Treatment of Pulmonary Arterial Hypertension With Sildenafil: From Pathophysiology to Clinical Evidence

REVIEW ARTICLE Martin J. London, MD William C. Oliver, Jr, MD Gregory A. Nuttall, MD Section Editors

Treatment of Pulmonary Arterial Hypertension With Sildenafil: From Pathophysiology to Clinical Evidence Shahzad G. Raja, MRCS, Mark D. Danton, FRCS, Kenneth J. MacArthur, FRCS, and James C. Pollock, FRCS

P

ULMONARY ARTERIAL HYPERTENSION (PAH) is defined as a sustained elevation of pulmonary arterial pressure (PAP) to more than 25 mmHg at rest or to more than 30 mmHg with exercise, with a mean pulmonary-capillary wedge pressure and left ventricular end-diastolic pressure of less than 15 mmHg.1 PAH comprises idiopathic pulmonary arterial hypertension (IPAH, formerly primary pulmonary hypertension); pulmonary arterial hypertension in the setting of collagen vascular disease (eg, in localized cutaneous systemic sclerosis, also known as the CREST syndrome [calcinosis cutis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia]), portal hypertension, congenital left-to-right intracardiac shunts, and infection with the human immunodeficiency virus; and persistent pulmonary hypertension of the newborn.2 The histologic appearance of lung tissue in each of these conditions is similar including intimal fibrosis, increased medial thickness, pulmonary arteriolar occlusion, and predominantly plexiform lesions.3 PAH is an unremitting disease that progresses inexorably to right ventricular failure and death in adults and children. In the past 2 decades, an exponential growth of interest and research in PAH have engendered several therapeutic options that were not available as recently as 5 years ago. The ideal goals of treatment are to improve symptoms and survival using the least invasive therapies possible. Earlier treatments included continuous intravenous prostacyclin infusion, oral calcium channel blockers, and anticoagulation.4 Newer therapies are emerging, such as endothelin-receptor blockers, continuous inhalation of nitric oxide (NO), and aerosolized prostacyclin and analogs.5 However, applicability of these therapies can be hampered by serious side effects and/or the necessity for elaborate application techniques. Sildenafil (Viagra; Pfizer, New York, NY), a highly selective inhibitor of phosphodiesterase type 5 (PDE5), is emerging as an effective and safe pulmonary vasodilator in various forms of pulmonary

From the Department of Cardiac Surgery, Royal Hospital for Sick Children, Glasgow, United Kingdom. Address reprint requests to Shahzad G. Raja, MRCS, Department of Cardiac Surgery, Royal Hospital for Sick Children, Yorkhill NHS Trust, Dalnair Street, Glasgow G3 8SJ, United Kingdom. E-mail: [email protected] © 2006 Elsevier Inc. All rights reserved. 1053-0770/06/2005-0022$32.00/0 doi:10.1053/j.jvca.2005.12.011 Key words: sildenafil, pulmonary hypertension, phosphodiesterase inhibitors, pathophysiology, clinical evidence 722

hypertension.6-10 This review article summarizes the pharmacology, clinical efficacy, and safety of sildenafil for the treatment of PAH. SILDENAFIL: A HIGHLY SELECTIVE PDE5 INHIBITOR

The discovery in 1989 of sildenafil (Viagra, Pfizer), a highly selective inhibitor of PDE5, was the result of extensive research on chemical agents targeting PDE5 that might potentially be useful in the treatment of coronary artery disease.11 Initial clinical studies on sildenafil in the early 1990s were not promising with respect to its antianginal potential. However, the incidental discovery of its anti-impotence effect led to its approval for the treatment of erectile dysfunction.11 Recently, identification of distribution of PDE5 in several tissues has led to enthusiasm among pharmacologists as well as physicians to define new indications for sildenafil other than its use as an aphrodisiac. Phosphodiesterases are comprised of a superfamily of metallophosphydrolases that specifically cleave the 3=,5=-cyclic phosphate moiety of cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP) to produce the corresponding 5= nucleotide. Currently, 21 PDE genes have been cloned and are classified into 11 families (Table 1) according to their sequence of homology, biochemical, and pharmacologic properties.12 PDE5 is one of the members of the superfamily that specifically cleaves cGMP, a key intracellular secondary messenger. It is composed of 875 amino acids and was first identified in lungs, vascular, and tracheal smooth muscle and platelets. PDE5 is selectively inhibited by sildenafil, vardenafil, and tadalafil, and less selectively by zaprinast and dipyridamole. The tissue distribution of the PDE5 family is relatively restricted compared with other PDEs. Still, recent immunohistochemical and reverse transcriptase-polymerase chain reaction analysis have shown the presence of anti-PDE5 antibodies and PDE5 transcripts in rat cerebellum; kidney; pancreas; aortic smooth-muscle cells; heart; placenta; skeletal muscle; and, to a much lesser extent, in other regions of the brain, liver, and lungs.12 Research in this field is intense, with a goal of identifying and developing new, selective PDE5 inhibitors as well as investigating the potential role of available PDE5 inhibitors, mainly sildenafil, that would be beneficial in a number of maladies, including angina, pulmonary hypertension, and erectile dysfunction. MECHANISM OF ACTION OF SILDENAFIL

Sildenafil (Fig 1) is a potent and selective inhibitor of cGMPspecific PDE5.13 This isozyme metabolizes cGMP, which is the

Journal of Cardiothoracic and Vascular Anesthesia, Vol 20, No 5 (October), 2006: pp 722-735

PULMONARY ARTERIAL HYPERTENSION

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Table 1. Isoforms of Human Cyclic Phosphodiesterase Characteristics

Tissue Distribution

Inhibitors

PDE1

Family

Ca2⫹/calmodulin stimulated

Heart, brain, lung, smooth muscle

PDE2

cGMP stimulated

PDE3

cGMP inhibited, cAMP selective

Adrenal gland, heart, lung, liver, platelets Heart, lung, liver, platelets, adipose tissue, immunocytes

KS-505a Vinpocetine EHNA (MEP-1)

PDE4

cAMP specific, cGMP insensitive

Sertoli cells, kidney, brain, liver, lung, immunocytes

PDE5

cGMP specific

Lung, platelets, smooth muscle

PDE6

cGMP specific

Photoreceptors

PDE7

cAMP specific, high affinity

PDE8

cAMP selective, IBMX insensitive

PDE9

cGMP specific, IBMX insensitive cGMP sensitive, cAMP selective cGMP sensitive, dual specificity

Skeletal muscle, heart, kidney brain, pancreas, T lymphocytes Testes, eye, liver, skeletal muscle, heart, kidney, ovary, brain, T lymphocytes Kidney, liver, lung, brain

PDE10 PDE11

Cilostamide Milrinone Siguazodan Enoximone CDP840 Rolipram SB 207499 Tibenelast Dipyridamole MY-5445 Sildenafil Zaprinast Dipyridamole Zaprinast Several in development None

None

Testes, brain

None

Skeletal muscle, prostate, kidney, liver, pituitary & salivary glands, testes

None

Abbreviations: PDE, phosphodiesterase; IBMX, 3-isobutyl-1-methylxanthine. Reprinted with permission from Raja and Nayak.11

second messenger of NO and a principal mediator of smooth muscle relaxation and vasodilatation. By inhibiting the hydrolytic breakdown of cGMP, sildenafil prolongs the action of cGMP. This results in augmented smooth-muscle relaxation (Fig 2).13 Sildenafil is highly selective for the cGMP-hydrolyzing isoform PDE5, with a half-maximal inhibition (IC50) of PDE5 activity at a concentration of 3.5 nmol/L, followed by IC50 values of 34 to 38 nmol/L for PDE6 (cGMP-hydrolyzing PDE in the retina) and 280 nmol/L for PDE1 (cAMP- and cGMP-

Fig 1.

Chemical structure of sildenafil.

Fig 2. Mechanism of action of sildenafil. NOS, nitric oxide synthase; Kⴙ, potassium; Caⴙⴙ, calcium.

