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How to Select a Drug for the Long-Term Treatment of Chronic Heart Failure

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How to Select a Drug for the Long-Term Treatment of Chronic Heart Failure December 1QQD Brodde American Heart Journal heart failure: concomitant reduction in betar- and betaz- Veld AJ, Schlieper P, Michel MC. Agonist-induced desensiti- adrenoceptor function related to the degree of heart failure in zation of P-adrenoceptor function in man. Subtype-selective patients with mitral valve disease. J Am Co11 Cardiol reduction in &- or @s-adrenoceptor-mediated physiological i989;14:323-31. effects by xamoterol or procaterol. Circulation 1990;81:914-21. 50. Bijhm M, Diet F, Feiler G, Kemkes B, Erdmann E. a-Adreno- 54. Motomura S, Khamssi M, Zerkowski H-R, Brodde O-E. Is ceptors and a-adrenoceptor-mediated positive inotropic ef- there a receptor reserve for isoprenaline in the human heart? fects in failing human myocardium. J Cardiovasc Pharmacol [Abstract]. Eur Heart J 1989;1O(suppl):427. 1988;12:357-64. 55. Levevre-Borg F, Lorrain J, Lechaire J, Thiry C, Hicks PE, 51. Bristow MR, Minobe W, Rasmussen R, Hershberger RE, Cavero I. Studies on the mechanisms of the development of Hoffman BB. Alpha-l adrenergic receptors in the nonfailing tolerance to the hypotensive effects of fenoldopam in rats. J and failing human heart. J Pharmacol Exp Ther 1988247: Cardiovasc Pharmacol 1988;11:444-55. 1039-45. 56. Eden RJ, Harvey CA, Hutchinson M, Owen DAA, Parker SG. 52. Schmitz W, Kohl C, Neumann J, Scholz H, Scholz J. On the Characterisation of the tolerance to the cardiovascular effects mechanism of positive inotropic effects of alpha-adrenoceptor of SK&F 101468-A in spontaneously hypertensive rats [Ab- agonists. Basic Res Cardiol 1989;84(suppl 1):23-33. stract]. Br J Pharmacol 1989;97(suppl):39OP. 53. Brodde O-E, Daul A, Michel-Reher M, Boomsma F, Man in’t How to select a drug for the long-term treatment of chronic heart failure First-line drugs for the treatment of chronic congestive heart failure should produce immediate symptomatic benefit, improve exercise tolerance, and thereby improve the quality of life. They should preferentially be active as monotherapy or at least reduce the need for comedication. The drugs must be safe and well tolerated by patients and change, in the end, the natural history of the disease, so that sudden death will be prevented and life expectancy improves. None of the currently available drugs satisfies all these criteria. Diuretics, digitalis, converting-enzyme inhibitors, and ibopamine come close to the described ideal. (Au HEART J 1990;120:1572-8.) Arie J. Man in ‘t Veld, MD, PhD Rotterdam, The Netherlands The question addressed in the title of this article is who are in sinus rhythm has been disputed for almost certainly not new and has, in fact, been discussed re- 200 years.l However, some recently reported, care- peatedly in several leading editorials in recent fully controlled, randomized, double-blind trials have years.lm6 Apparently the subject is still surrounded by now shown beyond any doubt that digoxin relieves controversies or new developments, particularly in disability and improves exercise tolerance in CHF, the field of innovations in drug treatment of the dis- thereby ending, to some extent, this long-lasting ease that are required for frequent reorientation. For discussion.8-‘2 many years digoxin and diuretics were the only It should be clearly noted that most of the infor- choices for the treatment of chronic congestive heart mation in this article as well as several considerations failure (CHF). However, even the combination of the for answering the question of how to choose a drug for two drugs fails to help patients with advanced disease the treatment of CHF, are from reviews by Packer.5y 6 and those who have the most debilitating forms of These criteria13 for choosing a drug for the treatment CHF. The efficacy of digoxin for patients with CHF of CHF will also be applied to the novel, orally active inodilator ibopamine in this article. DRUGSFORCHFTREATMENT From the Department of Internal Medicine I, University Hospital Dijkzigt, Erasmus University Rotterdam. During the past 5 years, more new drugs have been Reprint requests: Arie J. Man in’t Veld, MD, Department of Internal Med- synthesized and evaluated for the treatment of CHF icine I, University Hospital Dijkzigt, Erasmus University Rotterdam, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. than during the previous 200 years.5 More than 80 4/o/23941 different orally active compounds have been admin- 1572 Volume 120 Number 6, Part 2 Drug treatment of CHF 1573 Table I. Oral drugs for the treatment of CHF: Vasodilators Table II. 0ra.l drugs for the treatment of CHF: Neurohu- moral modulators Venodilators Isosorbide dinitrate ACE inhibitors Erythrityl tetranitrate Captopril Pentaerythritol