ORIGINAL ARTICLE Dosage dependent hormonal counter regulation to combination therapy in patients with left ventricular dysfunction A. M. Galløe* MD PhD, K. Skagen* MD ScD, Professor N. J. Christensen* ScD, S. L. Nielsen MD ScD, E. K. Frandsenà MSc , Professor P. Bie§ ScD, P. Dalgaard– MSc and K. Larsen– MSc *Medical Department F,  Department of Clinical Physiology, Copenhagen County Hospital in Herlev, àDepartment of Clinical Physiology, Copenhagen County Hospital in Glostrup, §Department of Medical Physiology and –Department of Biostatistics, Panum Institute, University of Copenhagen, Denmark SUMMARY 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 tran- dolapril and bumetanide was tested in a double blind, double placebo-controlled, randomized, multiple cross-over study in a 16 times six bal- anced incomplete Latin square design. Patients reported optimal quality of life on the sub max- imal dose bumetanide. Bumetanide decreased left ventricular function and increased heart rate and plasma noradrenaline in a dose dependent man- ner. Doses of bumetanide of more than 0Æ5 mg, given twice daily significantly decreased the quality of life and increased diuresis. Weight loss was maximal on 0Æ5 mg bumetanide twice daily. Trandolapril significantly reduced systolic blood pressure with the maximal effect at 0Æ5 mg daily. Both drugs significantly increased renin concen- tration with a significant potentiating interaction. It was not possible to detect beneficial effects of combination therapies. The optimal dosage of Bumetanide appeared to be 0Æ5 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 0Æ5 mg once daily. Conclusions: It appears that patients should be given less than the usually recommended dos- ages. Patients may be treated with a low dose loop diuretic, if signs of water retention are present or if symptomatic relief is desired. Keywords: angiotensin-converting enzyme inhib- itors, bumetanide, diuretics, drug dose–response relationship, adrenaline, left ventricular dysfunc- tion, myocardial infarction, quality of life, renin– angiotensin system, trandolapril, vasopressin. INTRODUCTION Patients with left ventricular dysfunction are usu- ally treated with several drugs concomitantly. This is justified if the treatment prolongs life and/or improves the quality of life. Specific drug actions on different organs presumably mediate these effects. The evidence for combination therapy has not been generated from studies on simultaneously initiated combination therapy but rather from studies, where one drug is added on top of ‘usual treatment’. Such designs may lead to identification of sub-optimal effects because of undiscovered J-curves in dosage–effect relationships caused by organ specific unwanted counter-regulations. We have not been able to identify double-blind, placebo-controlled studies on multiple dosage combinations in patients with heart failure in spite of the abundance of such patients. The combination of an ACE-inhibitor and a diuretic is widely used in Received 6 August 2004, Accepted 20 October 2004 Correspondence: Anders Michael Galløe, Medical Department P, Copenhagen County Hospital in Gentofte, 2900 Hellerup, Denmark. Tel.: (+45) 39 77 39 50; fax: (+45) 39 77 76 21; e-mail: a.galloe@dadlnet.dk Journal of Clinical Pharmacy and Therapeutics (2006) 31, 139–147 Ó 2006 Blackwell Publishing Ltd 139