title: Dosage dependent hormonal counter regulation to combination therapy in patients with left ventricular dysfunction.
abstract: The present study attempts to assess the efficacy combination therapy for heart failure. Genuine dose-response studies on combination therapy are not available and published studies involved adding one drug on top of 'usual treatment'. Sixteen different dosage combinations of trandolapril and bumetanide was tested in a double blind, double placebo-controlled, randomized, multiple cross-over study in a 16 times six balanced incomplete Latin square design. Patients reported optimal quality of life on the sub maximal dose bumetanide. Bumetanide decreased left ventricular function and increased heart rate and plasma noradrenaline in a dose dependent manner. Doses of bumetanide of more than 0.5 mg, given twice daily significantly decreased the quality of life and increased diuresis. Weight loss was maximal on 0.5 mg bumetanide twice daily. Trandolapril significantly reduced systolic blood pressure with the maximal effect at 0.5 mg daily. Both drugs significantly increased renin concentration with a significant potentiating interaction. It was not possible to detect beneficial effects of combination therapies. The optimal dosage of Bumetanide appeared to be 0.5 mg twice daily based on its effect on quality of life and weight loss. Estimated by the reduction in systolic blood pressure the optimal dosage of Trandolapril appeared to be 0.5 mg once daily.
  
  
  CONCLUSIONS
  It appears that patients should be given less than the usually recommended dosages. Patients may be treated with a low dose loop diuretic, if signs of water retention are present or if symptomatic relief is desired.
authors.affiliation: Medical Department F, Copenhagen County Hospital in Herlev, Denmark. a.galloe@dadlnet.dk
authors.forename: A M
authors.initials: AM
authors.lastname: Galløe
authors.forename: K
authors.initials: K
authors.lastname: Skagen
authors.forename: N J
authors.initials: NJ
authors.lastname: Christensen
authors.forename: S L
authors.initials: SL
authors.lastname: Nielsen
authors.forename: E K
authors.initials: EK
authors.lastname: Frandsen
authors.forename: P
authors.initials: P
authors.lastname: Bie
authors.forename: P
authors.initials: P
authors.lastname: Dalgaard
authors.forename: K
authors.initials: K
authors.lastname: Larsen
mesh_terms: D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002034:Bumetanide / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004232:Diuretics / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D011788:Quality of Life; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D004232:Diuretics; D007211:Indoles; D002034:Bumetanide; C052035:trandolapril