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hydrolyzing PDE isoform).11 The cAMP-hydrolyzing PDE3 and PDE4 and the cAMP- and cGMP-hydrolyzing isoform PDE2, as well as PDE7 to PDE11, are inhibited by sildenafil with an IC50 of more than 2,600 nmol/L.13 The affinity for PDE types 1 to 6 in a variety of different cells accounts for some of the side effects encountered with sildenafil use.14 PHARMACOKINETICS OF SILDENAFIL

Sildenafil is absorbed rapidly, and the peak drug concentration is achieved in approximately 60 minutes, accounting for the rapid onset of action of the drug. Forty percent of sildenafil is bioavailable after absorption because sildenafil undergoes extensive first-pass metabolism.15,16 The major route of sildenafil metabolism is hepatic via cytochrome P450 3A4. This enzymatic pathway is responsible for some of the most significant drug interactions associated with sildenafil.16 A minor pathway is through cytochrome P450 2C9.14,16 N-desmethyl sildenafil is an active metabolite of sildenafil, being responsible for approximately 40% of sildenafil serum concentration and responsible for 20% of the pharmacologic activity.16 Sildenafil has an apparent volume of distribution of 105 L (in a 70-kg individual) and is bound extensively by proteins.16 The elimination half-life of sildenafil and n-desmethyl sildenafil is 3 to 5 hours. Approximately 80% of the drug is eliminated fecally and 13% via renal excretion. Individuals with impaired renal function (⬍30 mL/min) have significantly reduced renal clearance.16 Sildenafil plasma concentrations are increased by hepatic impairment, severe renal dysfunction, and the concomitant use of cytochrome P450 inhibitors.14,16 PHARMACODYNAMICS OF SILDENAFIL

cGMP-specific PDE5 is present in vascular beds. Inhibition of PDE5 by sildenafil produces a non– dose-related reduction in blood pressure.14 Systolic and diastolic pressures are reduced by 8 to 10 mmHg and 5 to 6 mmHg, respectively, during therapeutic doses.11 Both intravenous dose escalation (20, 40, and 80 mg) and oral dose escalation studies (1.25-800 mg) have been performed17,18 and confirm that there is no evidence of a dose-response relationship. None of these studies showed an effect on heart rate. The blood-pressure–lowering effect of sildenafil is modest and therefore unlikely to trigger a reflex heart-rate response.19 Indeed, a mild sympathetic response directly to the vasculature may be responsible for the maintenance of blood pressure without triggering a reflex tachycardia.20 However, with pharmacologic drives resulting in greater reduction of blood pressure as seen with the nitrate interaction studies, there is a small reflex response in heart rate to maintain blood pressure.18 Interestingly, it has been shown that sildenafil in combination with a wide range of antihypertensive drugs (with the exclusion of NO donors), such as calcium channel blockers, ␤-blockers, angiotensin-converting enzyme inhibitors, or ␣1antagonists, are well tolerated.21 Sildenafil has both arteriodilator and venodilator effects on the peripheral vasculature.22 In normal volunteers, no significant changes in cardiac index were evident up to 12 hours after the dose for oral sildenafil (100-200 mg) or intravenous sildenafil (20-80 mg).22 Similarly, sildenafil does not affect cardiac contractility.23

Sildenafil induces heightened levels of sympathetic activity, both at rest and during physical, mental, and metabolic stress, as measured by intraneural recordings of muscle sympathetic nerve activity and by plasma catecholamine levels.20 It is conceivable that sildenafil may have direct central effects on sympathetic outflow. This potential mechanism is supported, in part, by evidence that sildenafil crosses the blood-brain barrier and that PDE5 is present in the brain.11 In human pulmonary circulation, the isoforms 1, 3, 4, and 5 of PDE seem to be involved in regulating pulmonary resistance.24,25 Thus, the blood-pressure–lowering effects of sildenafil in the pulmonary circulation are of special interest. Sildenafil markedly reduces the rise in PAP in response to breathing 11% inspiratory oxygen in healthy volunteers.26 Inhalation of nebulized sildenafil reduces pulmonary artery pressures significantly and has a synergistic effect with inhalation of NO.27 The effects of sildenafil on the coronary vasculature have also attracted significant interest.11 Studies performed by using canine models have shown a sildenafil-induced increase in coronary blood flow in normal coronary arteries at rest28-30 and during exercise.28 In humans also, it has been shown that sildenafil does not alter coronary flow reserve.31 Furthermore, it has been noted that the coronary flow reserve significantly increases in both stenosed and reference arteries 45 minutes after treatment with oral sildenafil, 100 mg, compared with baseline.32 Table 2 summarizes the cardiovascular effects of sildenafil. Initial data suggested that sildenafil has no direct effects on platelet function but modestly potentiates the inhibitory effect of the NO donor sodium nitroprusside on adenosine diphosphate–induced platelet aggregation ex vivo, consistent with the requirement for an NO drive for sildenafil to produce its pharmacologic effects.22 Despite this, no adverse bleeding episodes have been reported with the use of sildenafil.22 However, because the effects of sildenafil have not been evaluated in patients with bleeding disorders or in patients taking nonaspirin antiplatelet agents (eg, ticlopidine, clopidogrel, or dipyridamole), caution should be exercised when the drug is administered in these clinical settings.16 Inhibition of PDE5 and subsequent elevated or sustained concentrations of sildenafil account for vasodilation-related effects (headache, flushing, rhinitis, and dizziness) and the dyspepsia that some patients encounter.14,16 Inhibition of PDE6 has produced dose-related (⬎100 mg) ocular effects including blurred vision, changes in light perception, and transient bluegreen vision.14,16 RATIONALE FOR SILDENAFIL USE IN PULMONARY HYPERTENSION

The cyclic nucleotide cGMP is an intracellular second messenger that mediates vasodilatation and reduces proliferation of smooth-muscle cells (Fig 3). NO has been shown to increase intracellular cGMP by directly activating soluble guanylate cyclase. NO is liberated from l-arginine by NO synthases (NOSs), of which 3 isoforms are recognized: endothelial NOS (eNOS), inducible NOS, and neuronal NOS. NO released by eNOS is thought to be important in maintaining the low vascular tone of the healthy adult pulmonary circulation by increasing cGMP, which then activates cGMP kinases, opens

PULMONARY ARTERIAL HYPERTENSION

725

Table 2. Cardiovascular Effects of Sildenafil Variable

Principal Effect(s)

Cardiac contractility Blood pressure and heart rate

No effect on cardiac output Mild lowering of BP No effect on heart rate

Pulmonary vasculature

Pulmonary vasodilatation

Coronary vasculature

Dilatation of epicardial coronary arteries in patients with atherosclerosis Reverses endothelial dysfunction

Endothelium Cardiac repolarization

Chronic heart failure

Altered QT dynamics due to increased sympathetic modulation Improved LV and RV function

Potential Therapeutic Indication(s)/Significance

None so far BP lowering effect not associated with clinically significant adverse events. Safe in combination with other antihypertensive drugs (exception NO donors). Treatment for PHT (primary and secondary) alone or in combination with NO, prostacyclin, and ET-receptor antagonists. May be beneficial in vasospastic angina and diffuse coronary microvessel disease. May be beneficial in patients with vasomotor dysfunction because of diabetes and chronic heart failure. Could favor the onset of lethal ventricular arrhythmias in CHF.

Could be used in patients with cardiovascular diseases with the exception of severe obstructive CAD, hypertrophic subaortic stenosis, and patients with funduscopic alterations.

Abbreviations: BP, blood pressure; PHT, pulmonary hypertension; ET, endothelin; CHF, chronic heart failure; LV, left ventricular; RV, right ventricular; CAD coronary artery disease. Modified with permission from Raja and Nayak.11

potassium channels, and dilates blood vessels. In chronically hypoxic mice with targeted disruption of the gene encoding eNOS, sildenafil reduces mean PAP less than in wild-type controls and fails to decrease right ventricular hypertrophy or vascular muscularization.26 These findings suggest a role for the eNOS-NO-cGMP pathway in mediating pulmonary vasodilator responses to PDE5 inhibition and that other cGMP synthetic pathways might also be involved. The effects of intracellular cGMP are short-lived, however, because of rapid degradation by PDEs.33 Thus, inhibition of the enzymatic degradation of cGMP by PDE inhibitors offers a way to potentiate the increase in intracellular cGMP and amplify the pulmonary vasodilatory and antiproliferative effects, as evidenced by in vitro studies.34 Pharmacologic manipulation of this pathway

using agents that stimulate cGMP production and/or inhibit its inactivation offers approaches that might prove effective and safe for the therapy of PAH.35 The predominant PDE isoenzymes in pulmonary arteries include PDE5, a specific inactivator of cGMP, and PDE3, a specific inactivator of cAMP, which is also inhibited by cGMP.24 Animal data reveal that PDE5 is widely expressed in pulmonary vascular smooth muscle and in newly muscularized distal pulmonary arterioles and is enhanced in response to chronic hypoxia.35,36 The abundance of PDE5 in normal lung and increases in the vessels of hypertensive lungs suggest the possibility that PDE5 limits vasodilation in hypertensive lungs and that inhibition of PDE5 with sildenafil could ameliorate PAH. SILDENAFIL USE IN EXPERIMENTAL ANIMAL MODELS

Fig 3. Rationale for sildenafil use in pulmonary arterial hypertension. GC, guanylate cyclase; GTP, guanosine triphosphate. (Reprinted with permission from Steiner et al.35) (Color version of figure is available online.)

