Phosphodiesterase Inhibitors, Congestive Heart Failure, and Sudden Death: Time for Re-Evaluation
Michael L. Hess, MD, Department of Internal Medicine/Cardiology, CHF and Heart Transplant, Virginia Commonwealth University Health System, 1200 East Broad Street, Box 980204, Richmond, VA 23298
©2012 Wiley Periodicals, Inc.
A 42-year-old diabetic man was admitted with systolic heart failure and pulmonary hypertension being treated with sildenafil for the previous year. With an increase in creatinine, he experienced 3 episodes of ventricular tachycardia and ventricular fibrillation. Withdrawal of the phosphodiesterase (PDE) inhibitor resulted in no further episodes of dysrhythmias. The basic pharmacology of PDE inhibitors is presented and the use of PDE-3 inhibitors for the treatment of heart failure causing an increase in sudden death is also reviewed. There have been several cases of sudden death associated with sildenafil use and with its increasing use in patients with severe pulmonary hypertension and decompensated heart failure. The authors also reviewed the electrophysiologic effects of PDE-5 inhibitors associated with their use. The crossover between PDE-3 and PDE-5 inhibitors is also discussed and caution is urged when contemplating the use of PDE-5 inhibitors in patients with systolic heart failure and pulmonary hypertension.
RC was a 42-year-old man originally referred to the heart failure (HF) service of our institution with a documented primary cardiomyopathy with a left ventricular ejection fraction (LVEF) of 20% and edema to the level of his thighs in late 2008. His medical history was pertinent for meningococcemia in 1997 and an embolic stroke in 2005, with complete recovery of motor function. His comorbidities included obesity (body mass index ∼45) and insulin-dependent diabetes mellitus. Electrocardiography (ECG) showed a normal sinus rhythm with left bundle branch block and QRS duration of 140 ms. A right heart catheterization revealed significant elevations in right-sided pressures with a pulmonary artery systolic pressure (PASP) of 90 mm Hg, pulmonary capillary wedge pressure (PCWP) of 25 mm Hg, and pulmonary vascular resistance of 8 WU. He was treated with nesiritide and eventually initiated on an oral regimen of thrice-daily hydralazine and isosorbide dinitrate in addition to angiotensin-converting enzyme inhibitors and β-blockers. After management of his acute decompensated HF, a left ventricular lead and biventricular pacemaker were implanted. He was readmitted several months later with anasarca and similar right-sided pressures, and was started on sildenafil 20 mg 3 times daily for pulmonary hypertension with increased pulmonary vascular resistance.
Several months later during a hospital admission for acute renal failure related to intravenous antibiotics for nonhealing foot wounds, the patient developed sustained ventricular tachycardia (VT) followed by ventricular fibrillation (VF) and pulseless cardiac arrest. Cardiopulmonary resuscitation was performed and electrical defibrillation was successful. He was intubated and transferred to the coronary intensive care unit. Sildenafil therapy was continued. Three days later, another episode of VT was pace-terminated. He was eventually stabilized on amiodarone therapy and transferred to the telemetry floor. The patient subsequently had a third episode of sustained VT that was also pace-terminated. Sildenafil was withdrawn and there have been no further episodes of ventricular dysrhythmias, although he has had multiple subsequent admissions for HF.
A phosphodiesterase (PDE) is any enzyme that breaks a phosphodiester bond. More germaine to our discussion is the family of enzymes, which are cyclic nucleotide phosphodiesterases that degrade the phosphodiester bond in the secondary messenger molecules cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). These cyclic nucleotides regulate the duration, localization, and amplitude of cyclic nucleotide signaling at the subcellular level and are important regulators of signal transduction. Multiple subtypes of these cyclic nucleotide phosphodiesterases (PDE 1–11) were isolated in the early 1970s and were shown to be selectively inhibited by a variety of drugs, not only in the brain, but also in cardiovascular tissue.1–4 A PDE inhibitor is a drug that blocks one or more of the subtypes of PDE specifically with reference to cardiovascular tissue, PDE-3 and PDE-5. This inhibition increases the intracellular levels of either cAMP (PDE-3) or cGMP (PDE-5).
