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ACC/AHA Expert Consensus Document
Use of Sildenafil (Viagra) in Patients With
Cardiovascular Disease
Melvin D. Cheitlin, MD, FACC, Cochair; Adolph M. Hutter, Jr, MD, MACC, Cochair; Ralph G. Brindis, MD, MPH, FACC; Peter Ganz, MD, FACC; Sanjay Kaul, MD; Richard O. Russell, Jr, MD, FACC; Randall M. Zusman, MD, FACC* Technology and Practice Executive Committee James S. Forrester, MD, FACC, Chair; Pamela S. Douglas, MD, FACC; David P. Faxon, MD, FACC; John D. Fisher, MD, FACC; Raymond J. Gibbons, MD, FACC; Jonathan L. Halperin, MD, FACC; Adolph M. Hutter, Jr, MD, MACC; Judith S. Hochman, MD, FACC; Sanjiv Kaul, MD, FACC*; William S. Weintraub, MD, FACC; William L. Winters, Jr, MD, MACC; Michael J. Wolk, MD, FACC Executive Summary
Viagra. Thus, for patients who experience an acute cardiac The pharmaceutical preparation sildenafil citrate (Viagra) is ischemic event and who have taken Viagra within the past being widely prescribed as a treatment for male erectile 24 h, administration of nitrates should be avoided. In the dysfunction, a common problem that in the United States event that nitrates are given, especially within this critical affects between 10 and 30 million men. The introduction of time interval, it is essential to have the capability to support sildenafil has been a valuable contribution to the treatment of the patient with fluid resuscitation and ␣-adrenergic agonists erectile dysfunction, which is a relatively common occur- if needed. In patients with recurring angina after Viagra use, rence in patients with cardiovascular disease. This article is other nonnitrate antianginal agents, such as ␤-blockers, written to appropriately caution and not to unduly alarm physicians in their use of sildenafil in patients with heart Other patients in whom the use of Viagra is potentially hazardous include those with active coronary ischemia; those Reported cardiovascular side effects in the normal healthy with congestive heart failure and borderline low blood vol- population are typically minor and associated with vasodila- ume and low blood pressure status; those with complicated, tation (ie, headache, flushing, and small decreases in systolic multidrug, antihypertensive therapy regimens; and those tak- and diastolic blood pressures). However, although their inci- ing medications that may affect the metabolic clearance of dence is small, serious cardiovascular events, including sig- Viagra. With respect to patients following complicated mul- nificant hypotension, can occur in certain populations at risk.
tidrug, antihypertensive programs, the randomized studies Most at risk are individuals who are concurrently taking included a large number of hypertensive patients. However, organic nitrates. Organic nitrate preparations are commonly most patients were controlled with 1 antihypertensive agent, prescribed to manage the symptoms of angina pectoris. The and only a small number were controlled with 3 antihyper- coadministration of nitrates and Viagra significantly in- tensive agents. Until adequate studies are done in these creases the risk of potentially life-threatening hypotension.
subgroups of patients, sildenafil should be prescribed with Therefore, Viagra should not be prescribed to patients receiv- Viagra acts as a selective inhibitor of cyclic GMP Although definitive evidence is currently lacking, it is (cGMP)–specific phosphodiesterase type 5, resulting in possible that a precipitous reduction in blood pressure with smooth muscle relaxation, vasodilatation, and enhanced pe- nitrate use may occur over the initial 24 hours after a dose of nile erection. Although the cardiovascular effects of sildenafil The ACC/AHA Expert Consensus Document “Use of Sildenafil (Viagra) in Patients With Cardiovascular Disease” was approved by the Board of Trustees of the American College of Cardiology in September 1998 and the American Heart Association Science Advisory and Coordinating Committeein September 1998. Reprints of this document are available by calling 800-253-4636 (US only) or writing American College of Cardiology, EducationalServices, 9111 Old Georgetown Road, Bethesda, MD 20814-1699. To make photocopies for personal or educational use, call the Copyright ClearanceCenter at 978-750-8400.
*Those authors designated with an asterisk have indicated a potential conflict of interest with respect to the topic of this document. They have excused themselves from discussions or the preparation of the text whence this potential conflict would apply.
January 1999(J Am Coll Cardiol 1999;33:273– 82) 1998 American College of Cardiology and American Heart Association, Inc.
ACC/AHA Expert Consensus Document
reported in available randomized, controlled clinical trials men take nitrates on a regular basis for angina pectoris (5), were relatively minor, heart disease patients represented only and another half a million will experience a heart attack a small fraction of studied patients and patients with heart annually and are potential candidates for nitrate therapy (6).
