Nitrates have been for many years the cornerstone of cardiovascular therapy for various indications. Not only have nitrates stood the test of time for treatment of chronic stable angina pectoris, but the indications for them have markedly ex panded. They now include all forms of angina pectoris and myocardial ischemia, congestive heart failure and hypertensive emergencies. The beneficial effects of nitrates in all these conditions result from their vasodilatory properties, but it is still unclear whether the central or peripheral effects predominate in the thera peutic mechanism. Recently nitrates have been shown to fulfill the most important requirement for each and every drug - to reduce mortality. A large scale study revealed that isosorbide dinitrate, combined with hydralazine, reduced long-term mortality by 28% in patients with congestive heart failure. This finding will certainly stimulate research on nitrates, and it might be expected that interest in these drugs will markedly increase. The primarily used nitrates in clinical practice are nitroglycerin and the com plex organic nitrates, mainly isosorbide dinitrate. The organic mononitrates are now under clinical investigation, and isosorbide-5-mononitrate (IS-5-MN) appears to be especially promising.

The. first meeting of the cardiovascular drug therapy forum took place on April 13-15, 1988 in Montreux, Switzerland. In this meeting, which was closed to the public, approximately 150 leading investigators in the field of cardiovascular drug therapy, both academics and from the pharmaceutical industry, discussed the state of the art and future trends of this rapidly expanding field. The discussions concentrated on four major topics: (1) ischemic heart disease; (2) heart failure; (3) hyper tension; (4) arrhythmias. These topics were discussed by four committees in parallel, and thereafter the main points were reviewed by the whole forum. This framework allowed both intensive and interdisciplinary discussions. This book, the first publication of selected topics from the meeting, focuses mainly on nitrate therapy in ischemic heart disease and heart failure. Adam Schneeweiss, MD Chairman v Contents Opening Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Presentation of the Sir Thomas Lauder Brunton Award for Outstanding Nitrate Research . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Origins of Symptoms in Heart Failure - Relevance in Evaluation of New Drugs . . . . . . . . . . . . . . . . . . . . 5 Mononitrates in Congestive Heart Failure . . . . . . . . . . . . . . . . . 9 Are There Differences Between the Various Formulations of Nitrates in Heart Failure? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Long-Term Nitrate Therapy - A Decade of Changing Concepts . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Nitrate Therapy in Angina Pectoris . . . . . . . . . . . . . . . . . . . . . . . . 23 Mononitrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 Transdermal Administration of Nitrates . . . . . . . . . . . . . . . . . . . 53 Nitrates in Angina Pectoris - Rationale of Use and Avoidance of Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Treatment of Congestive Heart Failure - Summary . . . . . . . ."

Cardiovascular drug therapy has markedly progressed in the recent decades. Not only have new drugs been introduced to clinical practice, but new classes of drugs have been developed. While in 1960 the practicing cardiolo gist had a selection of about only ten drugs, in 1987 about 150 drugs are routinely used in cardiovascular diseases. Elderly patients, however, usually do not enjoy the full benefit of this progress. This might be due to lack of knowledge, a conservative approach, or the worldwide tendency not to try new drugs in the elderly. It is now clear that the majority of patients that will be treated in car diovascular clinics will be, in the near future, elderly patients. Even now, elderly patients form about one-third of the patients with cardiovascular diseases. These patients are approached, however, according to criteria devel oped for younger populations. This is despite the fact that elderly patients differ from younger ones in most aspects, including pathology, epidemiol ogy, pathophysiology, diagnostic approach, management, pharmacology, pharmacokinetics, rehabilitation, and supportive treatment. It is the purpose of this book to present to the clinician all drugs with which there is clinical experience in the elderly or which might be potentially useful for the elderly with cardiovascular diseases. The data are presented without the authors taking a position. This should allow the clinicians to make their own selection and individualize treatment, vii viii Preface based on a wide data base. Comparative data are presented only when specific comparative studies were performed."

Cardiovascular drug therapy has markedly progressed in the recent decades. Not only have new drugs been introduced to clinical practice, but new classes of drugs have been developed. While in 1960 the practicing cardiolo gist had a selection of about only ten drugs, in 1987 about 150 drugs are routinely used in cardiovascular diseases. Elderly patients, however, usually do not enjoy the full benefit of this progress. This might be due to lack of knowledge, a conservative approach, or the worldwide tendency not to try new drugs in the elderly. It is now clear that the majority of patients that will be treated in car diovascular clinics will be, in the near future, elderly patients. Even now, elderly patients form about one-third of the patients with cardiovascular diseases. These patients are approached, however, according to criteria devel oped for younger populations. This is despite the fact that elderly patients differ from younger ones in most aspects, including pathology, epidemiol ogy, pathophysiology, diagnostic approach, management, pharmacology, pharmacokinetics, rehabilitation, and supportive treatment. It is the purpose of this book to present to the clinician all drugs with which there is clinical experience in the elderly or which might be potentially useful for the elderly with cardiovascular diseases. The data are presented without the authors taking a position. This should allow the clinicians to make their own selection and individualize treatment, vii viii Preface based on a wide data base. Comparative data are presented only when specific comparative studies were performed."