Drugs that show selectivity to inhibition of PDE-3, eg, milrinone, vesnarinone, and flosequinan, lead to an intracellular increase in the concentration of cAMP. cAMP mediates the phosphorylation of protein kinases, activates cardiac calcium channels, and increases calcium influx from the sarcoplasmic reticulum, which thereby increases cardiac contractility. This increase in cAMP and activation of calcium channels also increases automaticity.5 This demonstration of the positive inotropic actions of the PDE-3 inhibitors led to the development of clinical analogs, which led to a flurry of research papers extolling their benefit.6 In randomized placebo-controlled clinical trials, amrinone was found to be of no significant benefit over placebo. This led to the development of more potent PDE-3 inhibitors, eg, milrinone, enoximone, flosequinan, and vesnarinone.
In a 16-week controlled trial of enoximone, investigators could find no improvement in symptoms or exercise capacity and unexpectedly found a worse survival rate with enoximone including sudden cardiac death.7 Unfortunately, there was no ECG monitoring in this study. Milrinone underwent a double-blind controlled trial with a mean duration of 6.1 months.8 Not only did they find an increase in mortality, but they also found an increase in hypotension and syncope (P<.002) compared with placebo. Flosequinan had a much more sordid course. Based on an improvement in exercise time and quality of life, the Food and Drug Administration approved the drug before survival data were available. Soon after release, however, the high dose was withdrawn from the market due to an increase in mortality. The low dose continued on the market, but further study revealed that even the low dose increased mortality and the drug was withdrawn. Finally, vesnarinone, a complex inotrope but with predominantly PDE-3 inhibition, was originally found to have a U-shaped survival curve with an increase in survival in the 30- and 60-mg doses, but an increase in mortality at 6 months with the 120-mg dose.9 As a result of these findings, a survival trial was conducted with 3833 patients, and vesnarinone was also found to increase mortality that was probably related to an increase in sudden cardiac death.10 A meta-analysis published in the Cochrane Database analyzed 21 randomized controlled trials that included 8408 patients, 4 specific PDE inhibitor derivatives, and 8 different PDE inhibitor molecules. When compared with placebo, they found that PDE inhibitors were associated with a significant 17% increase in mortality, with a relative risk of 1.17 (95% confidence interval, 1.06–1.30; P<.001) and an increase in cardiac death, sudden death, arrhythmias, and vertigo.11 This effect was independent of vasodilator use, New York Heart Association (NYHA) HF class, or type of PDE-3 inhibitor used.
This now brings us to the 21st century and to PDE-5 inhibitors with sildenafil (Viagra; Pfizer, New York, NY) being the prototype drug, which inhibits the degradation of cGMP by PDE-5. It must be noted that while sildenafil preferentially inhibits PDE-5, it is not truly selective, especially at high doses. Sildenafil is primarily metabolized by the cytochrome P450 enzyme CYP3A4 and somewhere between 13% and 15% is renally excreted. Thus, the potential exists for adverse drug reactions with other drugs that inhibit CYP3A4 such as the human immunodeficiency virus protease inhibitors, ketoconazole and organonitrates. Also, in preliminary safety trials, it was noted that healthy elderly patients older than 65 had an 84% higher steady-state plasma concentration than their younger counterparts secondary to reduced drug clearance. PDE-5 is present in the vascular smooth muscle of the pulmonary vasculature and therefore has become an effective treatment modality for patients with pulmonary arterial hypertension. However, compared with our knowledge of the clinical pharmacology of a single dose of sildenafil for erectile dysfunction (ED), little is known about the clinical pharmacology of chronic, long-term therapy and very little information is available in patients with congestive HF (CHF) and/or chronic kidney disease (CKD) and hepatic dysfunction. PDE-5 inhibitors are effective and widely used therapeutic agents for ED. Since 2005, sildenafil has also been approved for the treatment of PAH and, in 2009, we saw the approval of the long-acting PDE-5 inhibitor tadalafil for these patients as well. PDE-5 inhibitors have a number of contraindications and side effects, while renal and/or hepatic dysfunction or concomitant use of drugs that inhibit CYP3A4 can all create a scenario of supratherapeutic plasma levels.