failure, patients with myocardial infarction or stroke within 6 Sildenafil is potentially contraindicated in as many as 6 months or patients with uncontrolled hypertension were not included in these studies. Thus, there are possible problems in The introduction of sildenafil citrate (Viagra), a drug that the use of Viagra in these patients that have not been acts as a selective inhibitor of cGMP–specific phosphodies- terase type 5 (PDE5), which results in smooth muscle Given the increasing reports of deaths in which the use of relaxation, vasodilatation, and enhanced penile erection, has Viagra may be implicated, clinicians need to exercise caution been a major advancement in the treatment of erectile when advising their patients with heart disease about taking dysfunction (7). The vasodilating action of sildenafil affects this medication. Specific recommendations regarding silde- both the arteries and the veins, so the most frequent side effects nafil (Viagra) and the cardiac patient are summarized in the of sildenafil are headache and facial flushing (8). Sildenafil causes small decreases in systolic and diastolic blood pressures,but clinically significant hypotension is rare. Studies of sildenafil Summary Table of Clinical Recommendations
and nitrates taken together show much greater drops in bloodpressure. For that reason, it is contraindicated to use sildenafil in patients who take long-acting nitrates or who use short-acting, 1. Concurrent use of nitrates (see Appendix A) B. Cardiovascular effects of Viagra may be potentially hazardous (use In the phase II/III studies completed before Food and Drug dependent on individual clinical assessment) Administration (FDA) approval, Ͼ3700 patients received 1. Patients with active coronary ischemia who are not taking nitrates (eg, sildenafil and almost 2000 received placebo in double-blind and open-label studies. None were taking long-acting nitrates, 2. Patients with congestive heart failure and borderline low blood although patients with coronary artery disease were not pressure and borderline low volume status excluded. Approximately 25% of the patients had hyperten- 3. Patients on a complicated, multidrug, antihypertensive program sion and were taking antihypertensive medications, and 17% 4. Patients taking drugs that can prolong the half-life of Viagra (see were diabetic. In these studies, the incidence of serious cardiovascular adverse effects was similar in the double-blindsildenafil group, the double-blind placebo group, and the I. Preamble
open-label group. There were 28 patients who had a myocar- The present document is an expert consensus. This type of dial infarction. When adjusted for patient-years of exposure, document is intended to inform practitioners, payers and there were no differences in myocardial infarction rate other interested parties of the opinion of the American between the sildenafil group and the placebo group, and no College of Cardiology (ACC) concerning evolving areas of deaths were attributed to treatment. The incidence of myo- clinical practice and/or technologies that are widely available cardial infarction was 1.7/100 patient-years (95% CI, 0.8 to or are new to the practice community. Topics chosen for 2.6) in the sildenafil group and 1.4/100 patient-years (95% coverage by Expert Consensus Documents are so designated CI, 0.2 to 2.6) in the placebo group (9). In the subsequent because the evidence base and experience with the technol- analysis done in May 1998, sildenafil exposure had increased ogy or clinical practice are not sufficiently well developed to to 4913 patient-years (693 double-blind sildenafil; 4220 be evaluated by the formal ACC/American Heart Association open-label extensions), and 26 deaths had been reported, for (AHA) Practice Guidelines process. Thus, the reader should an incidence rate of 0.53/100 patient-years. The incidence for view the Expert Consensus Documents as the best attempt of placebo remained the same (ie, 2 deaths or 0.57/100 patient- the ACC to inform and guide clinical practice in areas in which rigorous evidence is not yet available. Where feasible, There have now been Ͼ3.6 million prescriptions (10) Expert Consensus Documents will include indications and written for sildenafil, and 4500 patients taking sildenafil have contraindications. Some topics covered by Expert Consensus been followed up without any change in the above conclu- Documents will be addressed subsequently by the ACC/AHA sions. A total of 69 deaths have been reported to the FDA as of August 26, 1998, in patients who have used Viagra(10,11). Twenty-one were due to unknown causes, 2 due to A. Sildenafil (Viagra) Use for Erectile Dysfunction
stroke, and 46 related to probable cardiac events (10,11).
Male erectile dysfunction defined as “the inability to attain Twelve deaths involved a possible interaction between Vi- and/or maintain penile erection sufficient for satisfactory sexual performance (1)” is a common problem in the United Patients with erectile dysfunction are mostly over age 45 States affecting between 10 and 30 million men (2,3). Sexual and are in general more likely to have risk factors predispos- dysfunction in men after the diagnosis of coronary artery ing them to cardiovascular disease, including myocardial disease or a myocardial infarction is common. Most is due to infarction and stroke. The vast majority of patients in the fear that the exertion of sexual activity will precipitate clinical development program did not have known coronary another myocardial infarction, but 10% to 15% is due to disease or congestive heart failure, nor were hypertensive organic causes of impotence (4). Approximately 5.5 million patients taking complicated, multidrug, antihypertensive Cheitlin and Hutter Jr., et al.
January 1999
medical regimens included in the program. Furthermore, 62% II. Background
of the patients taking Viagra were within the 45- to 64-year- A. Physiology of Erection
old age category, and only 23% were aged Ն65 years (Pfizer Penile erection is accomplished by engorgement of cavernous Inc, unpublished data). Although sildenafil is not presently spaces within the corpora cavernosa under near-arterial pres- indicated in women, the cautions referred to in this document sures and involves dilation of arterial inflow, relaxation of should probably apply to both men and women, pending corpora cavernosa smooth muscle, and constriction of venous studies performed specifically in women.
outflow (12). The blood flow to the penis is supplied by thecavernosal arteries and their branches, the helicine arteries,which empty directly into the cavernous spaces (12). Erection B. Development of an ACC Expert
is initiated by dilation of helicine arteries, resulting in marked Consensus Document
augmentation of blood inflow and transmission of arterial In July 1998, responding to inquiries from both concerned pressures to the cavernosal spaces. Relaxation of smooth physicians and the press, ACC president Spencer King asked muscle trabeculae surrounding cavernosal spaces facilitates the ACC Technology and Practice Executive Committee blood pooling and engorgement. Restriction of venous out- (TPEC) to supervise the writing of a press release, summary flow is also essential to entrapment of blood in the corpora statement and Expert Consensus Document on sildenafil cavernosa and is caused by compression of venules by the (Viagra). This article was written to appropriately caution and expanding smooth muscle trabeculae against the thick tunica not to unduly alarm physicians in their use of sildenafil in Dr. King and TPEC chair Dr James Forrester selected a B. Role of Nitric Oxide and cGMP
group of physicians with specific expertise to prepare the The relaxation of the penile arterial smooth muscle, the document. Drs. Melvin Cheitlin and Adolph Hutter, Jr, were corporal smooth muscle, and therefore erection is under the chosen as cochairs of the Writing Group, on the basis of their control of the autonomic nervous system (13). The principal status as well-recognized senior clinical cardiologists and neural mediator of penile smooth muscle relaxation is nitric their experience in producing clinical practice guidelines.