More than 60 animal studies have examined the hemodynamic effects of PDE inhibition in pulmonary hypertensive models induced by thromboxane analogs, hypoxia, monocrotaline, or oleic acid.35 These studies consistently show the pulmonary vasodilator actions of PDE inhibitors and suggest that PDE5 inhibitors vasodilate pulmonary vessels more effectively than do PDE3 inhibitors.37 PDE5 inhibition attenuates the severity of PAH in chronically hypoxic pulmonary hypertensive rats.36 In addition, sildenafil reduces the proportion of muscularized distal pulmonary arteries in chronically hypoxic rat lungs, indicating that PDE5 inhibitors block pulmonary vascular remodeling in the presence of continued exposure to hypoxia. In monocrotalineinduced pulmonary hypertensive rats, sildenafil administered in drinking water for 6 weeks not only improved survival but also increased cGMP and reduced PAH, muscularization of the peripheral pulmonary arteries, and right-heart hypertrophy without affecting gas exchange or systemic arterial pressure.38

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RAJA ET AL

These results show that sildenafil is effective for long-term therapy of PAH in experimental models.

Table 3. Grading of Recommendations and Level of Evidence Grade A Level 1a

CLINICAL EFFICACY OF SILDENAFIL

Clinicians are currently practicing in an era in which decisions concerning treatments in health care should be based on the best available knowledge, a principle better known as the more fashionable term “evidence-based medicine.”39 In this era of evidence-based medicine, randomized controlled trial (RCT) is regarded as the gold standard to produce unbiased results for health care interventions with blinding used to eliminate the subjective preferences of the caregiver, the observer, or the patient. However, a logical and comprehensive approach to evaluating clinically relevant research incorporates many different types of evidence including RCTs, nonrandomized clinical trials, and experimental data and analyzes the information’s content for its consistency, coherence, and clarity.40 This section evaluates current clinical evidence for the efficacy of sildenafil as a pulmonary vasodilator.

Level 1b Level 1c

Level 1d Grade B Level 2

Level 3 Level 4 Grade C Level 5

Evidence from large randomized controlled trials (RCTs) or systematic reviews (including metaanalyses) of multiple randomized trials Evidence from at least 1 high-quality cohort study Evidence from at least 1 moderate-sized RCT or a meta-analysis of small trials that collectively have only a moderate number of patients Evidence from at least 1 RCT Evidence from at least 1 high-quality study of nonrandomized cohorts that did and did not receive the new therapy Evidence from at least 1 high-quality case-control study Evidence from at least 1 high-quality case series Opinions from experts without reference or access to any of the above

Search Methodology To evaluate the efficacy of sildenafil for the treatment of pulmonary hypertension, the English language scientific literature was reviewed primarily by searching MEDLINE from 1966 through June 2005 by using the PubMed interface.41 Key words used in the search included sildenafil, Viagra, phosphodiesterase inhibitors, phosphodiesterase type 5 inhibitors, pulmonary hypertension, and pulmonary arterial hypertension. The “related articles” function was used to broaden the search, and all abstracts, studies, and citations scanned were reviewed. The reference lists of articles found through these searches were also reviewed for relevant articles. In addition, links on web sites containing published articles were searched for relevant information. The authors for this article chose all short- and long-term clinical studies recruiting at least 5 patients with pulmonary hypertension and evaluating the hemodynamic and clinical effects of sildenafil as monotherapy and in combination with other agents. The search was performed in stages to achieve the search strategy with a high sensitivity (meaning that it has the highest likelihood of retrieving all relevant papers). Similar search terms were combined by using the Boolean operator “or” to find all abstracts that contained information about a particular search term. These individual terms were then combined by using the Boolean operator “and” to find articles that contained information on all the search terms. This is a well-recognized method for performing sensitive searches and has been described in detail in the British Medical Journal.42 Data Extraction and Validation of the Studies A total of 25 studies 6-10,26,43-61 relevant to this review were selected. The articles found by the search strategy were then appraised. The appraisal of each article was performed in a structured format by using critical appraisal checklists. These are widely available in several formats and aid in assessing the article for methodologic and analytical soundness and help uncover any significant methodologic flaws.62 The following information was extracted from each study: first author, year of publication, study population characteristics, number of patients, dosage, formulation used, duration of therapy, and key

outcome(s). In addition, after appraisal, the article was categorized in terms of the type of study and the level of evidence presented.63 The levels of evidence are presented in Table 3 and enable readers of the article to come to a conclusion about the certainty to which evidence exists on the topic. SILDENAFIL USE IN ADULT PATIENTS

A total of 22 studies6-9,26,43,45,46,48-61 have reported the effects of sildenafil use in adult patients with PAH of varied origin (Table 4). Of these, 2 studies9,59 included both children and adults. The majority of these studies included between 5 and 60 patients with a mean age range of 18 to 81 years. Sildenafil was administered orally in these studies, with single doses ranging from 12.5 to 100 mg. Hemodynamic Studies In healthy volunteers, a randomized double-blind study showed that oral sildenafil, 100 mg, almost completely reversed the pulmonary arterial vasoconstriction induced by hypoxic conditions.26 Sildenafil had decreased trends45,48 or significant decreases in PAP46,49,52 and pulmonary vascular resistance (PVR) or PVR index45,46,49 compared with baseline. Sildenafil also showed significant improvements45,46,52 or trends48,49 in cardiac output/cardiac index compared with baseline. Ghofrani et al52 showed that sildenafil produced dose-dependent changes in cardiac index, PAP, and PVR index, although significant differences were not reported between the 12.5- and 50-mg doses. Most studies reported that sildenafil decreased the ratio of pulmonary-to-systemic vascular resistance, suggesting pulmonary vascular selectivity; however, the results of one of these trials suggested that sildenafil may be less pulmonary selective at higher doses.52 Sildenafil had either no effect on arterial saturation or increased partial pressure of arterial oxygen.46,48,49,52 Short-term Clinical Trials Five short-term (ⱕ3 months) clinical trials have been conducted,8,43,54-56 3 of which were well designed.8,43,54 The largest, ran-

PULMONARY ARTERIAL HYPERTENSION

domized, double-blind, placebo-controlled trial to date, Sildenafil Use in Pulmonary Arterial Hypertension,43 enrolled 278 patients randomized to placebo (n ⫽ 70) or to 1 of 3 doses of sildenafil 3 times daily: 20 mg (n ⫽ 69), 40 mg (n ⫽ 68), or 80 mg (n ⫽ 71). Seventy-five percent of the patients were women, and the mean age of patients was 49 years. Thirty-eight percent of the patients were New York Heart Association (NYHA) class II, and 58% were class III. The mean baseline 6-minute walking distance was 344 m, and the baseline mean PAP was 53 mmHg. After 12 weeks of treatment, patients receiving 80 mg of sildenafil 3 times daily increased 6-minute walk results by 50 m, whereas patients receiving 40 mg of sildenafil 3 times daily increased their distance by 46 m, and patients at the lowest dose (20 mg 3 times daily) increased by 45 m. This was significant at p ⬍ 0.001. In addition to improved 6-minute walk test results, 35% of patients in the pooled sildenafil groups improved functional class compared with 7% of patients in the placebo group. Moreover, mean PAP decreased by an average of 5.1 mmHg, but this was not statistically significant. Another randomized, double-blind, placebo-controlled crossover trial evaluated the efficacy of sildenafil in patients with IPAH.54 Sildenafil or placebo was administered for 6 weeks, and patients were then crossed over to the alternate therapy with no washout period. No other vasodilators were permitted. One patient in the sildenafil-first group withdrew from the study 1 week after randomization, and 1 patient in the placebo-first group died 1 week after randomization. In the placebo-first group, the exercise times were 459.6 seconds at baseline, 452.1 seconds at the end of the placebo phase, and 687 seconds at the end of the sildenafil phase (p ⬍ 0.0001 for placebo v sildenafil). In the sildenafil-first group, the exercise times were 451.6 seconds at baseline, 698.1 seconds at the end of the sildenafil phase (p ⬍ 0.001 v baseline), and 527.4 seconds at the end of the placebo phase (p ⬍ 0.005 v sildenafil; p ⬍ 0.001 v baseline). When results for the 2 groups were combined, the exercise times were 475 seconds for placebo and 686 seconds after 6 weeks of sildenafil (p ⬍ 0.0001). The cardiac index was 2.80 L/m2 for placebo compared with 3.45 L/m2 for sildenafil (p ⬍ 0.0001). The difference in pulmonary arterial systolic pressure was not significantly different between sildenafil and placebo (98 v 105 mmHg, p ⫽ 0.09). Quality-of-life scores for dyspnea (p ⫽ 0.009) and fatigue (p ⫽ 0.04) were significantly higher for sildenafil compared with placebo. The emotional function component of the quality-of-life score was slightly lower with sildenafil, but this was not statistically significant (p ⫽ 0.06). There was no significant change in systemic blood pressure with sildenafil therapy.54 A similarly designed study in which sildenafil was given for 2 weeks showed comparable findings related to exercise tolerance and hemodynamic improvements.8 In addition, the mean Borg dyspnea score was significantly improved with sildenafil (5.22 at baseline, 5.11 for placebo, and 3.56 for sildenafil; p ⬍ 0.01). The NYHA class improved in 2 patients. A 6-week open-label trial also supported the findings of improved PAP, NYHA class, and dyspnea with sildenafil compared with baseline.55 Another open-label trial conducted to evaluate optimal dosing of sildenafil in IPAH recruited 15 patients who received

