Does the new angiotensin converting enzyme inhibitor cilazapril prevent restenosis after percutaneous transluminal coronary angioplasty? Results of the MERCATOR study: a multicenter, randomized, double-blind placebo-controlled trial. Multicenter European Research Trial with Cilazapril after Angiopla

BACKGROUND Cilazapril is a novel angiotensin converting enzyme inhibitor with antiproliferative effects in the rat model after balloon injury. METHODS AND RESULTS We conducted a randomized, double-blind placebo-controlled trial to assess the effect of cilazapril in angiographic restenosis prevention after percutaneous transluminal coronary angioplasty (PTCA). Patients received cilazapril 2.5 mg in the evening after successful PTCA and 5 mg b.i.d. for 6 months or matched placebo. In addition, all patients received aspirin for 6 months. Coronary angiograms before PTCA, after PTCA, and at 6-month follow-up were quantitatively analyzed. In 94% of 735 recruited patients, PTCA was successful and all inclusion and exclusion criteria were met. For the per-protocol analysis, quantitative angiography after PTCA and at follow-up was available in 595 patients who complied with the treatment regimen (309 control, 286 cilazapril). The mean difference in minimal coronary lumen diameter between post-PTCA and follow-up angiogram (primary end point) was -0.29 +/- 0.49 mm in the control group and -0.27 +/- 0.51 mm in the cilazapril group. Clinical events during 6-month follow-up, analyzed on an intention-to-treat basis, were ranked according to the most serious clinical event ranging from death (control, two; cilazapril, three), nonfatal myocardial infarction (control, eight; cilazapril, 5), coronary revascularization (control, 51; cilazapril, 53), or recurrent angina requiring medical therapy (control, 67; cilazapril, 68) to none of the above (control, 224; cilazapril, 212). There were no significant differences in ranking. CONCLUSIONS Long-term angiotensin converting enzyme inhibition with cilazapril in a dose of 5 mg b.i.d. does not prevent restenosis and does not favorably influence the overall clinical outcome after PTCA.

[1]  Louis E. Teichholz,et al.  Angiographie morphology and the pathogenesis of unstable angina pectoris , 1985 .

[2]  M. Daemen,et al.  Angiotensin II induces smooth muscle cell proliferation in the normal and injured rat arterial wall. , 1991, Circulation research.

[3]  M. Reidy,et al.  Role of basic fibroblast growth factor in vascular lesion formation. , 1991, Circulation research.

[4]  J. J. Gerbrands,et al.  Assessment of short-, medium-, and long-term variations in arterial dimensions from computer-assisted quantitation of coronary cineangiograms. , 1985, Circulation.

[5]  H. Baumgartner,et al.  The proliferative response to vascular injury is suppressed by angiotensin-converting enzyme inhibition. , 1990, Journal of cardiovascular pharmacology.

[6]  T. Resink,et al.  Induction of Thrombospondin Expression in Vascular Smooth Muscle Cells by Angiotensin II , 1990, Journal of cardiovascular pharmacology.

[7]  W. Siegenthaler,et al.  Nonoperative dilatation of coronary-artery stenosis: percutaneous transluminal coronary angioplasty. , 1979, The New England journal of medicine.

[8]  T. Ryan,et al.  Platelet accumulation in experimental angioplasty: time course and relation to vascular injury. , 1987, Circulation.

[9]  Y. Christen,et al.  Oral Administration of DuP 753, a Specific Angiotensin II Receptor Antagonist, to Normal Male Volunteers: Inhibition of Pressor Response to Exogenous Angiotensin I and II , 1991, Circulation.

[10]  M. Reidy,et al.  Role of platelets in smooth muscle cell proliferation and migration after vascular injury in rat carotid artery. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[11]  W. Wijns,et al.  Detection of restenosis after successful coronary angioplasty: improved clinical decision making with use of a logistic model combining procedural and follow-up variables. , 1990, Journal of the American College of Cardiology.

[12]  P. Serruys,et al.  Prevention of Restenosis After Percutaneous Transluminal Coronary Angioplasty With Thromboxane A2‐Receptor Blockade: A Randomized, Double‐Blind, Placebo‐Controlled Trial , 1991, Circulation.

[13]  S. Schwartz,et al.  PDGF ligand and receptor gene expression during repair of arterial injury , 1990, The Journal of cell biology.

[14]  D. Holmes,et al.  Intracoronary thrombus: role in coronary occlusion complicating percutaneous transluminal coronary angioplasty. , 1985, Journal of the American College of Cardiology.

[15]  S L Winters,et al.  Angiographic morphology and the pathogenesis of unstable angina pectoris. , 1985, Journal of the American College of Cardiology.

[16]  Robert S. Schwartz,et al.  Cardiac Imaging: A Companion to Braunwald's Heart Disease , 1992 .

[17]  R. Ross.  The pathogenesis of atherosclerosis--an update. , 1986, The New England journal of medicine.

[18]  Lynne H. Taylor,et al.  Aspirin and dipyridamole in the prevention of acute coronary thrombosis complicating coronary angioplasty. , 1987, Circulation.

[19]  H. Rupp,et al.  The metabolic syndrome and signal transduction of gene expression. , 1991, Basic research in cardiology.

[20]  V. Fuster,et al.  Balloon angioplasty. Natural history of the pathophysiological response to injury in a pig model. , 1985, Circulation research.

