Cilostazol

Third-degree AV block (3DAVB) of a persistent and not potentially reversible type associated with symptomatic bradycardia is a class I (beneficial, useful, and effective) indication to implant a permanent pacemaker (pp). (1,2) Large experience with this procedure and phenomenal technological advances in the pacemaker generators, pacing leads, and programmability of these devices have established this mode of therapy as the "gold standard" to be implemented with almost no exception. Although such a recommendation is provided in the guidelines, it is also stated that alternative therapies can be considered if in the judgment of the physician this is deemed appropriate and/or the patient wishes not to undergo a device implantation. Occasionally, debilitation or incompetence of the patient, serious comorbidities, short expected survival, or involvement of the patients' relatives lead to a decision not to implant a device. Also, for patients destined to undergo the procedure, some patient- or health system-dependent delays are often unavoidable (ie, the patient is anticoagulated or febrile, arrangements with the implanting physician or operating room had to be cancelled, or the implantation was unsuccessful). Thus, for such a seemingly straightforward therapeutic recommendation as the implantation of a PP for 3DAVB, it is sobering even for seasoned clinicians to experience the chain of events/actions often interspersed between diagnosis and implantation of the pacemaker. This latent period, up to a point, is useful for many reasons: (1) the diagnosis needs to be established, (2) the permanent or reversible (partially or completely) nature of the conduction abnormality should be determined, (3) the association of symptoms should be sought and managed, (4) the patient must be prepared, and (5) arrangements for PP implantation must be made. In the meantime, the patient can be observed and have drugs administered; if symptomatic, the patient can undergo a temporary transvenous ventricular pacemaker insertion (3) or be paced via a transcutaneous noninvasive pacemaker. (4) Most clinicians favor to have a pacing system in place for prophylaxis even in asymptomatic patients. Such devices can be either used for pacing at a faster than the intrinsic escape rate, or can be switched to a demand mode at a lower than the intrinsic patient's rate to ensure protection if the escape rate falls further. The latter particularly applies to the transcutaneous pacemaking systems, since their activation is associated with some discomfort to the patients. Insertion of a temporary pacemaker requires expertise that should be acquired and maintained per issued guidelines. (5) Complications of this procedure, which include local hematomas, pneumothorax, arrhythmias, and pericardial invasion, are decreasing with the more recent favor of the employment of the internal jugular venous route. (5,6) Since some failures to pace with a temporary pacemaker occasionally occur, clinicians should start seeing with a more favoring eye the transcutaneous noninvasive pacing modalities; such systems were found to be tolerable in 89% of the cases, evoked effective ECG response in 78.4% of the patients, and were kept in place for periods up to 1 month in a clinical trial. (4)

Advances in knowledge of physiologic consequences of 3DAVB per se, and ventricular, as opposed to sequential AV pacemaking, with serial hemodynamic assessment and measurement of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) have established the superiority of AV stimulation for both short-term and long-term application. (7-9) These workers have dissected the underlying physiologic ramifications of the 3DAVB, AV, and ventricular pacing, and have documented selective responses in the release of ANP and BNP, depending on the presence of AV dissociation or retrograde ventriculoatrial conduction with ventricular stimulation. (7-9) What has emerged from their work is that patients with 3DAVB or implanted PPs show evidence that a complex dual natriuretic peptide system is in place that modulates its function in response to the different pacing modes. (7-9) A corollary of this could point to an additional diagnostic role for the natriuretic peptides for the patients with ventricular PPs and the "pacemaker syndrome." It is apparent that what currently is a very active area of research and practice with the natriuretic peptides as indexes of left ventricular dysfunction or congestive heart failure (CHF) (10) will have soon its parallel in the fields of 3DAVB and pacemaking.

Consideration of the role of drugs in the management of 3DAVB is unavoidable not only because under rare circumstances this remains the only alternative, but even for patients scheduled for PP implantation a drug-elicited faster escape ventricular rate may be needed as preparations are underway for insertion of a temporary IV pacemaker or application of a transcutaneous noninvasive pacemaker, or when such modalities fail. Moreover some diagnostic insights are afforded by the use of drugs, such as when atropine (a vagolytic agent) abolishes the conduction impairment at the AV node or the supra-Hisian environs. (1,2) For patients with idiopathic (and thus nonreversible) 3DAVB, use of oral drugs such as aminophylline or other xanthines (adenosine receptor inhibitors), or IV drugs like isoproterenol (a synthetic catecholamine with a [[beta].sub.1] and [[beta].sub.2] receptor agonist effects) is often attempted, but results are not favorable, and complications arise particularly with use for more than a few hours to days. (2) Of particular concern is the use of isoproterenol or other synthetic amines in patients with coronary artery disease or myocardial infarction, situations that call for its use only in emergencies. (1,2) Oral aminophylline has shown excellent dromotropic effects in patients with atrial fibrillation with slow ventricular response, by increasing the heart rate at rest and exercise (11); it would be interesting to evaluate its use for such patients who acquire the "regularization phenomenon," a form of 3DAVB.

