ◽

Performance Status ◽

Fetal Hemoglobin ◽

Standard Of Care ◽

Cell Disease ◽

Off Label ◽

Clinically Significant

Abstract Interventions such as immunization, penicillin prophylaxis, hydroxyurea and transfusion have extended life in patients with sickle cell disease (SCD). Nonetheless, these interventions are limited by toxicity or effectiveness; continued substantial morbidity and mortality in SCD indicates the need for better disease modification. In previous phase I/II clinical trials, 13 of 13 patients treated with the DNA hypomethylating agent decitabine responded with clinically significant fetal hemoglobin and total hemoglobin elevation and improvement in surrogate clinical end-points. However, in these early studies, no clinical end-points were measured and further studies have been delayed by funding issues. We describe an off-label experience in four patients with severe SCD that suggests remarkable clinical effectiveness in patients who have exhausted standard of care and are severely ill; tolerability even in the severely ill; a mechanism of action based on increased reticulocytosis in addition to increased fetal hemoglobin. All four patients had multiple alloantibodies and red-cell auto-antibodies that limited availability and increased risks of transfusion, and had previously been treated with hydroxyurea with continued clinical deterioration. Three of the four patients had relative reticulocytopenia (absolute reticulocyte count <250x109/L and hemoglobin <9g/dl) and were receiving erythropoietin or darbopoietin for more than 8 weeks with continued progressive anemia and progressive congestive heart failure. All four patients were ECOG performance status 3 and ineligible for available clinical trials. Based on the clinical trial experience conducted at our institution, decitabine therapy at 0.1–0.2 mg/kg 1–2X/week was initiated in these patients not for research purposes but with the intent to produce direct clinical benefit. The limited clinical data and potential for unanticipated toxicity was discussed in full with each patient and family members. IRB approval was obtained for a retrospective chart review. No decitabine related adverse events occurred. All patients demonstrated >2g/dl increases in hemoglobin levels with an associated improvement in clinical status - decrease in pain, improvement in performance status, improvement in congestive heart failure symptoms/signs. Upward trends in the platelet and reticulocyte counts concurrent with downward trends in the neutrophil counts were consistent with previously observed effects of low dose decitabine or the related compound 5-azacytidine. Clinically significant neutropenia was avoided by dose reductions that did not reverse the improved hemoglobin levels. The differentiation altering effects of low dose decitabine relieve SCD anemia by decreasing hemolysis (through elevated HbF) and increasing reticulocytosis. Previous clinical trials, and this off-label experience, suggest that decitabine holds remarkable promise as a disease modifying agent for SCD and β-thalassemia. Further clinical trials to confirm this impression should be supported.

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