oxide (NO) (13,14). NO and its derivatives have received Other members were selected for specific expertise: Dr much attention because they also account for the biological Brindis (managed care), Dr Ganz (vascular reactivity), Dr activity of the endothelium-derived relaxation factor and of Kaul (nitric oxide donors), and Dr Zusman (pharmacology of organic and inorganic nitrate vasodilators. Three isoforms ofNO synthase (NOS) that convert antihypertensive agents). Dr King also invited the AHA to identified: neuronal (nNOS; type I NOS), inducible (iNOS; jointly author the document. Dr Richard Russell (critical care type II NOS), and endothelial (eNOS; type III NOS). Termi- cardiology) was appointed to the Writing Group by AHA nals containing nNOS densely innervate the corpus caverno- president Dr Valentin Fuster. All members of the Writing sum and its arterial supply (13,14). NO derived from the Group were asked to carefully review any potential conflicts endothelium lining penile arteries and cavernosal sinuses also of interest they might have regarding their industry relation- participates in the erectile response. The arterial dilator ships. Those writers who indicated conflicts are identified in actions of NO and its relaxant effect on the smooth muscle of the corpus cavernosum are mediated by the activation of The Writing Group reviewed both the limited published soluble guanylate cyclase and production of cGMP, which data on Viagra and unpublished data provided by the manu- acts as a second messenger (13,14). Accumulation of cGMP facturer of Viagra, Pfizer Inc. With respect to the unpublished leads to a reduction in intracellular calcium and smooth data, all members of the Writing Group who had access to muscle relaxation. The degradation of cGMP into its inactive these documents signed statements that they would not form, GMP, is catalyzed by cyclic nucleotide phosphodies- distribute this information outside of the Writing Group until terase enzymes (15,16). The predominant isoform of this such time as it became public information. Members of the enzyme in the corpus cavernosum is PDE5 (12,15). Inhibitors Writing Group were instructed to channel all communications of the activity of this enzyme prevent the breakdown of with Pfizer through ACC professional staff to eliminate the cGMP, resulting in enhanced penile erection.
After completion of the document, 10 external referees III. Sildenafil
reviewed the text. A copy of the draft was also provided to A. Introduction and Mechanism of Action
Pfizer and to the FDA for comment. The comments from Sildenafil belongs to a class of compounds called PDE external review, which were kept anonymous, were provided inhibitors. PDEs comprise a diverse family of enzymes that to the Writing Group, which made revisions as they deemed hydrolyze cyclic nucleotides (cAMP and cGMP) and there- appropriate. The Expert Consensus Document was approved fore play a critical role in the modulation of second- by vote of the TPEC for presentation to the ACC Board of Trustees, which voted to approve its publication in the Sildenafil is a potent and selective inhibitor of cGMP- Journal of the American College of Cardiology. The AHA specific PDE5 (Pfizer, unpublished data), the predominant Scientific Advisory Committee also reviewed and approved isozyme that metabolizes cGMP in the corpus cavernosum of this document for publication in Circulation. the penis. cGMP is the second messenger of NO and, a ACC/AHA Expert Consensus Document
principal mediator of smooth muscle relaxation and vasodi- such as ketoconazole and itraconazole) (18). Protease inhib- latation in the penis. By inhibiting the hydrolytic breakdown itors such as indinavir, ritonavir, nelfinavir, and saquinavir of cGMP, sildenafil prolongs the action of cGMP. This have not been formally studied but, being potent 3A4 inhib- results in augmented smooth muscle relaxation and hence, itors, are anticipated to have similar effects on sildenafil prolongation of the erection. Prior production of cGMP by metabolism (Pfizer, unpublished data).
NO, released primarily from the nonadrenergic, noncholin-ergic (nitroxidergic) cavernosal nerves in response to sexual C. Pharmacodynamics
stimulation, is required for sildenafil to be effective (13,14).
The pharmacodynamic end points that have been investigated Relatively high levels of PDE5 are found in the human with sildenafil reflect the distribution of PDE5 in different corpus cavernosum; in vascular, visceral and tracheal smooth tissues, ie, human corpus cavernosum (penile tumescence), muscle; and in platelets (15). Sildenafil is a potent inhibitor of vascular smooth muscle (vasodilatation), and platelets (anti- PDE5, with favorable selectivity (Ͼ1000-fold) for human PDE5 over human PDE2 (isozyme found predominantly in 1. Effects on Penile Tumescence
the adrenal cortex) (15), PDE3 (found predominantly in The efficacy of sildenafil in enabling patients with erectile smooth muscles, platelets, and cardiac tissue) (15), and PDE4 dysfunction due to a broad spectrum of causes, including (found predominantly in the brain and lung lymphocytes) vasculogenic (diabetes), neuroreflexogenic (spinal cord inju- (15) and moderate selectivity (Ͼ80-fold) over PDE1 (a ry), and psychogenic (nonorganic), to achieve and maintain cGMP-hydrolyzing isozyme found predominantly in the erection sufficient for satisfactory sexual intercourse has been brain, kidney, and smooth muscle) (15). Sildenafil is onlyϷ demonstrated in all 21 double-blind, randomized, placebo- 10-fold as potent for PDE5 as for PDE6 (an enzyme found controlled, multicenter studies (Pfizer, unpublished data).