A class of agents known as phosphodiesterase (PDE) inhibitors has also been studied in the management of bradyarrhythmias and AV conduction abnormalities. PDEs are a group of catalytic enzymes that play a wide role in many cellular processes. Xanthines are a type of PDE inhibitors, and examples of PDE type III inhibitors are the drugs amrinone and milrinone. PDE III inhibitors exert their effects by preventing cyclic adenosine monophosphate (cAMP) breakdown, while [beta]-agonists act by increasing cAMP production. Amrinone and milrinone have been employed in the critical care environment for patients with decompensated CHF, but they have led to decreased survival with long-term administration in patients with CHF. (12) Amrinone has increased the ventricular response of atrial flutter in a canine model, suggesting facilitation of AV conduction. (13) Also, in clinical studies, amrinone and milrinone was shown to improve conduction in the right atrium and the AV node. (14-16) Cilostazol, a quinolinole derivative with PDE III inhibitory action was introduced 14 years ago in Japan and 3 years ago in the United States as an antiplatelet/antithrombotic agent for the symptomatic management of patients with arterial occlusive disease and intermittent claudication. (17-22) Vast literature exists on the effects of this drug on platelets, various vascular beds and organs, and their blood flows, and its therapeutic role in cardiac diseases, stroke, and management of patients who have undergone percutaneous coronary interventions, including "stenting." (18,23-26) The pharmacokinetics, pharmacodynamics, safety, and side effects of single doses, short-term, and long-term administration have been extensively studied. (27,28) It has been found that cilostazol exerts positive chronotropic and dromotropic effects resulting in increased heart rates in patients with sick sinus syndrome, atrial fibrillation, and Mobitz I second-degree (Wenckebach) AV block. (29-32) The positive chronotropic effect of the drug has been clearly demonstrated, and the dromotropic effect was shown by the increase in ventricular response of patients with atrial fibrillation (30-32); however, the Mobitz I second-degree AV block persisted. (29) This experience has set the stage for evaluating the effect of cilostazol in patients with 3DAVB.

In this issue of CHEST (see page 1161), Kodama-Takahashi et al present their findings with the use of oral cilostazol in the management of patients with idiopathic 3DAVB. What is in order is a careful reading of the article to appreciate their selection criteria and other particulars. Briefly, the authors studied 12 carefully screened patients (mean age, approximately 80 years) of 22 patients with idiopathic 3DAVB of intra-Hisian and infra-Hisian .variety diagnosed i to 208 weeks prior to the initiation of therapy who were in New York Heart Association class II and III; none of these had severe dyspnea, presyncope, or Adams-Stokes attacks, or had prior myocardial infarction, other significant heart disease, atrial fibrillation/flutter, or renal failure, or were experiencing pulmonary congestion or hemodynamic compromise. Cilostazol, 100 mg po bid for 1 to 12 weeks, effected a significant increase in the total QRS count and decrease in the maximum R-R interval as determined by continuous 24-h ECG monitoring; none of the patients experienced alleviation or abolishment of the 3DAVB, or change in the frequency of premature ventricular beats. Also, the drug led to a significant decrease in the concentrations of ANP and BNP. Eventually, 9 of the 12 patients had a PP implanted without bleeding complications. Based on the favorable effect on the ventricular escape rate and the absence of side effects, the authors recommended short-term therapy with cilostazol for selected patients with 3DAVB.

