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Combination products

Editor, – We refer to the article `Combination products - love them or loathe them?' and comment on the unrealised potential of this type of agent in treating medical syndromes. Polypharmacy is a chief cause of poor compliance.1 The recent trend for evidence-based medicine supports the use of multi-drug regimens. This is exemplified by heart failure, in which angiotensin-converting enzyme inhibitors2,beta blockers3 and spironolactone4 have all been shown to improve mortality. In addition, diuretics ameliorate symptoms5,and digoxin reduces hospital admissions.6 Heart failure thus demands a pharmaceutical quintet, even before addressing the cause of the cardiac dysfunction. We believe that the true niche for combination products is in the management of medical syndromes, such as heart failure or the metabolic syndrome, rather than in specific risk factor control. In this context the arguments against combination therapies, as outlined in the article, are less persuasive. The doses may still need to be initially adjusted, but the stable dose will depend upon the evidence from the trials. A starter pack with graded dosages may ease initial concerns and allow manipulation of certain dose sensitive components. There would not be `unnecessary risk' as all the components would be of proven benefit. The differing pharmacokinetics of the components would, however, still need consideration. Validation would require randomised trials comparing the combination product to the individual drugs, on an intention-to-treat basis. These combinations, rather than promoting `lazy prescribing' would help doctors to ensure the best, evidence-based care for patients with complex problems.

Liza Phillips
Medical Intern
Daniel Worthley
Medical Resident
Royal Adelaide Hospital

Associate Professor Robert Moulds, author of `Combination products - love them or loathe them?', comments:

Editor, – Dr Phillips and Dr Worthley have raised an interesting point. However, it is not necessarily correct to assume that because ACE inhibitors, beta blockers and spironolactone have each individually been shown to improve mortality in heart failure, then all, or even most, patients should be treated with all three drugs. Similarly, trials which show digoxin reduces hospital admissions do not mean all patients should be treated with digoxin. Each of the sets of trials studying those drugs had significant (and different) inclusion and exclusion criteria, and the results cannot necessarily be extrapolated to all patients with heart failure. Indeed it would be an interesting exercise to look at a series of patients with heart failure and see how many would have met the entry criteria, and would have had no exclusion criteria, for each of the trials showing the benefits of ACE inhibitors, beta blockers, spironolactone and digoxin. My guess is relatively few patients would qualify.

There would also be difficulty in finding kinetically suitable combinations, and difficulty with the initial dose titration required with some of the drugs, not to mention finding a pharmaceutical company with deep enough pockets to sponsor the clinical trials necessary to establish that a combined heart failure tablet is equally as efficacious as the individual components.

Despite the seeming attraction, I doubt we will see a combination treatment for heart failure in the near future.


  1. Corlett AJ. Aids to compliance with medication.Br Med J 1996;313: 926-9.2. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA 1995;273:1450-6.3. Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. US Carvedilol Heart Failure Study Group. N Engl J Med 1996;334:1349-55.4. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709-17.5. Lonn E, McKelvie R. Drug treatment in heart failure. Br Med J 2000;320:1188-92.6. The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med 1997;336:525-33 .