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sildenafil, 50 mg twice daily for 4 weeks, with the dose increased to 100 mg twice daily for an additional 4 weeks.56 Nifedipine was administered to 5 patients who showed an initial response to this vasodilator, and none of the patients had received specific pulmonary vasodilators in the past. The 6-minute walk test improved significantly compared with baseline 1 week after starting sildenafil (p ⫽ 0.002) and after 4 weeks of the 50-mg dose (377 v 234 m, p ⫽ 0.001). Sildenafil, 50 mg, twice daily, also significantly improved the mean Borg dyspnea index (8.1 v 4.4, p ⫽ 0.0007) and mean NYHA class (3.8 v 2.4, p ⫽ 0.002). The clinical parameters did not significantly improve further when the dose of sildenafil was doubled. Mean pulmonary artery systolic pressure was significantly reduced with sildenafil, 50 mg, twice daily, compared with baseline (113 v 125 mmHg, p ⫽ 0.05). Overall, 12 (80%) patients showed response to sildenafil. Eleven of these patients responded to a dose of 50 mg twice daily, and 1 patient responded when the dose was doubled.56 Long-term Clinical Trials Sildenafil monotherapy. Five open-label, long-term (⬎3 months) trials evaluated the clinical effects of sildenafil monotherapy in patients with pulmonary hypertension.6,9,57-59 Three of the studies included only adults,6,57,58 and 2 included both children and adults.9,59 The studies evaluated between 5 and 29 patients, with an average age of 15.6 to 40.2 years. These trials included a heterogenous patient population with predominantly thromboembolic pulmonary disease and patients with PAH related to collagen vascular disease, congenital heart disease, and idiopathic pulmonary hypertension. Before receiving sildenafil, most patients were receiving conventional therapy with anticoagulants, diuretics, and/or other vasodilators.57,59 Sildenafil was administered orally in these studies, with daily doses ranging from 75 to 300 mg. The trials ranged from 3 to 7.3 months. In all of these studies, sildenafil significantly improved exercise tolerance, as measured by the 6-minute walk test, compared with baseline. Four of the trials reported improvement in NYHA functional class,6,9,57,59 whereas one did not evaluate this endpoint.58 In contrast to the short-term clinical studies, none of these studies evaluated changes in dyspnea. In the study by Mikhail et al,57 7 (78%) patients had improvement in overall health and well-being and 2 patients reported no change. Most investigators reported significant decreases in PAP,6,57 PVR/PVR index,6,57-59 and trends toward increased cardiac output/cardiac index.57,59 No deterioration in arterial, venous, or pulmonary oxygen saturation was observed,57-59 and some noted a significant trend toward improvement in oxygen saturation with sildenafil.57,58 Sildenafil combination. Two long-term trials evaluated the clinical effects of combination therapy with sildenafil and other vasodilators. The best-designed trial was a prospective uncontrolled comparison of addition of sildenafil to iloprost.60 Combination therapy with iloprost and sildenafil appeared to lower the mean PAP (50.7 v 47.8 mmHg) and increase the cardiac index (2.3 v 2.6 L/min/m2), although significant differences were not reported. Combination therapy also significantly decreased the PVR index (1,640 v 1,309 dynes/cm2/m2, p ⫽ 0.014). Compared with iloprost monotherapy, combination therapy significantly increased the 6-minute walking distance at

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Table 4. Clinical Studies on the Use of Sildenafil in PAH Study Type (Level of Evidence)

Study Humpl et

al,10

2005

Sheth et al,55 2005

SD, OL, Pilot study (Level 4) OL, non-R (Level 4)

Number of Patients

Preparation

Duration of Therapy

0.25-1 mg/kg 4 times daily

Oral

12 months

6b

50 mg tid

Oral

6 weeks

15

50 mg twice a day for 4 wk, then 1 100 mg twice a day for 4 wk

Oral

8 weeks

14a

Dose

Chokalingam et al,56 2005

OL, non-R (Level 4)

Wilkins et al,61 2005

DB, RCT (Level 1d)

26c

50 mg twice a day for 4 wk, then 50 mg 3 times a day for 12 wk

Oral

16 weeks

SUPER-1,43 2004

DB, PC, RCT (Level 1a)

278d,e

20 mg, 40 mg or 80 mg 3 times a day

Oral

12 weeks

Leuchte et al,49 2004

OL, non-R (Level 4)

10

50 mg followed by 50 mg after 30 min

Oral

30 min

Ghofrani et al,53 2004

SD, OL, RT (Level 1c)

60f

50 mg

Oral

Single dose

Kuhn et al,50 2004

SD, OL (Level 4)

8

50 mg

Oral

Single dose

Sastry et al,54 2004

R, DB, PC crossover (Level 1d)

22

Oral

12 weeksg

Mikhail et al,57 2004

OL, non-R (Level 4)

10

⬍25 kg ⫽ 25 mg 3 times a day; 25-50 kg ⫽ 50 mg 3 times a day; ⬎51 kg ⫽ 100 mg 3 times a day 25 mg titrated to 50 mg 3 times a day

Oral

3 months

Stocker et al,44 2003

RT (Level 1d)

0.35 mg/kg

Intravenous

20 min

Schulze-Neick et al,47 2003

OL, non-R (Level 4)

1 mg/kg & 0.25 mg/kgn

Intravenous

10-15 minn

Michelakis et al,6 2003

OL, non-R, Pilot study (Level 4)

5o

50 mg, 8 hourly

Oral

3 months

Bhatia et al,7 2003

Retrospective (Level 4)

13

25 mg, 8 hourly up to max 100 mg, 8 hourly

Oral

24-48 hrs & 117 ⫾ 70 days

Bahrani et al,8 2003

R, DB, PC crossover (Level 1 d)

10

25 mg, 8 hourly

Oral

2 weeks

Ghofrani et al,58 2003

OL, non-R (Level 4)

12

50 mg 3 times a day, 1 over the first 4-5 days

Oral

6.5 ⫾ 1.1 months

15a

24a,m

Main Outcome Improved hemodynamics and exercise capacity for up to 12 months. Improvement in MPAP, MPCWP, MRC score, NYHA class and gas transfer. Significant improvement in NYHA class, Borg dyspnea index, 6-min walk distance and PAP with 50 mg twice a day. No further benefit with 100 mg twice a day. Significant reductions in RV mass and plasma BNP levels and improvements in 6-min walk distance, cardiac index and systolic left ventricular eccentricity index. Significant improvement in 6-min walk distance and NYHA class with all 3 doses. Significant improvement in pulmonary hemodynamics in patients with PPH. All three PDE5 inhibitors caused significant pulmonary vasorelaxation but only sildenafil produced significant improvement in arterial oxygenation. Significant reductions in MPAP (p ⬍ 0.05) and PVR (p ⬍ 0.005). Significant improvements in exercise time and cardiac index (p ⬍ 0.0001).

Significant reductions in MPAP and PVR with a significant increase in 6min walk distance. IV sildenafil augmented the pulmonary vasodilator effects of iNO in infants early after cardiac surgery. IV sildenafil is as effective as inhaled NO as a pulmonary vasodilator in children with congenital heart disease. Significant improvement in functional class, 6-min walking distance and significant reductions in mean PAP, PVRI, and RV mass. Immediately cardiac output increased significantly while PASP, MPAP, PVR, and MAP decreased significantly. Long-term effects on right heart function and functional status were equivocal. Significant improvements in symptoms, functional class, exercise tolerance, and PASP. Significant improvements in PVR index, cardiac index, and 6-min walk distance.

PULMONARY ARTERIAL HYPERTENSION

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Table 4. Clinical Studies on the Use of Sildenafil in PAH (Cont’d)

Study

Study Type (Level of Evidence)

Number of Patients

Dose

Preparation

Duration of Therapy

⬎OL, non-R (Level 4)

14h

25 mg 3 times a day to 50 mg 3 times a day over 3-4 days

Oral

9-12 months

Ghofrani et al,52 2002

OL, RCT (Level 1d)

30h

Oral

Single dose

Ghofrani et al,48 2002

OL, RT (Level 1d)

16i

12.5 mg and 50 mg SD alone and combined with 2.8 ␮g inhaled iloprost 50 mg

Oral

Single dose

Lepore et al,45 2002

OL, non-R (Level 4)

9j

50 mg

Oral

Single dose

Michelakis et al,46 2002

OL, non-R (Level 4)

13k

75 mg

Oral

Single dose

Sastry et al,59 2002

OL, non-R (Level 4)

29

Oral

3 months

Kothari et al,9 2002

OL, non-R (Level 4)

14

25 mg 3 times a day 1 to 100 mg 3 times a day as tolerated Median dose of 87.5 mg/day (for ⬍ 30 kg) & 150 mg (for ⬎ 30 kg)

Oral

Wilkens et al,51 2001

OL (Level 4)

5l

7.3 ⫾ 2.4 months (range 3-14 months) 1 hour

Zhao et al,26 2001

SD, DB, PC, RT (Level 1d)

10

Ghofrani et 2003

al,60

25 mg incremental dose until a response obtained

Oral

100 mg

Oral

Single dose

Main Outcome Significant and favorable improvements in NYHA class, 6-min walk distance, and pulmonary hemodynamic parameters. 50 mg sildenafil ⫹ iloprost were most effective in reducing PVR and increasing cardiac index. Sildenafil causes preferential pulmonary vasodilation and improves gas exchange in patients with severe lung fibrosis and secondary PAH. Sildenafil augmented pulmonary vasodilator effect of iNO without causing systemic hypotension. A single oral dose of sildenafil is as effective and selective a pulmonary vasodilator as iNO. Significant improvements in NYHA class and 6-min walk distance with significant reduction in PAP. Significant improvements in functional class, 6-min walk test and RVSP at 3 months and 6 months, respectively. Sildenafil caused long-lasting reductions in MPAP and PVR, with a further additional improvement after iloprost inhalation. Sildenafil attenuates hypoxiainduced PAH.