[21]  M. Reidy,et al.  Proliferation of smooth muscle cells after vascular injury is inhibited by an antibody against basic fibroblast growth factor. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[22]  A. Lumsden,et al.  Effects of Angiotensin Converting Enzyme Inhibition With Ciiazapril on Intimal Hyperplasia in Injured Arteries and Vascular Grafts in the Baboon , 1991, Hypertension.

[23]  H. Baumgartner,et al.  Cilazapril suppresses myointimal proliferation after vascular injury: effects on growth factor induction in vascular smooth muscle cells. , 1991, Basic research in cardiology.

[24]  M. Reidy,et al.  Intimal lesion formation in rat carotid arteries after endothelial denudation in absence of medial injury. , 1990, Arteriosclerosis.

[25]  H. Baumgartner,et al.  Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. , 1989, Science.

[26]  T. Ryan,et al.  Angiotensin converting enzyme inhibition reduces restenosis in experimental angioplasty , 1991 .

[27]  M. Nobuyoshi,et al.  Restenosis after successful percutaneous transluminal coronary angioplasty: serial angiographic follow-up of 229 patients. , 1988, Journal of the American College of Cardiology.

[28]  C Vallbracht,et al.  Recurrence rate after successful coronary angioplasty. , 1985, European heart journal.

[29]  B. Waeber,et al.  True Versus Immunoreactive Angiotensin II in Human Plasma , 1985, Hypertension.

[30]  V. Mooser,et al.  Correlation between plasma concentration of cilazapril and haemodynamic and hormonal effects in healthy man. , 1989, British journal of clinical pharmacology.

[31]  R. Sahni,et al.  Prevention of restenosis by lovastatin after successful coronary angioplasty. , 1991, American heart journal.

[32]  S. Schwartz,et al.  Replication of smooth muscle cells in vascular disease. , 1986, Circulation research.

[33]  M. Fishbein,et al.  A paradigm for restenosis based on cell biology: clues for the development of new preventive therapies. , 1991, Journal of the American College of Cardiology.

[34]  S. P. Karas,et al.  Restenosis following coronary angioplasty , 1991, Clinical cardiology.

[35]  D. Faxon,et al.  Percutaneous transluminal coronary angioplasty in 1985-1986 and 1977-1981. The National Heart, Lung, and Blood Institute Registry. , 1988, The New England journal of medicine.

[36]  Spencer B. King,et al.  Restenosis After Coronary Angioplasty: Potential Biologic Determinants and Role of Intimal Hyperplasia , 1989 .

[37]  延吉 正清.  Restenosis after successful percutaneous transluminal coronary angioplasty : serial angiographic follow-up of 229 patients , 1990 .

[38]  S. Kelsey,et al.  Percutaneous Transluminal Coronary Angioplasty: Report of Complications from the National Heart, Lung, and Blood Institute PTCA Registry , 1983, Circulation.

[39]  B. Chaitman,et al.  Multilesion coronary angioplasty: clinical and angiographic follow-up. , 1987, Journal of the American College of Cardiology.

[40]  G. Owens,et al.  Influence of blood pressure on development of aortic medial smooth muscle hypertrophy in spontaneously hypertensive rats. , 1987, Hypertension.

[41]  P. Serruys,et al.  Prevention of restenosis after percutaneous transluminal coronary angioplasty: the search for a "magic bullet". , 1991, American heart journal.

[42]  P. Serruys,et al.  Lumen narrowing after percutaneous transluminal coronary balloon angioplasty follows a near gaussian distribution: a quantitative angiographic study in 1,445 successfully dilated lesions. , 1992, Journal of the American College of Cardiology.

[43]  P. Serruys,et al.  Coronary angioplasty for unstable angina: immediate and late results in 200 consecutive patients with identification of risk factors for unfavorable early and late outcome. , 1988, Journal of the American College of Cardiology.

[44]  U. Hellman,et al.  A major part of platelet-derived growth factor purified from human platelets is a heterodimer of one A and one B chain. , 1988, The Journal of biological chemistry.

[45]  M. Reidy,et al.  Hyperplastic growth response of vascular smooth muscle cells following induction of acute hypertension in rats by aortic coarctation. , 1985, Circulation research.

[46]  V. Fuster,et al.  Syndromes of accelerated atherosclerosis: role of vascular injury and smooth muscle cell proliferation. , 1990, Journal of the American College of Cardiology.

[47]  S. Schwartz,et al.  Vascular Smooth Muscle Cell Hypertrophy and Hyperploidy in the Goldblatt Hypertensive Rat , 1983, Circulation research.

[48]  V. Dzau,et al.  Induction of platelet-derived growth factor A-chain and c-myc gene expressions by angiotensin II in cultured rat vascular smooth muscle cells. , 1989, The Journal of clinical investigation.

[49]  L Schwartz,et al.  Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty. , 1988, The New England journal of medicine.

[50]  K. Gould,et al.  Patterns in visual interpretation of coronary arteriograms as detected by quantitative coronary arteriography. , 1991, Journal of the American College of Cardiology.

[51]  P W Serruys,et al.  Incidence of restenosis after successful coronary angioplasty: a time-related phenomenon. A quantitative angiographic study in 342 consecutive patients at 1, 2, 3, and 4 months. , 1988, Circulation.