in the photoreceptors of the human retina); this lower selec-tivity is presumed to be the basis for abnormalities related to 2. Cardiovascular Effects
color vision observed with higher doses or plasma levels ofsildenafil (Pfizer, unpublished data). The Ϸ4000-fold greater a. Effects on Cardiac ContractilityUnlike cAMP-specific PDE3 inhibitors (milrinone, vesnari- selectivity for PDE5 over PDE3 is important because inhib- none, and enoximone) that increase long-term mortality in itors of PDE3 (the isozyme involved in regulation of cardiaccontractility), such as milrinone, vesnarinone and enoximone, patients with heart failure (17,19), sildenafil is highly selec- that have been used in patients with heart failure, are tive (Ͼ4000-fold) for human PDE5 over human PDE3 and generally associated with increased incidence of cardiac has not been found to elevate cAMP (Pfizer, unpublished arrhythmias and other serious side effects (17).
data). The cardiotoxic effects of PDE3 inhibitors are thoughtto be related to increases in intracellular cAMP in the B. Pharmacokinetics and Metabolism
myocardium (15,19,20). Furthermore, PDE5 is not present in Sildenafil is rapidly absorbed after oral administration, with cardiac myocytes, and sildenafil has been shown to have no absolute bioavailability of Ϸ40%. Plasma concentrations direct inotropic effects on dog trabeculae muscle (Pfizer, peak within 30 to 120 minutes (median, 60 minutes) of oral unpublished data). However, sildenafil has not been investi- dosing in the fasted state. Sildenafil is primarily metabolized gated extensively in heart failure patients.
by the cytochrome P450 3A4 (major route) and 2C9 (minor b. Effects on Blood Pressure and Heart Rate route) hepatic microsomal isoenzymes, which convert it to an Sildenafil produces a transient modest reduction in systolic (8 active N-desmethyl metabolite that has been shown to possess to 10 mm Hg) and diastolic (5 to 6 mm Hg) blood pressures, 50% of the parent drug’s potency for inhibiting PDE5.
with peak effects evident at 1 hour after the dose (coincident Plasma concentrations of this metabolite are Ϸ40% of those with peak plasma concentrations) and returning to baseline seen for sildenafil, so that the metabolite accounts for Ϸ20% values by 4 hours after the dose (Pfizer, unpublished data).
of the pharmacological effects of sildenafil. Sildenafil and its No significant effects are observed on heart rate. The hypo- active metabolite are both highly bound to plasma proteins tensive effects of sildenafil are neither age dependent (similar (Ϸ96%), and their terminal half-lives are Ϸ4 hours each. The reductions in blood pressure in patients aged Ͻ65 years mean steady-state volume of distribution for sildenafil is 105 compared with those Ͼ65 years) nor dose related (over the L, indicating distribution into the tissues. Sildenafil is ex- range of 25 to 100 mg) and rarely result in reports of creted as metabolites predominantly in the feces (Ϸ80% of orthostatic effects. Doses as high as 800 mg have been well administered oral dose) and to a lesser extent in the urine tolerated in some healthy volunteers (13).
(Ϸ13% of the administered oral dose). Less than 0.001% ofthe administered dose appears in the semen; this dose is very c. Effects on Central Hemodynamics and Peripheral unlikely to have any effects in the partners of patients taking sildenafil. Plasma levels of sildenafil are increased in patients In normal volunteers, no significant changes in cardiac index aged Ͼ65 years (40% increase) and in patients with hepatic were evident up to 12 h after the dose for oral sildenafil (100 impairment (eg, cirrhosis; 80% increase), severe renal impair- to 200 mg) or intravenous sildenafil (20 to 80 mg) (Pfizer, ment (creatinine clearance Ͻ30 mL/min; 100% increase), and unpublished data). Significant decreases in systemic vascular concomitant use of potent cytochrome P450 3A4 inhibitors resistance index were reported at the end of intravenous (eg, macrolide antibiotics such as erythromycin [200% in- sildenafil infusion (20 to 80 mg), when plasma concentrations crease] and clarithromycin; cimetidine; and antifungal agents were highest (Pfizer, unpublished data). Sildenafil has both Cheitlin and Hutter Jr., et al.
January 1999
arteriodilator and venodilator effects on the peripheral vas- 3. Visual abnormalities resulting in blue-green color- culature (Pfizer, unpublished data). In 8 patients with stable tinged vision, increased perception of light, and blurred angina, intravenous sildenafil reduced systemic and pulmo- vision (3%), especially at higher doses (Pfizer, unpub- nary arterial pressures and cardiac output by 8%, 25%, and 4. Musculoskeletal effects resulting in myalgias, especially 7%, respectively, consistent with its mixed arterial (systemic with multiple daily doses. No treatment-related changes and pulmonary hypotension) and venous (drop in stroke in serum creatine kinase or electromyogram have been volume secondary to decreased preload) vasodilator effects observed, however (Pfizer, unpublished data). There is no obvious pharmacological explanation for this effect.