Abbreviations: SD, single drug; OL, open label; non-R, nonrandomized; DB, double-blind; RCT, randomized controlled trial; RT, randomized trial; PC, placebocontrolled; wks, weeks; PPH, primary pulmonary hypertension; IV, intravenous; NYHA, New York Heart Association; iNO, inhaled nitric oxide; PAP, pulmonary artery pressure; PVRI pulmonary vascular resistance index; RVSP, right ventricular systolic pressure; MPAP, mean pulmonary artery pressure; PASP, pulmonary artery systolic pressure; MAP, mean arterial pressure; MPCWP, mean pulmonary capillary wedge pressure; MRC, Medical Research Council; PAH, pulmonary arterial hypertension. aStudies recruiting pediatric patients only. bAll patients had severe pulmonary hypertension secondary to chronic thromboembolic disease that was not amenable to pulmonary thromboendarterectomy. cComparative study between sildenafil and bosentan. Twelve patients received bosentan 62.5 mg twice a day for 4 weeks, then 125 mg twice a day (⫹ midday placebo for 12 weeks). d 278 patients randomized to placebo (n ⫽ 70) or to 1 of 3 doses of sildenafil 3 times daily: 20 mg (n ⫽ 69), 40 mg (n ⫽ 68), or 80 mg (n ⫽ 71). eFDA approval based on the results of SUPER-I trial. fStudy to compare the short-term impact of 3 different PDE5 inhibitors on pulmonary and systemic hemodynamics and gas exchange parameters in patients with PAH. Sixty patients were assigned to oral intake of 50 mg sildenafil (n ⫽ 19); 10 mg (n ⫽ 7) or 20 mg (n ⫽ 9) vardenafil; or 20 mg (n ⫽ 9), 40 mg (n ⫽ 8), or 60 mg (n ⫽ 8) tadalafil. gPlacebo or sildenafil for 6 weeks, then crossover for 6 weeks (no washout). hAdjunctive sildenafil to inhaled iloprost. iAfter inhalation of nitric oxide (10-20 ppm), patients were assigned to either maximum tolerated dose of intravenous epoprostenol (mean 8.0 ng/kg per min; n ⫽ 8) or oral sildenafil (50 mg; n ⫽ 8). jConcomitant administration of 50 mg sildenafil with 80 ppm inhaled nitric oxide. kConcomitant administration of 75 mg sildenafil with 80 ppm inhaled nitric oxide. lConcomitant administration of sildenafil (25-50 mg) with 8.4 to 10.5 ␮g of aerosolized iloprost. mTwelve children underwent catheterization and 12 were postoperative. nStep-wise increment of dosage over 10- to 15-minute intervals. oOne patient with Eisenmenger’s syndrome.

3 months (346 v 256, p ⫽ 0.002) and provided a sustained improvement in exercise tolerance up to 9 to 12 months (349 v 256, p ⫽ 0.002). Combination treatment also improved NYHA functional class. A retrospective study reported mixed findings.7 This study evaluated the clinical and hemodynamic effects of adding sil-

denafil to various vasodilators, including epoprostenol, bosentan, and calcium channel blockers, in 13 patients with pulmonary hypertension predominantly because of IPAH. Overall, patients did not have a significant improvement in the 6-minute walk test; however, 3 patients showed improvement in NYHA functional class. The epoprostenol dosing regimen was de-

730

creased over time in 2 patients because of symptomatic improvement. The addition of sildenafil significantly decreased mean PAP (peak 43 v 48, p ⫽ 0.01), decreased PVR index (peak 8.6 v 6.7, p ⬍ 0.001), and increased cardiac output (peak 6.2 v 7.2 L/min, p ⫽ 0.04) compared with baseline. Comparative Studies of Sildenafil With Other Pulmonary Vasodilators Sildenafil versus NO. Five studies compared the effects of sildenafil versus NO, 20 to 80 ppm.45,46,48,49,53 Sildenafil appeared to have comparable or greater effects in decreasing PAP and PVR/PVR index compared with NO. Similarly, sildenafil appeared to show a similar or greater increase in cardiac output/cardiac index compared with NO. Two studies48,52 reported that sildenafil had prolonged hemodynamic effects compared with NO (⬎120 v 15 minutes). Sildenafil appeared to have similar effects on oxygen saturation versus NO.46,49 However, in the study by Lepore et al,45 NO produced a greater decrease in the ratio of PVR/systemic vascular resistance than sildenafil (0.44 v 0.5), suggesting a greater pulmonary vasoselectivity. Lepore et al45 and Michelakis et al46 also compared the effects of NO and sildenafil monotherapy with combination therapy. In both studies, combination treatment was more effective at decreasing PAP and PVR/PVR index than monotherapy with either agent and provided an additive effect in increasing cardiac index. Lepore et al45 reported that the hemodynamic effects were prolonged with combination therapy compared with monotherapy with nitric oxide (10-15 v 5-10 minutes), but no comparison was made with sildenafil monotherapy. Combination therapy appeared to increase arterial oxygen saturation versus NO (97.6% v 96%) or sildenafil.46 In addition, combination therapy had a comparable ratio of pulmonary to systemic vascular resistance compared with NO monotherapy (0.44 v 0.44). Combination therapy had a significantly lower ratio than sildenafil monotherapy (0.44 v 0.5, p ⬍ 0.05), suggesting greater pulmonary selectivity. Sildenafil versus iloprost. Three studies evaluated the effects of sildenafil versus inhaled iloprost (2.8-20 ␮g).49,51,52 In the studies by Leuchte et al49 and Wilkens et al,51 iloprost decreased PAP greater than sildenafil; whereas in the trial by Ghofrani et al,52 the PAP appeared to be similar for the drugs. One reason for this difference may be that Ghofrani et al52 used a much lower dose of iloprost (2.8 ␮g) than the other researchers (8.4-20 ␮g). The percent change in PVR/PVR index was lower for iloprost than sildenafil for all studies. In all of the trials, the percent change in cardiac output/cardiac index appeared to be higher with iloprost compared with sildenafil.49,51,52 Combination treatment with iloprost and sildenafil provided enhanced hemodynamic benefits.51,52 Compared with sildenafil alone, combination treatment provided additive or synergistic reductions in PAP and PVR. Moreover, combination treatment had a greater effect on cardiac output than sildenafil monotherapy. Interestingly, the pulmonary vascular effects52 of combination treatment were greater with higher doses of sildenafil (12.5 v 50 mg) and prolonged than with sildenafil monotherapy (180-210 v 90-120 min).51,52 Combination therapy was associated with significant or nonsignificant decreases in the PVR/