This work, the first to focus on cilostazol and 3DAVB, is limited due to the small number of patients studied, the briefness of follow-up (the patients received the drug for a mean of approximately 3 weeks and a maximum of 12 weeks), and the lack of information on the quality of life that the patients experienced. Nevertheless, it demonstrates the feasibility of impacting the escape rate of patients with 3DAVB who have not undergone a PP implantation for whatever reason. It should be understood that the drug did not abolish or ameliorate the 3DAVB, and only some inconsistent transient changes in AV synchrony were noted in a few patients. Physicians could start administering cilostazol to carefully selected patients with 3DAVB following as blueprint the authors' study design. It is unfortunate that there are no data in the literature about the long-term behavior of the escape rate in untreated patients with 3DAVB, against which cilostazol could be compared at follow-up. However the heart rate of patients under treatment should be checked both at rest and following the routine tasks elderly patients engage in to appreciate adequacy of the escape ventricular activity, and whether ventricular ectopy has arisen. Occasional long-term ambulatory ECG monitoring sessions could provide more substantial data on these, and also resolve whether cilostazol results in meaningfully prolonged intervals of returned AV synchrony. Also it is important that this therapy is assessed in reference to its long-term contribution in the patient's lifestyle, as compared with how the patients fared prior to acquiring 3DAVB. Cilostazol, like other PDE III inhibitors, should be avoided in patients with CHF (12) or left ventricular dysfunction; four patients in the study were in class III, and possible progression to class IV status should be kept in mind. Finally drug interactions (known and emerging) of cilostazol should be reviewed and followed, as other medications are added to the patients' regimens; a case in point is the co-administration of cilostazol and clopidogrel (the latter recommended for primary and secondary prevention of stroke), which is currently undergoing evaluation. Other such interactions may prove advantageous like the combined use of cilostazol and [beta]-agonists or adenosine receptor antagonists, as in the case of the three patients in the study who did not receive a PP. There are no data as to what prompts the delays often encountered in the permanent management of 3DAVB in many patients; perhaps this may be due to uncertainty about the permanency of the conduction abnormality on the part of the clinician, ambivalence/procrastination in the patient or relatives to agree with the procedure, or unavailability of local expertise to implant the device. In any case, it is reassuring to have an addition in the pharmacologic armamentarium available for the management of patients with 3DAVB. More research on this topic and clinical use of cilostazol will clarify its role in the stabilization of the bulk of patients awaiting implantation of a PP, and clinical amelioration and improved lifestyle for those in the minority who do not undergo such a procedure. It is in the context of all of the above that this early experience with cilostazol in patients with 3DAVB constitutes an advancement.

REFERENCES

(1) Gregoratos G, Cheitlin MD, Freedman RA, et al. ACC/AHA guidelines for implantation of cardiac pacemakers and anti-arrhythmia devices: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Pacemaker Implantation). J Am Coil Cardiol 1998; 31:1175-1209

(2) Braunwald E, Zipes D, Libby P, eds. Heart disease: a textbook of cardiovascular medicine. 6th ed. Philadelphia, PA: W.B. Saunders, 2001; 700-815 (3) Furman S, Robinson G. The use of an intracardiac pacemaker in the correction of total heart block. Surg Forum 1958; 9:24,5-248

(4) Zoll PM, Zoll RH, Falk RH, et al. External noninvasive temporary cardiac pacing: clinical trials. Circulation 1985; 71:937-944

(5) Francis GS. Insertion of a temporary transvenous ventricular pacemaker competence statement: clinical competence in insertion of a temporary transvenous ventricular pacemaker. ACP/ACC/AHA Task Force on Clinical Privileges in Cardiology. J Am Coll Cardiol 1994; 23:1254-1257

(6) Hynes JK, Holmes DR, Harrison CE. Five-year experience with temporary pacemaker therapy in the coronary care unit. Mayo Clin Proc 1983; 58:122-126

(7) Vardas PE, Travill CM, Williams TDM, et al. Effects of dual chamber pacing on raised plasma atrial natriuretic peptide concentrations in complete atrioventricular block. BMJ 1988; 296:94

(8) Baratto MT, Berti S, Clerico A, et al. Atrial natriuretic peptide during different pacing modes in a comparison with hemodynamic changes. Pacing Clin Electrophysiol 1990; 13:432-442

(9) La Villa G, Padeletti L, Lazzeri C, et al. Plasma levels of natriuretic peptides during ventricular pacing with a dual chamber pacemaker. Pacing Clin Electrophysiol 1994; 17: 953-958

(10) Davidson NC, Naas AA, Hanson JK, et al. Comparison of atrial natriuretic peptide B-type natriuretic peptide, and N-terminal proatrial natriuretic peptide as indicators of left ventricular systolic dysfunction. Am J Cardiol 1996; 15:823831

(11) Alboni P, Ratto B, Scarfo S, et al. Dromotropic effects of oral theophylline in patients with atrial fibrillation and slow ventricular response. Eur Heart J 1991; 12:630-634