tetranitrate Enalapril Isosorbide 5-mononitrate Lisinopril Molsidomine Quinapril Arterial dilators Ramipril Hydralazine Cilazapril Dihydralazine Perindopril Endralszine Zofenopril Cadralazine Spirapril Dipyridamole Benazapril Minoxidil Sympathetic inhibitors Ro 12-4713 Clonidine Fenoldopam Methyldopa Pinacidil Guanabenz L-Dopa Bromocriptine Ibopamine Lu-Methyl-p-tyrosine Calcium antagonists Guanethidine Verapamil Ibopamine Nifedipine a-Adrenoreceptor blockers Diltiazem Phenoxybenzamine Nicardipine Prazosin Nisoldipine Trimazosin Isradipine Terazosin Felodipine Doxazosin Amlodipine Bunazosin Nitrendipine Indoramin Mixed Urapidil Flosequinan &Adrenergic blockers More than 30 *(3-Adrenergic partial agonista Xamoterol istered to patients with CHF, and more than 30 ad- Prenalterol ditional drugs have been tested by the intravenous Serotonin antagonist Ketanserin route. Although some of these new drugs have either directly or indirectly multiple actions on the complex ACE, Angiotensin-converting enzyme. hemodynamic and neurohumoral derangements in heart failure, on the basis of their pharmacodynamic actions, they can be classified as follows: (1) vasodi- CLASSIFICATION OF CHF PATIENTS lators (arterial-venous, mixed, including a-adrenore- The clinical syndrome of CHF represents an enor- ceptor antagonists and calcium antagonists), (2) mous heterogenous entity. The patient with symp- inotropic agents, (3) o-adrenoreceptor antagonists toms may present in an early or relatively late stage (including @-adrenoreceptor “buffers” or “modula- of the disease. However, early and late are certainly tors”), (4) angiotensin-converting enzyme inhibitors, not synonymous with mild as opposed to severe, since and (5) diuretics. different causes of heart failure (ischemic vs nonis- Some drugs with a combined vasodilator and ino- chemic) and different stages of neurohumoral adap- tropic action are classified as “inodilators” according tion and cardiac remodeling complicate the picture. to the concept postulated by Opie.14 Ibopamine, a Furthermore, heart failure with left ventricular hy- prodrug, which is converted into epinine, is one of pertrophy as opposed to left ventricular dilatation these inodilators with a combined action on adrener- requires a different approach. Also, abnormalities in gic and dopaminergic receptors, through which ino- systolic and diastolic cardiac function should be tropic and vasodilator effects are mediated.15 Beyond taken into account. Still in most trials, patients are this inodilator effect, the drug also has a diuretic and classified according to the New York Heart Associa- natriuretic effect, which is mediated through renal tion (NYHA) classification despite the fact that its dopamine receptors. l6 Most of the different com- limitations are widely recognized: (1) The classifica- pounds that have been tested in patients with CHF tion does not take into account the cause of heart are listed in Tables I through IV. failure or the drugs used at the time of assessment; December 1990 1574 Man in ‘t Veld American Heart Journal Table III. Oral drugs for the treatment of CHF: Inotropics Table IV. Oral drugs for the treatment of CHF: Diuretics c-AMP independent Direct Digoxin Thiazides DPI 201-106 Loop of Henle Taurine Ibopamine Carnitine Indirect Co-enzyme QlO Aldosterone antagonists (3-adrenoreceptor stimulants Ephedrine Denopamine Pirbuterol Salbutamol Table V. Requirements for first-line drugs for the treat- Terbutaline ment of CHF, according to Packer Ibopamine Dopamine agonists Rapid relief of symptoms Improve exercise tolerance Fenoldopam Improve quality of life Dopa Reduce mortality Prevent sudden death Ibopamine (arrhythmias) Phosphodiesterase inhibitors Change natural history of Amrinone the disease (reduced Milrinone medication requirement, Enoximone hospitalizations, decline in Imazodan left ventricular function) Piroximone Effective as monotherapy CI-930 Safe, well tolerated Compliance with Ro-13-6438 prescription OPC-8212 Theophylline Calcium sensitizers Sulmazol Pimobendan GOALS IN CHF TREATMENT c-AMP, Cyclic adenosine monophosphate. CHF is a chronic, disabling, and killing disease. In modern Western society, the admission rate to hos- pitals because of the disease has increased more than (2) the lifestyle of the patient is one of the major de- threefold within 15 years.20 It is the most common terminants of the severity of symptoms; (3) the stage disease in subjects over the age of 65 years. Further- and success of compensatory mechanisms are not more, the disease carries a prognosis often worse than taken into account, and (4) above all, the classifica- cancer: &year survival rates of only 50% for even tion is notoriously subjective.4s”7 Nevertheless, since mild cases and l-year survival rates of 40 % to 60 % the classification judges the functional status of the in heart failure after a myocardial
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