RAJA ET AL

systemic vascular resistance ratio (⫺5% to ⫺12%) and increased51 or no52 changes in oxygen saturation. Sildenafil versus epoprostenol. Only 1 study compared the effects of monotherapy with epoprostenol versus sildenafil.48 The percent change in PVR index was not significantly different between the treatment groups; however, epoprostenol appeared to produce the greatest change. Compared with sildenafil, epoprostenol had a greater effect on increasing cardiac index. Sildenafil showed pulmonary selectivity, as evidenced by a greater percent reduction in the ratio of PVR-to-systemic vascular resistance compared with epoprostenol (⫺24% v ⫺2%). Furthermore, pulmonary shunt flow was increased with epoprostenol (⫹17%) but was unchanged from baseline with sildenafil. As a result, epoprostenol reduced partial pressure of oxygen (⫺15%) because of increased perfusion to low ventilation areas, whereas sildenafil increased PaO2 (⫹14%). Kuhn et al50 compared the hemodynamic efficacy of combination therapy with epoprostenol and sildenafil. Combination treatment was more effective at decreasing mean PAP and PVR than epoprostenol alone (defined as baseline in study). Although a statistically significant difference was not reported, epoprostenol plus sildenafil appeared to be more effective at increasing cardiac output compared with epoprostenol alone. Combination therapy increased the ratio of mean arterial pressure to mean PAP compared with epoprostenol alone (2.1 v 1.9), and no changes were reported with systemic oxygen saturation. These results support the finding by Ghofrani et al,48 suggesting that sildenafil shows a preferential vasodilation of the pulmonary vasculature. Sildenafil versus bosentan. Only 1 study to date has compared the effects of sildenafil with those of a specific pulmonary vasodilator.61 This randomized, double-blind, 16-week Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension trial compared hemodynamic and clinical effects of sildenafil with those of bosentan in patients on conventional therapy. Although 26 World Health Organization functional class III patients were enrolled, 1 patient in the sildenafil group died during week 14. Both the sildenafil and bosentan groups had a significant improvement in cardiac index compared with baseline, with no difference between treatments (mean change from baseline 0.3 L/min/m2, p ⬍ 0.01 for both). In addition, both groups had a significant improvement in the mean 6-minute walk test compared with baseline, with sildenafil producing a 55-m greater mean change from baseline versus bosentan (p ⫽ 0.044). The Borg dyspnea index scores did not significantly change from baseline for either treatment. Quality-of-life scores improved significantly with sildenafil (change from baseline 27, p ⬍ 0.01) but not with bosentan (change from baseline 6), with a significant difference between sildenafil and bosentan (p ⫽ 0.002). Comparison of Sildenafil With Other PDE5 Inhibitors as Pulmonary Vasodilator At present, only 1 study has compared the hemodynamic responses of sildenafil among various doses of other PDE5 inhibitors.53 This randomized prospective study showed that sildenafil, vardenafil, and tadalafil decreased mean PAP and PVR index and increased cardiac index compared with baseline (with NO). Overall, sildenafil had the greatest percent decrease

PULMONARY ARTERIAL HYPERTENSION

in PVR index compared with baseline but had similar effects on cardiac index and mean PAP versus the other treatment groups. The peak pulmonary vasodilating effects were the most rapid with vardenafil (40-45 minutes), followed by sildenafil (60 minutes) and tadalafil (75-90 minutes). Sildenafil, 50 mg, tadalafil, 40 mg, and tadalafil, 60 mg, significantly reduced the pulmonary-to-systemic vascular resistance ratio, suggesting that these agents had pulmonary vasoselectivity, whereas vardenafil, 10 and 20 mg, had minimal effects. Sildenafil significantly improved arterial oxygenation compared with vardenafil and tadalafil, suggesting that sildenafil may have beneficial effects on ventilation/perfusion matching. SILDENAFIL USE IN PEDIATRIC PATIENTS

To date, only 1 randomized trial44 to investigate the acute effects of intravenous sildenafil on hemodynamics and oxygenation and its interaction with inhaled nitric oxide (iNO) in infants at risk of pulmonary hypertension early after cardiac surgery has been performed. In this trial by Stocker et al,44 16 ventilated infants early after closure of ventricular or atrioventricular septal defects were randomly assigned to 1 of 2 groups. The study was completed in 15 infants. Studies were commenced within 7 hours of separation from bypass. Seven infants received iNO (20 ppm) first, with the addition of intravenous sildenafil (0.35 mg/kg over 20 minutes) after 20 minutes. Eight infants received sildenafil first; iNO was added after 20 minutes. Vascular pressures, cardiac output, and blood gas were recorded at 0, 20, and 40 minutes. In infants receiving iNO first, iNO lowered the PVR index from 3.45 to 2.95 units (p ⫽ 0.01); sildenafil further reduced PVR index to 2.45 units (p ⬍ 0.05). In those receiving sildenafil first, PVR index was reduced from 2.84 to 2.35 units (p ⬍ 0.05) with sildenafil and decreased to 2.15 units (p ⫽ 0.01) with the addition of iNO. In both groups, sildenafil reduced the systemic blood pressure and systemic vascular resistance (p ⬍ 0.01) and worsened arterial oxygenation and the alveolar-arterial gradient (p ⬍ 0.05). In a prospective nonrandomized study, Schulze-Neick et al47 compared the effects of iNO before and after the specific inhibition of the PDE5 by intravenous sildenafil in preoperative and postoperative children with increased PVR because of congenital heart disease. Twelve children with congenital heart disease (ages 0.2-15.7 years; median, 2.4 years) and increased mean pulmonary arterial pressure and 12 postoperative children (ages 0.11-0.65 years; median, 0.32 years) with increased PVR (8.3 ⫾ 1.0 Wood units/m2) were studied during cardiac catheterization (“cath laboratory”) or within 2 hours after return from cardiac surgery (“postop”), respectively. All were sedated, tracheally intubated, and paralyzed. During alveolar hyperoxygenation (FIO2 ⫽ 0.65), the effects of iNO (20 ppm) were compared before and after the stepwise infusion of sildenafil (“cath laboratory,” 1 mg/kg; “postop,” 0.25 mg/kg). Intravenous sildenafil more effectively reduced PVR than NO (11.5% v 4.3% in the “cath laboratory” patient group, p ⬍ 0.05, and 25.8% v 14.6% in the “postop” patient group, p ⫽0.09). The increase in cGMP in response to NO was potentiated (2- to 2.4-fold) by PDE5 inhibition. Although the vasodilating effects of sildenafil showed pulmonary selectivity, its infusion was associated with increased intrapul-

731

monary shunting in the postoperative patients (Qs/Qt ⫽ 16.5% ⫾ 4.7% to 25.5% ⫾ 18.2%; p ⫽ 0.04). In the recently published 12-month clinical trial of a single-drug, open-label, pilot study, Humpl et al10 have shown beneficial effect of oral sildenafil therapy on childhood PAH. After baseline assessment of hemodynamics by cardiac catheterization and distance walked in 6 minutes, oral sildenafil was administered at 0.25 to 1 mg/kg 4 times daily to 14 children (median age, 9.8 years; range, 5.3-18). Diagnoses were primary (n ⫽ 4) and secondary (n ⫽ 10) PAH. The 6-minute walk test was repeated at 6 weeks and at 3, 6, and 12 months (n ⫽ 14) and cardiac catheterization (n ⫽ 9) after a median follow-up of 10.8 months (range, 6-15.3). During sildenafil therapy, the mean distance walked in 6 minutes increased from 278 ⫾ 114 to 443 ⫾ 107 m over 6 months (p ⫽ 0.02), and at 12 months, the distance walked was 432 ⫾ 156 m (p ⫽ 0.005). A plateau was reached between 6 and 12 months (p ⫽ 0.48). Mean pulmonary artery pressure decreased from a median of 60 mmHg (range, 50-105) to 50 mmHg (range, 38-84; p ⫽ 0.014). Median pulmonary vascular resistance decreased from 15 Wood units/m2 (range, 9-42) to 12 Wood units/m2 (range, 5-29; p ⫽ 0.024). Important data on therapeutic dosage as well as long-term safety of sildenafil in pediatric patients are still missing. SILDENAFIL AND POSTOPERATIVE PULMONARY HYPERTENSION AFTER CARDIAC SURGERY

Pulmonary hypertension can present a formidable challenge in the management of patients undergoing cardiac surgery.64 The use of iNO has become the treatment of choice over the last decade in patients who have pulmonary hypertension postoperatively. However, the need for continuous therapy because of its short half-life and life-threatening rebound pulmonary hypertension on its discontinuation have led to trials with other selective pulmonary vasodilators. Trachte et al,64 in a recently published retrospective review, have shown that sildenafil produces marked pulmonary vasodilation when added to a preexisting regimen of nitrosovasodilators in patients with pulmonary hypertension following cardiac surgery. The pulmonary hypertension in this series of patients was refractory to conventional pharmacologic agents and was reduced on average by 20% with sildenafil. Sildenafil not only provided an additive pulmonary vasodilatory effect but also allowed the successful weaning of inhaled and intravenous pulmonary vasodilators. Similar successful use of sildenafil for treating postoperative pulmonary hypertension has been reported by several other anecdotal reports.65-67 SAFETY PROFILE OF SILDENAFIL

Sildenafil can potentially cause serious adverse effects, which reflect its pharmacologic activity of inhibition of PDE5 in various tissues.11 However, research evaluating the use of sildenafil for pulmonary hypertension has shown that it is well tolerated. One of the best-designed studies had no reports of adverse effects.8 A similarly designed study re-

732

RAJA ET AL

Fig 4.