There have been several cases of sudden cardiac death associated with sildenafil use, and with its increasing use in patients with PAH and numerous published and ongoing studies evaluating its use in diastolic HF, we decided to review the electrophysiologic effects of PDE-5 inhibitors as well as any clinical case reports of ventricular arrhythmias associated with their use.
Potential Mechanisms in Cardiomyocytes and Electrophysiologic Effects
In a clinical study by Alpaslan and colleagues,12 36 patients with ED, 21 of whom also had coronary artery disease, QT dispersion with corrected and uncorrected QT intervals were measured before and 1 and 4 hours after ingestion of 50-mg sildenafil using a standard 12-lead ECG. They found no change in mean heart rate, no prolongation of QT interval, and no increase in QT dispersion. In another study, tadalafil (single, high dose of 100 mg [5-fold the maximum therapeutic dose for ED]), investigators compared its use with placebo and an active control, ibutilide, in 99 healthy men (mean age, 30 years).13 They found that placebo and high-dose tadalafil produced equivalent effects on the QT interval, whereas ibutilide produced an increase of 6.9 ms and 8.9 ms compared with tadalafil and placebo, respectively.13 A double-blind, placebo- and positive-controlled, period-balanced, 6-way crossover study evaluated the therapeutic and supratherapeutic oral doses of vardenafil (10 mg and 80 mg, respectively) and sildenafil (50 mg and 400 mg, respectively), therapeutic doses of moxifloxacin (400 mg), and placebo in 58 healthy men (mean age, 53 years).14 Six replicate, 12-lead ECGs were recorded at 3 time points before and 5 time points after dosing. Therapeutic and supratherapeutic doses produced only small, clinically insignificant increases in the QTcF (measured by Fridericia formula) and revealed shallow dose-response curves to QTc relationship for each PDE-5 inhibitor. As expected, moxifloxacin increased the absolute QTc by a mean of 8 ms. These clinical studies have shown that with single therapeutic or supratherapeutic doses in healthy patients (no CKD or CHF), there is no QTc-prolonging effect of PDE-5 inhibitors.
A number of investigators have also performed animal studies using both isolated heart models and whole-cell patch clamp techniques in ventricular myocytes to study the effects of PDE-5 inhibitors on repolarization, albeit the results on the exact mechanism remain controversial. In 2000, Geelen and colleagues15 used isolated guinea pig hearts measuring monophasic action potentials and whole-cell patch clamp in human Ether-a-go-go Related Gene (hERG) transfected HEK293 cells. They found a 15% increase in action potential duration (APD) during pacing at a basic cycle length of 250 ms and a 6% increase at a basic cycle length of 150 ms. The hERG-transfected HEK293 cells showed a concentration-dependent block of the rapid component (IKr) of the delayed rectifier potassium current compared with control. Therefore, they concluded that sildenafil prolonged cardiac repolarization by blocking (IKr), the hERG current, and therefore its electrophysiologic effects are similar to that of other class III antiarrhythmics15 (Table).