In conclusion, consistent with the anticipated effects re- sulting from an increase in cGMP levels in vascular smooth IV. Drug-Drug Interactions and Concomitant
muscle, sildenafil possesses vasodilatory properties, which Disease States
result in mild, generally clinically insignificant decreases in A. Interaction With Nitrates
The vasodilator actions of nitrates are profoundly amplified with concomitant use of sildenafil, resulting in major hemo- Sildenafil has no direct effects on platelet function but will dynamic compromise and potentially fatal events (Pfizer, modestly potentiate the inhibitory effect of the NO donor unpublished data). This interaction likely applies to all sodium nitroprusside on ADP-induced platelet aggregation ex nitrates and NO donors, irrespective of their predominant vivo, consistent with the requirement for an NO drive for hemodynamic site of action (see Appendix A for a list of sildenafil to produce its pharmacological effects (Pfizer, commonly used nitrates). Sildenafil may also potentiate the unpublished data). No effects on bleeding or prothrombin hypotensive effects of an inhaled form of nitrate, such as times were seen in healthy subjects receiving sildenafil alone amyl nitrate or nitrite, also known as “poppers,” and therefore or concurrently with aspirin or warfarin. In addition, no is contraindicated. Poppers act by dilating blood vessels, and adverse bleeding episodes have been reported with the use of the concurrent recreational use of poppers and sildenafil sildenafil (Pfizer, unpublished data). However, because the could result in sudden and marked lowering of blood pres- effects of sildenafil have not been evaluated in patients with sure, which can be potentially serious or even fatal. This bleeding disorders or in patients taking nonaspirin antiplatelet interaction may be even more pronounced in patients taking agents (eg, ticlopidine, clopidogrel or dipyridamole), caution protease inhibitors concurrently (eg, indinavir [Crixivan], should be exercised when the drug is administered in these ritonavir [Norvir], nelfinavir [Viracept], or saquinavir Dietary sources of nitrites, nitrates, and L-arginine (the 3. Effects on Visual Function
substrate from which NO is synthesized) do not contribute to Transient visual abnormalities (mostly color-tinged [blue- the circulating levels of NO in humans and therefore are green] vision, increased perception of light, and blurred unlikely to interact with sildenafil. The anesthetic agent vision) have been reported in patients taking sildenafil, nitrous oxide does not undergo any detectable biotransforma- especially at high oral doses (Ͼ100 mg) (Pfizer, unpublished tion and is eliminated unchanged from the body, mostly via data). These visual effects appear to be related to the weaker the lungs, usually within minutes of its administration.
inhibiting action of sildenafil on PDE6, which regulates Because it does not form NO in the human body and does not signal transduction pathways in the retinal photoreceptors.
itself activate guanylate cyclase, there is no contraindication Sildenafil is 10-fold selective for PDE5 over PDE6 (Pfizer, to its use after administration of sildenafil.
unpublished data). In patients with inherited disorders of It is not known how much time must elapse from the time retinal PDE6, such as retinitis pigmentosa, sildenafil should at which a patient takes sildenafil before a nitrate-containing be administered with extreme caution (Pfizer, unpublished medication might be given without the marked hypotensive effect being produced. On the basis of the pharmacokineticprofile of sildenafil, it can be assumed that the coadministra- 4. Adverse Effects
tion of a nitrate within the first 24 hours is likely to produce The adverse effects of sildenafil reflect its pharmacological an exaggerated hypotensive response and is therefore contra- activity of inhibition of PDE5 in various tissues and can be indicated unless the benefits are determined to far outweigh broadly classified into 4 major adverse reactions: the risks. After 24 h, the administration of a nitrate may beconsidered, but once again, the response to initial dosages 1. Vasodilatory effects resulting in headache (16%), flush- must be monitored carefully. In patients in whom the half-life ing (10%), and rhinitis (4%) (the latter presumably as a of sildenafil may be prolonged (see below), a more extended result of hyperemia of nasal mucosa where PDE5 is period of time from sildenafil administration to nitrate ad- present). Dizziness (2%), hypotension (Ͻ2%), and pos- ministration may be required. The preferred form of nitrate tural hypotension (Ͻ2%) have been reported rarely andoccur at a similar rate in sildenafil- and placebo-treated therapy in this setting would be short-acting intravenous patients (Pfizer, unpublished data).
nitroglycerin infusion under close hemodynamic monitoring.
2. Gastrointestinal effects resulting in dyspepsia and burn- Similarly, all patients taking either sildenafil or nitrates ing sensation from reflux due to relaxation of lower must be warned of the contraindications and the potential esophageal sphincter (7%) (Pfizer, unpublished data).
consequences of taking sildenafil in the 24-hour interval after ACC/AHA Expert Consensus Document
taking a nitrate preparation, including sublingual nitroglycer- dine and erythromycin are commonly prescribed drugs that in. Although sublingual nitroglycerin is very short-acting, its inhibit the P450 3A4 pathway. As indicated in the approved need in the previous 24 hours suggests that it may be needed product labeling, the simultaneous administration of either of again after sildenafil-enhanced sexual relations. Furthermore, these agents significantly increases the plasma concentrations the presence of even trace amounts of nitrates may have of sildenafil; a lower initial dose (25 mg) should be consid- unknown effects in combination with sildenafil. The admin- ered in the coadministration of sildenafil to patients receiving istration of sildenafil to a patient who has taken a nitrate in the preceding 24 hours is contraindicated.
Many drugs are metabolized by the P450 3A4 pathway but Appendix A is a listing of nitrate preparations available in are not inhibitors of the pathway. The coadministration of 1 the United States. Other preparations may be available in of these drugs may lead to a competitive inhibition of the other countries. A careful history of the medications taken by metabolism of sildenafil, although the 3A4 system is a a patient who has taken sildenafil is essential before treatment high-capacity enzymatic system. The effects of these agents of the patient for presumed myocardial ischemia or infarction on the half-life, physiological effects, and side effects of sildenafil are unknown; physicians should be cognizant of thepotential interaction of such agents. Appendix B includes a B. Interaction With Antiplatelet Agents
partial listing of commonly prescribed drugs metabolized via A clinical trial combining sildenafil with aspirin showed no pharmacokinetic interaction between the 2 medications andno additional effect of sildenafil on bleeding time. Dipyri- E. Concomitant Administration of
damole is believed to exert antiplatelet effects by at least two Antihypertensive Drugs
mechanisms. Its nonspecific PDE action increases platelet Sildenafil administration has been associated with reductions cAMP, and it increases plasma adenosine by blocking its in blood pressure (compared with placebo) of as much as reuptake by erythrocytes (21). Ticlopidine and clopidogrel 8/5 mm Hg (systolic/diastolic values). In a drug interaction produce antiplatelet aggregatory activity by inhibiting ADP- study of sildenafil and amlodipine, the additional blood mediated platelet activation (22). No specific interaction pressure reduction in the patient population receiving both studies have been conducted between sildenafil and dipyri- sildenafil and amlodipine was not significantly different from damole, ticlopidine, or clopidogrel.