Treatment algorithm for PAH.

ported no serious adverse effects requiring discontinuation of sildenafil.54 In this study, the adverse effects that were more frequently reported with sildenafil compared with placebo were backache (3 v 1), headache (3 v 1), and numbness of hands and feet (4 v 1). No or few adverse effects were reported in other clinical trials and hemodynamic studies.46,48,49,51,59,60 Common adverse effects among these and other studies included headache, nausea, mild abdominal discomfort, nasal congestion, flushing, and dizziness.7,9 Although asymptomatic decreases in blood pressure were reported, there were no significant differences in mean arterial pressure and/or heart rate compared with baseline for the majority of the trials.6,7,9,45,46,48-54,57 Two studies did report significant reductions in mean systemic arterial pressure from baseline, with most patients being asymptomatic.7,58 Only 1 patient in 1 study required discontinuation of sildenafil because of hypotension.7 Prospective placebo-controlled studies involving the use of sildenafil for erectile dysfunction reported similar adverse effects.11 In those stud-

ies, the most commonly reported adverse effects were headache (16%), flushing (10%), dose-related dyspepsia (7%), and nasal congestion (4%).11 Serious adverse effects requiring drug discontinuation have occurred infrequently in studies evaluating sildenafil for pulmonary hypertension and have included peripheral edema (combined with malaise and nasal congestion), transient visual disturbance, severe hypotension, facial edema associated with shortness of breath, and chills.7,57 The manufacturer has reported that priapism, stroke, or cardiovascular events have occurred rarely in patients taking sildenafil for erectile dysfunction68; however, these adverse events were not observed in the studies evaluating sildenafil for pulmonary hypertension. Few or no deaths were reported,9,54,57,58,60 and none was associated with sildenafil therapy. The manufacturer cautions against the use of sildenafil in patients with retinitis pigmentosa, a visual disorder in which progressive atrophy of the retina results in blindness.68 In clinical trials of sildenafil for erectile dysfunction, transient

PULMONARY ARTERIAL HYPERTENSION

733

dose-related visual changes have been reported (3%; color tinge, increased sensitivity to light, or blurred vision).68 Although the majority of ocular adverse effects are dose related and reversible, there have been rare reports of retinopathy and long-term visual disturbances. A case of premature retinopathy was reported in an infant after receiving sildenafil for ⬎2 weeks.69 After sildenafil was discontinued and the patient received laser photocoagulation, the retinopathy regressed. Fourteen cases of nonarteritic ischemic optic neuropathy (NAION) have been reported in adults soon after use of sildenafil for erectile dysfunction.68 Permanent visual deficits occurred in some of these patients. Patients with preexisting atherosclerotic risk factors (eg, hyperlipidemia, hypertension, and diabetes) may be at increased risk for NAION. In patients with NAION in 1 eye, sildenafil may increase the risk for development of NAION in the other eye. Therefore, sildenafil should be used cautiously in these patients.70 In clinical trials with sildenafil in pulmonary hypertension, no irreversible visual disturbances were reported.6,7,9,54,57-60 Although no reports of respiratory decompensation have been described in patients with pulmonary hypertension, animal studies involving experimental models of lung injury have shown that sildenafil may worsen gas exchange as a result of impaired ventilation-perfusion matching.71 Similar findings have been reported by Stocker et al44 in their RCT designed to investigate the acute effects of intravenous sildenafil on hemodynamics and oxygenation and its interaction with iNO in infants at risk of pulmonary hypertension early after cardiac surgery. As a result, the American College of Chest Physicians recommends that sildenafil should be used cautiously in patients with pulmonary hypertension and severe lung disease.72

CURRENT STATUS OF SILDENAFIL IN THE THERAPY OF PULMONARY ARTERIAL HYPERTENSION

Until recently, based on the evidence as previously described, sildenafil was recommended for patients with PAH who have failed or who are not candidates for other vasodilator therapies (Fig 4). However, as of June 6, 2005, the US Food and Drug Administration (FDA) has approved sildenafil citrate (Revatio, Pfizer) as a treatment for PAH.73 The FDA granted Revatio a priority review, and the FDA approval was based on results of the Sildenafil Use in Pulmonary Arterial Hypertension trial.43 The approved dosage is limited to 20 mg 3 times daily. Revatio is the first oral treatment for PAH to be approved for patients with an early stage of the disease, allowing physicians to treat patients earlier in this progressive disorder.73 CONCLUSION

Major advances in the elucidation of the pathogenic sequence leading to PAH have led to the development of new therapeutic approaches. Among them inhibition of PDE5 with sildenafil has received considerable attention and generated hope for both clinicians and patients. Current available evidence from clinical studies on the safety and efficacy of sildenafil as a monotherapy for PAH appears encouraging. However, it is extremely important to realize that important data on long-term safety of sildenafil are still unavailable. Furthermore, data on dosage for pediatric patients as well as safety profile of sildenafil in patients with severe lung disease and combination of sildenafil with other pulmonary vasodilators are still missing. Hence, large, randomized, controlled clinical trials evaluating sildenafil as monotherapy and in combination with other vasodilators, extending a year or longer, are needed to confirm the long-term safety of sildenafil in patients with PAH of varied origin.

REFERENCES 1. Gaine SP, Rubin LJ: Primary pulmonary hypertension. Lancet 352:719-725, 1998 2. Farber HW, Loscalzo J: Pulmonary arterial hypertension. N Engl J Med 351:1655-1665, 2004 3. Rubin LJ: Primary pulmonary hypertension. N Engl J Med 336: 111-117, 1997 4. Wanstall JC, Jeffery TK: Recognition and management of pulmonary hypertension. Drugs 56:989-1007, 1998 5. Hoeper MM: Drug treatment of pulmonary arterial hypertension: Current and future agents. Drugs 65:1337-1354, 2005 6. Michelakis ED, Tymchak W, Noga M, et al: Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension. Circulation 108:2066-2099, 2003 7. Bhatia S, Frantz RP, Severson CJ, et al: Immediate and long-term hemodynamic and clinical effects of sildenafil in patients with pulmonary arterial hypertension receiving vasodilator therapy. Mayo Clin Proc 78:1207-1213, 2003 8. Bharani A, Mathew V, Sahu A, et al: The efficacy and tolerability of sildenafil in patients with moderate-to-severe pulmonary hypertension. Indian Heart J 55:55-59, 2003 9. Kothari SS, Duggal B: Chronic oral sildenafil therapy in severe pulmonary artery hypertension. Indian Heart J 54:404-409, 2002 10. Humpl T, Reyes JT, Holtby H, et al: Beneficial effect of oral sildenafil therapy on childhood pulmonary arterial hypertension:

Twelve-month clinical trial of a single-drug, open-label, pilot study. Circulation 111:3274-3280, 2005 11. Raja SG, Nayak SH: Sildenafil: Emerging cardiovascular indications. Ann Thorac Surg 78:1496-1506, 2004 12. Kulkarni SK, Patil CS: Phosphodiesterase 5 enzyme and its inhibitors: Update on pharmacological and therapeutical aspects. Methods Find Exp Clin Pharmacol 26:789-799, 2004 13. Reffelmann T, Kloner RA: Therapeutic potential of phosphodiesterase 5 inhibition for cardiovascular disease. Circulation 108:239244, 2003 14. Krenzelok EP: Sildenafil: Clinical toxicology profile. J Toxicol Clin Toxicol 38:645-651, 2000 15. Ballard SA, Gingell CJ, Tang K, et al: Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. J Urol 159: 2164-2171, 1998 16. Cheitlin MD, Hutter AM Jr, Brindis RG, et al: ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. American College of Cardiology/American Heart Association. J Am Coll Cardiol 33:273-282, 1999 17. Jackson G, Benjamin N, Jackson N, et al: Effects of sildenafil citrate on human hemodynamics. Am J Cardiol 83:13C-20C, 1999 18. Gillies HC, Roblin D, Jackson G: Coronary and systemic hemodynamic effects of sildenafil citrate: From basic science to clinical