(12) Packer M, Carver JR, Chesebro JH, et al. Effect of oral milrinone on mortality in severe chronic heart failure: the PROMISE Study Research Group. N Engl J Med 1991; 325:1468-1475

(13) Piwonka RW, Healey JF, Canniff PC, et al. Electrophysiological actions of amrinone in dogs with cardiac lesions. J Cardiovasc Pharmacol 1983; 5:1052-1057

(14) Naccarelli GV, Gray EL, Dougherty AH, et al. Amrinone: acute electrophysiologic and hemodynamic effects in patients with congestive heart failure. Am J Cardiol 1984; 54:600-604

(15) Naccarelli GV, Goldstein RA. Electrophysiology of phosphodiesterase inhibitors. Am J Cardiol 1989; 63:35A-40A

(16) Goldstein RA, Geraci SA, Gray EL, et al. Electrophysiologic effects of milrinone in patients with congestive heart failure. Am J Cardiol 1986; 57:624-628

(17) Okuda Y, Kimura Y, Yamashita K. Cilostazol. Cardiovasc Drug Rev 1993; 11:451-465

(18) Shintani S, Watanabe K, Kawamura K, et al. General pharmacological properties of cilostazol, a new antithrombotic drug. Part II: effect on the peripheral organs. Arzneimittelforschung 1985; 35:1163-1172

(19) Uchikawa T, Murakami T, Furukawa H. Effects of the anti-platelet agent cilostazol on peripheral vascular disease in patients with diabetes mellitus. Arzneimittelforschung 1992; 42:322-324

(20) Liu Y, Fong M, Cone J, et al. Inhibition of adenosine uptake and augmentation of ischemia-induced increase of interstitial adenosine by cilostazol, an agent to treat intermittent claudication. J Cardiovasc Pharmacol 2000; 36:351-360

(21) Reilly MP, Mohler ER III. Cilostazol: treatment of intermittent claudication. Ann Pharmacol 2001; 35:48-56

(22) Cariski AT. Cilostazol: a novel treatment option in intermittent claudication. Int J Clin Pract 2001; 119(Suppl):11-18

(23) Tanaka T, Muneyuki T, Oka Y, et al. Effects of long-term administration on coronary flow velocity and coronary flow reserve. J Cardiol 1999; 34:183-188

(24) Tsusui M, Shimokawa H, Higuchi S, et al. Effect of cilostazol, a novel anti-platelet drug, on restenosis after percutaneous transluminal coronary angioplasty. Jpn Circ j 1996; 60:207-215

(25) Yoshitomi Y, Kojima S, Sugi T, et al. Antiplatelet treatment with cilostazol after stent implantation. Heart 1998; 80:393-396

(26) Park SW, Lee CW, Kim HS, et al. Comparison of cilostazol versus ticlopidine therapy after stent implantation. Am J Cardiol 1999; 84:511-514

(27) Niki T, Mori H. Phase I study of cilostazol: safety evaluation at increasing single doses in healthy volunteers. Arzneimittelforschung 1985; 35:1173-1185

(28) Suri A, Forbes WP, Bramer SL. Pharmacokinetics of multiple-dose cilostazol in middle-age and elderly men and women. J Clin Pharmacol 1998; 38:144-150

(29) Atarashi H, Endoh Y, Saitoh H, et al. Chronotropic effects of cilostazol, a new antithrombotic agent, in patients with bradyarrhythmias. J Cardiovasc Pharmacol 1998; 31:534-539

(30) Yamashita S, Miyagawa K, Inagaki T, et al. Cilostazol increased heart rate with improvement of activity of daily living in an elderly patient with sick sinus syndrome. Nippon Rouen Igakkai Zasshi 1999; 36:561-564

(31) Toyonaga S, Nakatsu T, Murakami T, et al. Effects of cilostazol on heart rate and its variation in patients with atrial fibrillation associated with bradycardia J Cardiovasc Pharmacol 2000; 5:183-191

(32) Kishida M, Watanabe K, Tsuruoka T. Effects of cilostazol in patients with bradycardiac atrial fibrillation. J Cardiol 2001; 37:27-33

Dr. Madias is from the Division of Cardiology, Elmhurst Hospital Center, and the Mount Sinai School of Medicine, of the New York University.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: John E. Madias, MD, Professor of Medicine (Cardiology), Division of Cardiology, Elmhurst Hospital Center, 79-01 Broadway, Elmhurst, NY 11373; e-mail: madiasj@ nychhc.org

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