the population receiving sildenafil and a placebo (Pfizer,unpublished data). Although formal drug-drug interaction C. Interaction With Other PDE Inhibitors
studies have not been conducted with the following medica- PDEs are considered to be major mediators of cross talk tions, no increase in blood pressure–related adverse events or between different second-messenger signaling pathways (15), systematic enhancement of the blood pressure–lowering ef- eg, cGMP is known to inhibit PDE3, which hydrolyzes fects of thiazide, loop and potassium-sparing diuretics, ACE cAMP, thereby resulting in enhanced cAMP levels (15,20).
inhibitors, calcium channel blockers, or ␣- or ␤-adrenergic This increase in cAMP levels can potentially augment cAMP- receptor antagonists have been observed in clinical trials.
mediated effects in various tissues where PDE3 is localized, However, the potential for a hypotensive reaction in patients taking antihypertensive medications as well as sildenafil must Ca) and inotropy in cardiac myocytes (23), vascular smooth muscle relaxation (24), and platelet inhibi- be considered and the patient alerted to this possibility.
tion (25). The risk of precipitating a cardiotoxic, hypotensive Although not supported by data from the clinical trials, there or hemorrhagic event secondary to combining sildenafil with may be a theoretical concern in a patient receiving multiple specific PDE3 inhibitors (such as milrinone, vesnarinone or medications that include antihypertensive therapy and an enoximone) or with nonspecific PDE inhibitors (such as inhibitor of the metabolic pathway (cytochrome P450 3A4) of theophylline, dipyridamole, papaverine, and pentoxifylline) is currently unknown, but such effects are unlikely (17).
F. Concomitant Disease States
D. Drug-Drug Interactions Affecting Metabolic
1. Renal Dysfunction
Clearance of Sildenafil
Patients with severe renal impairment (creatinine clearance Sildenafil is an inhibitor of the cytochrome P450 2C9 Ͻ30 mL/min) have a reduced clearance of sildenafil. Plasma metabolic pathway. It is possible that the administration of levels of the parent drug and of its metabolites in patients with sildenafil could result in a significant increase in the plasma severe renal impairment are approximately twice those found concentrations of other drugs metabolized through this path- in healthy subjects. Thus, the duration of the effect of way. Although tolbutamide and warfarin are metabolized by sildenafil in these patients will be prolonged and also may be the P450 2C9 pathway, there is no evidence to date that the enhanced at any given dosage of the medication. Particular concomitant administration of sildenafil affects the metabolic care should be taken in the administration of concomitant medications that may lower blood pressure in patients receiv- Sildenafil is predominantly metabolized by both the P450 ing sildenafil whose renal function is severely impaired. The 2C9 pathway and the P450 3A4 pathway (a low-affinity but effects of less-severe degrees of renal dysfunction on the high-capacity system). Thus, potent inhibitors of the P450 metabolism of sildenafil have been evaluated. There were no 3A4 pathway may increase the plasma concentrations of significant effects on the metabolism of sildenafil seen in sildenafil and therefore its pharmacological effect. Cimeti- subjects with mild (creatinine clearance 50 to 80 mL/min) or Cheitlin and Hutter Jr., et al.
January 1999
moderate (creatinine clearance 30 to 49 mL/min) renal All patients with ischemia during coitus also demonstrated impairment (24). Of note, the plasma creatinine concentration ischemia at ETT. Drory et al also noted significant variation of the elderly patient with a lower body mass may not in heart rate response to coitus, with an average heart rate of accurately reflect the patient’s creatinine clearance, and thus 118 bpm but with some patients attaining a heart rate of 185 initiation of therapy at 25 mg rather than 50 mg may be bpm at orgasm. Other small studies with ECG monitoring during intercourse in patients with coronary artery diseaseconcluded that sexual activity may provoke increased ven- 2. Hepatic Dysfunction
tricular ectopic activity that is not necessarily elicited by Patients with hepatic dysfunction have a decreased clearance other stimuli (28). Jackson (29) found that in 19 patients with of sildenafil compared with normal subjects. Plasma concen- ischemic heart disease who developed angina during sexual trations of sildenafil and of its metabolites may be signifi- intercourse, these symptoms were abolished with ␤-blockade.
cantly increased in patients with hepatic dysfunction. Under The mean maximum heart rate during sexual intercourse with such conditions, the duration of activity of sildenafil may be and without use of ␤-blockers was 82 and 122 bpm, respec- prolonged and the extent of its effects enhanced. As in tively. This would suggest that these patients may have patients with renal dysfunction, the initiation of therapy at 25 different hemodynamics while taking antianginal medication mg rather than 50 mg may be appropriate in patients with that may afford them some protection or lower their risk of ischemia. It should be emphasized that coital death is rare, V. Cardiovascular Effects of Sexual
encompassing only 0.6% of sudden death cases (30). Mulleret al (31) found by retrospective case-crossover methodology Intercourse in Patients With Coronary
that although sexual activity can trigger the onset of myocar- Artery Disease
dial infarction, the relative risk in the 2 hours after sexual There is potential for a high incidence of overt and covert activity is very low (2.5; 95% CI, 1.7 to 3.7). Furthermore, coronary artery disease in patients with erectile dysfunction sexual activity was a likely contributor to the onset of on the basis of the epidemiological profiles of both patient myocardial infarction only 0.9% of the time. Additionally, groups. Therefore, when prescribing sildenafil, physicians they found that the relative risk of myocardial infarction is should consider the potential implications of coronary artery not increased in patients with a prior history of cardiac disease in sedentary patients who plan to resume sexual disease and that regular exercise appears to prevent trigger- activity. Because nitrates are contraindicated for the manage- ing. It should be cautioned that these reassuring data should ment of coronary ischemic syndromes in patients taking not be extrapolated to patients taking sildenafil if they sildenafil, review of the patient’s ability to tolerate the perform at higher cardiac and metabolic expenditures during cardiovascular stresses involved with sexual intercourse, coitus. The hemodynamic changes associated with sexual particularly patients with coronary artery disease or at in- activity may be far greater with an unfamiliar than with a creased risk of coronary artery disease, may aid the treating familiar partner, in unfamiliar settings, and after excessive eating and consumption of alcohol. The person most at risk is Cardiac and metabolic expenditures during sexual inter- usually middle-aged and having extramarital relations.