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studies in patients with cardiovascular disease. Int J Cardiol 86:131-141, 2002 19. Zusman RM, Morales A, Glasser DB, et al: Overall cardiovascular profile of sildenafil citrate. Am J Cardiol 83:35C-44C, 1999 (suppl) 20. Phillips BG, Kato M, Pesek CA, et al: Sympathetic activation by sildenafil. Circulation 102:3068-3073, 2000 21. Kloner RA, Brown M, Prisant LM, et al: Effect of sildenafil in patients with erectile dysfunction taking antihypertensive therapy. Am J Hypertens 14:70-73, 2001 22. Wallis RM: The pharmacology of sildenafil, a novel and selective inhibitor of phosphodiesterase (PDE) type 5. Nippon Yakurigaku Zasshi 114:22P-26P, 1999 (suppl 1) 23. Corbin J, Rannels S, Doss N, et al: Sildenafil citrate does not affect cardiac contractility in human or dog heart. Curr Med Res Opin 19:747-752, 2003 24. Rabe KF, Tenor H, Dent G, et al: Identification of PDE isozymes in human pulmonary artery and effect of selective PDE inhibitors. Am J Physiol 266:L536-L543, 1994 25. Jeffery TK, Wanstall JC: Phosphodiesterase III and V inhibitors on pulmonary artery from pulmonary hypertensive rats: Differences between early and established pulmonary hypertension. J Cardiovasc Pharmacol 32:213-219, 1998 26. Zhao L, Mason NA, Morrell NW, et al: Sildenafil inhibits hypoxia-induced pulmonary hypertension. Circulation 104:424-428, 2001 27. Ichinose F, Erana-Garcia J, Hromi J, et al: Nebulized sildenafil is a selective pulmonary vasodilator in lambs with acute pulmonary hypertension. Crit Care Med 29:1000-1005, 2001 28. Traverse JH, Chen YJ, Du R, et al: Cyclic nucleotide phosphodiesterase type 5 activity limits blood flow to hypoperfused myocardium during exercise. Circulation 102:2997-3002, 2000 29. Chen Y, Du R, Traverse JH, et al: Effect of sildenafil on coronary active and reactive hyperemia. Am J Physiol Heart Circ Physiol 279:H2319-H2325, 2000 30. Ishikura F, Beppu S, Hamada T, et al: Effects of sildenafil citrate (Viagra) combined with nitrate on the heart. Circulation 102:25162521, 2000 31. Dietz U, Tries HP, Merkle W, et al: Sildenafil does not change coronary flow reserve in diabetics with erectile dysfunction. Dtsch Med Wochenschr 128:190-195, 2003 32. Herrmann HC, Chang G, Klugherz BD, et al: Hemodynamic effects of sildenafil in men with severe coronary artery disease. N Engl J Med 342:1622-1626, 2000 33. Schoeffter P, Lugnier C, Demesy-Waeldele F, et al: Role of cyclic AMP- and cyclic GMP-phosphodiesterases in the control of cyclic nucleotide levels and smooth muscle tone in rat isolated aorta. A study with selective inhibitors. Biochem Pharmacol 36:3965-3972, 1987 34. Maclean MR, Johnston ED, Mcculloch KM, et al: Phosphodiesterase isoforms in the pulmonary arterial circulation of the rat: Changes in pulmonary hypertension. J Pharmacol Exp Ther 283:619624, 1997 35. Steiner MK, Preston IR, Klinger JR, et al: Pulmonary hypertension: Inhaled nitric oxide, sildenafil and natriuretic peptides. Curr Opin Pharmacol 5:245-250, 2005 36. Sebkhi A, Strange JW, Phillips SC, et al: Phosphodiesterase type 5 as a target for the treatment of hypoxia-induced pulmonary hypertension. Circulation 107:3230-3235, 2003 37. Matot I, Gozal Y: Pulmonary responses to selective phosphodiesterase-5 and phosphodiesterase-3 inhibitors. Chest 125:644-651, 2004 38. Schermuly RT, Kreisselmeier KP, Ghofrani HA, et al: Chronic sildenafil treatment inhibits monocrotaline-induced pulmonary hypertension in rats. Am J Respir Crit Care Med 169:39-45, 2004

RAJA ET AL

39. Jacobs WC: Methodology and reporting of randomised controlled trials. Knee 11:423-425, 2004 40. Raja SG, Dreyfus GD: Off-pump coronary artery bypass surgery: To do or not to do? Current best available evidence. J Cardiothorac Vasc Anesth 18:486-505, 2004 41. Tomasulo P: The NLM Gateway: Something old, something new. Med Ref Serv Q 23:41-49, 2004 42. Greenhalgh T: How to read a paper: The Medline database. BMJ 315:180-183, 1997 43. Sulica R, Poon M: Medical therapeutics for pulmonary arterial hypertension: From basic science and clinical trial design to evidencebased medicine. Expert Rev Cardiovasc Ther 3:347-360, 2005 44. Stocker C, Penny DJ, Brizard CP, et al: Intravenous sildenafil and inhaled nitric oxide: A randomised trial in infants after cardiac surgery. Intensive Care Med 29:1996-2003, 2003 45. Lepore JJ, Maroo A, Pereira NL, et al: Effect of sildenafil on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension. Am J Cardiol 90:677-680, 2002 46. Michelakis E, Tymchak W, Lien D, et al: Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: Comparison with nitric oxide. Circulation 105:2398-2403, 2002 47. Schulze-Neick I, Hartenstein P, Li J, et al: Intravenous sildenafil is a potent pulmonary vasodilator in children with congenital heart disease. Circulation 108:II167-II173, 2003 (suppl 1) 48. Ghofrani HA, Wiedemann R, Rose F, et al: Sildenafil for treatment of lung fibrosis and pulmonary hypertension: A randomized controlled trial. Lancet 360:895-900, 2002 49. Leuchte HH, Schwaiblmair M, Baumgartner RA, et al: Hemodynamic response to sildenafil, nitric oxide, and iloprost in primary pulmonary hypertension. Chest 125:580-586, 2004 50. Kuhn KP, Wickersham NE, Robbins IM: Acute effects of sildenafil in patients with primary pulmonary hypertension receiving epoprostenol. Exp Lung Res 30:135-145, 2004 51. Wilkens H, Guth A, Konig J, et al: Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension. Circulation 104:1218-1222, 2001 52. Ghofrani HA, Wiedemann R, Rose F, et al: Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 136:515-522, 2002 53. Ghofrani HA, Voswinckel R, Reighenberger F, et al: Differences in hemodynamic and oxygenation response to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension-randomized prospective study. J Am Coll Cardiol 44:14881496, 2004 54. Sastry BK, Narasimhan C, Reddy NK, et al: Clinical efficacy of sildenafil in primary pulmonary hypertension: A randomized, placebocontrolled, double-blind, crossover study. J Am Coll Cardiol 43:11491153, 2004 55. Sheth A, Park JE, Ong YE, et al: Early haemodynamic benefit of sildenafil in patients with coexisting chronic thromboembolic pulmonary hypertension and left ventricular dysfunction. Vascul Pharmacol 42:41-45, 2005 56. Chockalingam A, Gnanavelu G, Venkatesan S, et al: Efficacy and optimal dose of sildenafil in primary pulmonary hypertension. Int J Cardiol 99:91-95, 2005 57. Mikhail GW, Prasad SK, Li W, et al: Clinical and haemodynamic effects of sildenafil in pulmonary hypertension: Acute and mid-term effects. Eur Heart J 25:431-436, 2004 58. Ghofrani HA, Schermuly RT, Rose F, et al: Sildenafil for long-term treatment of nonoperable chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 1667:1139-1141, 2003

PULMONARY ARTERIAL HYPERTENSION

59. Sastry BK, Narasimhan C, Reddy NK, et al: A study of clinical efficacy of sildenafil in patients with primary pulmonary hypertension. Indian Heart J 54:410-414, 2002 60. Ghofrani HA, Rose F, Schermuly RT, et al: Oral sildenafil as long-term adjunct therapy to inhaled iloprost in severe pulmonary arterial hypertension. J Am Coll Cardiol 42:158-164, 2003 61. Wilkins MR, Paul GA, Strange JW, et al: Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) study. Am J Respir Crit Care Med 171:1292-1297, 2005 62. Mackway-Jones K, Carley CD, Morton RJ: Best BETs critical appraisal worksheets. Available at: http://www.bestbets.org/cgi-bin/ public_pdf.pl. Accessed July 15, 2005 63. CEBM. Oxford Centre for Evidence-Based Medicine. Available at: http://www.cebm.net. Accessed July 15, 2005 64. Trachte AL, Lobato EB, Urdaneta F, et al. Oral sildenafil reduces pulmonary hypertension after cardiac surgery. Ann Thorac Surg 79:194-197, 2005 65. Bentlin MR, Saito A, De Luca AK, et al: Sildenafil for pulmonary hypertension treatment after cardiac surgery. J Pediatr (Rio J) 81:175-178, 2005 66. Saygili A, Canter B, Iriz E, et al: Use of sildenafil with inhaled nitric oxide in the management of severe pulmonary hypertension. J Cardiothorac Vasc Anesth 18:775-776, 2004

735

67. Nemoto S, Umehara E, Ikeda T, et al: Oral sildenafil citrate as an effective alternate in the treatment of postoperative pulmonary hypertensive crisis after congenital heart surgery. Kyobu Geka 57:842845, 2004 68. Lee AJ, Chiao TB, Tsang MP: Sildenafil for pulmonary hypertension. Ann Pharmacother 39:869-884, 2005 69. Marsh CS, Marden B, Newsom R: Severe retinopathy of prematurity (ROP) in a premature baby treated with sildenafil acetate (Viagra) for pulmonary hypertension. Br J Ophthalmol 88:306-307, 2004 70. Pomeranz HD, Bhavsar AR: Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (viagra): A report of seven new cases. J Neuroophthalmol 25:9-13, 2005 71. Kleinsasser A, Loeckinger A, Hoermann C, et al: Sildenafil modulates hemodynamics and pulmonary gas exchange. Am J Respir Crit Care Med 163:339-343, 2001 72. Badesch DB, Abman SH, Ahearn GS, et al: Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 126:35S-65S, 2004 (suppl) 73. News from Pfizer: FDA approves Pfizer’s Revatio as treatment for pulmonary arterial hypertension. Available at: www.pfizer.com/ pfizer/are/news_releases/2005pr/ mn_2005_0606.jsp. Accessed July 8, 2005