course will vary depending on the type of sexual activity. In The ETT can gauge the potential cardiac stress of sexual a laboratory setting, healthy males with their usual female activity. If a patient can achieve 5 or 6 METS on the ETT partners achieved an average peak heart rate of 110 bpm with without demonstrating arrhythmias or ischemia electrocardio- woman-on-top coitus and an average peak heart rate of 127 graphically, they most likely are not at high risk for devel- bpm with man-on-top coitus (26). When oxygen uptake was oping myocardial ischemia as a result of their normal sexual measured in these men, an average metabolic expenditure during stimulation and orgasm of 2.5 metabolic equivalents(METS) for woman-on-top coitus and 3.3 METS for man- VI. Recommendations for Sildenafil and the
on-top coitus was attained. There was a significant individualvariation of cardiovascular responses among patients ranging Cardiac Patient
from 2.0 to 5.4 METS for man-on-top coitus. Thus, to simply A. Prescribing Sildenafil to Patients at
equate a level of cardiac or metabolic expenditure during Clinical Risk
sexual intercourse to an activity such as “climbing 1 or 2flights of stairs” may underestimate the level of cardiovascu- 1. Sildenafil is absolutely contraindicated in patients un- lar response in individual patients.
dergoing any long-acting nitrate drug therapy or using In patients with known coronary artery disease whose short-acting nitrates because of the risk of developing antianginal medicines were stopped for study purposes (27), potentially life-threatening hypotension.
2. If a patient has stable coronary disease, is not taking a Drory et al compared the electrocardiographic monitoring long-acting nitrate, has short-acting nitrate use as the findings in sexual activity with a near-maximal exercise only contraindication to sildenafil, and does not appear treadmill test (ETT). Most patients had previous myocardial to need the nitrate on a consistent basis, the physician infarctions and were in New York Heart Association func- and the patient should carefully weigh the risks and tional class I or II. ECG criteria for ischemia during inter- benefits of sildenafil treatment. If the patient requires course were found in one third of the patients; two thirds of nitrates for mild or moderate exercise limitation, sil- the time, this was silent rather than symptomatic ischemia.
denafil should probably not be used.
ACC/AHA Expert Consensus Document
3. All patients taking organic nitrates, even if they have with fluid resuscitation and ␣-adrenergic agonists if not asked for Viagra, should be informed about the needed. After 24 hour, the administration of a nitrate nitrate-sildenafil hypotensive interaction. There is a may be considered, but once again, appropriate caution substantial potential for patients to obtain Viagra from with careful monitoring of initial dosages must be used.
another physician, a friend, or through the “black In patients in whom the half-life of sildenafil may be market,” circumventing healthcare providers who could prolonged, such as in renal and hepatic dysfunction or offer appropriate caution. Because sildenafil also poten- patients concurrently taking a potent CYP 3A4 inhibi- tiates the hypotensive effect of an inhaled form of tor, a more extended period of time from sildenafil nitrate such as amyl nitrate or poppers, the concurrent administration to the time of nitrate administration may recreational use of poppers and sildenafil could result in be required. In patients with recurring mild angina after sudden and marked hypotensive response that could be sildenafil use, other nonnitrate antianginal agents, such serious or fatal. This interaction may be more pro- as ␤-blockers, should be considered.
nounced in patients taking protease inhibitors concur- 2. Patients taking sildenafil who have an acute myocardial rently (eg, indinavir, ritonavir, nelfinavir, and infarction should be treated in the usual manner as described in the ACC/AHA clinical practice guidelines 4. Similarly, patients must be warned of the contraindica- (32) including, where appropriate, primary angioplasty tion of taking sildenafil in the 24-hour time interval or thrombolytics. The only difference is that nitrates are after taking a nitrate preparation, including sublingual contraindicated for these patients. If the patient had nitroglycerin. The administration of sildenafil to a already used nitrates and sildenafil together, the acute patient who has taken a nitrate in any form in the myocardial infarction may have been caused by the low preceding 24 hours is contraindicated.
diastolic perfusion pressure of the coronary circulation.
5. Although firm data are lacking, pre-Viagra treadmill Blood pressure support may be sufficient to prevent tests to assess for the presence of stress-induced ische- further myocardial damage if no acute plaque rupture is mia in patients with overt and covert coronary artery disease can guide the patient and physician relative to 3. In patients with unstable angina, therapy should include the risk of cardiac ischemia during sexual intercourse. If only nonnitrate antianginal medications but should oth- the patient can achieve Ն5 to 6 METS on an ETT erwise adhere to principles established in the clinical without demonstrating ischemia, the risk of ischemia practice guideline available from the Agency for Health during coitus with a familiar partner, in familiar set- Care Policy and Research (33). To date, there is no tings, without the added stress of a heavy meal or evidence of significant interactions between sildenafil alcohol ingestion, is probably low. We wish to stress and heparin, ␤-adrenergic blockers, calcium channel that the physical and emotional stresses of sexual blockers, narcotics, or aspirin. These agents can be used intercourse can be excessive in some people, particu- as appropriate. After 24 hours, nitrates may be admin- larly those who have not performed this activity in some istered if close monitoring is provided and proper time and who are not in good condition. These stresses facilities are available for fluid and vasopressor support.
themselves may produce acute ischemia or precipitatemyocardial infarction. Such patients should be advised C. Treatment of the Hypotensive Patient With
to use common sense and to moderate their physical Inadvertent Sildenafil-Nitrate Combination Effect
exertion and their emotional expectations was they In patients who inadvertently received nitrates while taking begin their experience with taking Viagra.
sildenafil and who manifest a severe hypotensive response, 6. If patients are taking a combination of antihypertensive nitrate and nitroprusside (ie, NO donor) therapy should be medications, they should be cautioned about the possi- immediately stopped. Depending on clinical circumstances, bility of sildenafil-induced hypotension. Because both any of the following therapies should be considered alone or venous and arterial vasodilatation occur with sildenafil, initial monitoring of the blood pressure with the insti-tution of Viagra use would identify patients with an 1. Place the patient in Trendelenburg position.
undesired hypotensive blood pressure response. This is 2. Provide aggressive fluid resuscitation.
an area of particular concern for the patient with 3. Provide judicious use of an intravenous ␣-adrenergic congestive heart failure who has a borderline low blood agonist such as phenylephrine (Neo-Synephrine).
volume and a low blood pressure status as well as for 4. Provide an ␣- and ␤-adrenergic agonist (norepineph- the patient who is following a complicated, multidrug, rine) for blood pressure support, with the realization that this could exacerbate or lead to an acute ischemic B. Management of Acute Ischemic Syndromes
5. Provide intra-aortic balloon counterpulsation.
With Patients Taking Sildenafil
D. Limitations and Unresolved Issues
1. The physician should try to establish the time of the last Expert Consensus Documents, as noted in the preamble, are dose of sildenafil. Definitive evidence is currently often written in circumstances in which the evidence base and lacking, but it is possible that a precipitous reduction inblood pressure may occur over the initial 24 hours after experience with the technology or practice are limited. This is a dose of sildenafil. Administration of nitrates in this clearly the case with Viagra. The evidence base had signifi- time interval should be avoided. In the event that cant limitations, and many important issues remain unre- nitrates are given after sildenafil administration, it is solved. Of special significance to the current report is the fact essential to have the capability to support the patient that the preapproval clinical trials of Viagra excluded certain Cheitlin and Hutter Jr., et al.
January 1999
high-risk groups of patients with significant cardiac disease (ie, patients with heart failure, patients with myocardial infarction or stroke within 6 months, or patients with uncon- trolled hypertension) or patients with blood pressures of Ͻ90/50 or Ͼ170/100 mm Hg. More research needs to be done to assess the specific risks of Viagra use among these Pentaerythritol Tetranitrate
The authors of this Expert Consensus Document identified a number of other unresolved issues that could affect clinicalmanagement of the cardiovascular consequences of sildenafil Erythrityl Tetranitrate
Cardilate
Isosorbide Dinitrate/Phenobarbital
1. Interaction with nonaspirin antiplatelet agents (eg, ticlo- pidine, clopidogrel, and dipyridamole).
2. Interaction with other PDE inhibitors, including specific Illicit Substances Containing Organic Nitrates
PDE inhibitors (eg, milrinone, vesnarinone, and enoxi- Amyl nitrate or nitrite (It is known that amyl nitrate or nitrite issometimes abused. In abuse situations, amyl nitrate or nitrite may be mone) and nonspecific PDE inhibitors (eg, theophyl- known by various names, including “poppers.”) line, dipyridamole, papaverine, and pentoxifylline).
3. Central nervous system effects of sildenafil (PDE5 is Appendix B
4. Hypotensive effects with sildenafil alone in high-risk Drugs That Are Metabolized by or That Inhibit
cardiac patients (severe heart failure).
Cytochrome P450 3A4
5. Musculoskeletal effects (myalgias with chest pains that Antibiotic/Antifungal
As more evidence is accumulated, the ACC will consider an update of this Expert Consensus Document.
Appendix A
List of Representative Organic Nitrates
Nitroglycerin
Deponit
Cardiovascular
HMG
Central Nervous System
Isosorbide Mononitrate
Isosorbide Nitrate
Other
ACC/AHA Expert Consensus Document
reports of death in Viagra users received from marketing (late March) through July 1998. Available at http:/www.fda.gov/cder/consumerinfo/ viagraupdate721.htm. Accessed August 31, 1998.
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Hismanal and Propulsid are registered trademarks of Janssen Phar- 18. Terrett NK, Bell AS, Brown D, et al. A potent and selective inhibitor of maceutica Inc. Noroxin, Cozaar, Mevacor and Zocor are registered type 5 cGMP phosphodiesterase with utility for the treatment of male trademarks of Merck & Co, Inc. Plendil and Prilosec are registered erectile dysfunction. Bioorg Med Chem Lett 1996;1819 –24.
trademarks of Astra Merck Inc. DynaCirc is a registered trademark 19. Nony P, Boissel JP, Lievre M, et al. Evaluation of the effect of phospho- of Norartis Pharmaceuticals Corporation. Posicor is a registered diesterase inhibitors on mortality in chronic heart failure patients: a trademark of Roche Pharmaceuticals. Lipitor and Rezulin are regis- meta-analysis. Eur J Clin Pharmacol 1994;46:191– 6.
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