Table TABLE. PDE-5 Inhibitors and Electrophysiologic Effects
|Geelen et al15||Sildenafil||Concentration-dependent block||Not tested||Not tested||Not tested||Prolonged|
|Chiang et al16||Sildenafil||No effect||No effect||Concentration-dependent block||No significant effect||Shortened|
|Dustan Sarazan et al18||Sildenafil, vardenafil, tadalafil||Concentration-dependent block||Not tested||Not tested||Not tested||Not tested|
In 2002, Chiang and colleagues used guinea pigs and canine Purkinje fibers to investigate the effects of therapeutic and supratherapeutic doses of sildenafil on repolarization. Dosages used to achieve therapeutic serum concentrations were those typically found in patients being treated for ED. They found that APD was not affected at therapeutic doses, but shortened at significantly higher doses in both the papillary muscle and Purkinje fibers.16 Sildenafil had no effect on the rapid (IKr) or slow (IKs) components of the delayed rectifier potassium currents at any dose concentration. Sildenafil did dose-dependently block the L-type calcium current (ICa,L) in ventricular myocytes (Table). They went on to show that the QTc-prolonging effect produced by sotalol or amiodarone could be reversed by administering supratherapeutic concentrations of sildenafil.16 There are several possible explanations as to why in this study sildenafil had an APD-shortening effect. At significantly high plasma levels, sildenafil can cross-react with PDE-3 and increase intracellular cAMP levels, which, in turn, can enhance IK- and cAMP-dependent Cl− channels. Furthermore, they showed that sildenafil had a blocking effect on ICa,L with higher plasma concentrations, which depresses the plateau of the action potential.17 One study that supports the results from the Geelen study evaluated whether tadalafil, vardenafil, or sildenafil could inhibit the hERG (IKr) channel and found a dose-dependent reduction in the hERG current amplitude over a large concentration range of 0.1 μM to 100 μM. They concluded, however, that at clinically therapeutic plasma levels, none of these PDE-5 inhibitors could potently inhibit the hERG channel.18
The effect of sildenafil on VF and VT in the preclinical setting has also been investigated. Swissa and colleagues19 evaluated the effects of sildenafil with and without the use of nitric oxide (NO) donors on promoting VT or VF in isolated swine right ventricles after rapid pacing. Sildenafil at lower concentrations with or without an NO donor could not induce VT/VF. However, higher concentrations of sildenafil with an NO donor did produce a dramatic increase in VT/VF. Investigators have also evaluated the effects of sildenafil at supratherapeutic levels on VF threshold. Also using a swine model, high-dose sildenafil was associated with a reduction in the VF threshold when compared with normal doses and placebo.20 These findings are similar to another study by the same group which showed that supratherapeutic levels of sildenafil decreased the defibrillation efficacy by increasing the defibrillation threshold 19% by voltage and 38% by total energy compared with placebo.21 This indicates that for each shock delivered, a higher shock strength would be required to restore a perfusing rhythm.
These preclinical studies are largely at odds on the exact mechanism of action in the ventricular myocyte. Two studies15,18 support the notion that the APD is prolonged via a dose-dependent blocking effect on the hERG (IKr) channel, whereas the other has shown that the ICa,L channel is blocked, also in a dose-dependent manner, thus shortening the APD.16 However, all studies did show that at clinically relevant plasma concentrations, no significant effect on cardiac repolarization was seen. The VT/VF studies indicate that in various in vivo and ex vivo swine models, supratherapeutic concentrations of sildenafil may reduce the efficacy of defibrillation, that significantly more energy may be required during shock delivery to restore perfusion, and that the myocardium may be more susceptible to VT/VF, especially in the presence of NO donors. Further studies are needed before any firm conclusion on the exact electrophysiologic mechanism of PDE-5 inhibitors can be made.
Sildenafil and HF
Since the approval of sildenafil for the treatment PAH, numerous clinical trials have been ongoing, and some recently published, on the treatment of PAH with HF, either with concomitant right ventricular failure or preserved LVEF. In a 6-month study, patients with stable CHF were treated with sildenafil 50 mg twice daily or placebo (each arm, n=23 patients).22 At 3 and 6 months, PASP, ergoreflex effect on ventilation, and ventilation to carbon dioxide production slope were all significantly decreased, while peak oxygen consumption and brachial artery flow–mediated dilation, an indicator of improved endothelial function, both increased. This same group recently published another study in which 44 patients with HF signs and symptoms, PASP >40 mm Hg, but preserved LVEF >50% (diastolic dysfunction), were given placebo or sildenafil 50 mg 3 times daily.23 At 6 months they found that patients treated with sildenafil had a significant reduction in right atrial pressure (54±7.2%), a 42%±13% reduction in mean pulmonary artery pressure, improved PCWP, and isovolumetric relaxation time, and showed that these improvements were preserved at 1 year. Currently, larger randomized controlled trials are being conducted in patients with diastolic HF and are looking to evaluate the benefits of chronic PDE-5 use, such as the PhosphodiesteRasE-5 Inhibition to Improve Quality of Life and Exercise Capacity in Diastolic Heart Failure (RELAX) trial.24
PDE-5 Inhibitors and Ventricular Arrhythmias in Patients
In 1998, Shah25 first reported two patients with a history of coronary artery disease who had VT associated with sildenafil use. In a few cases, sildenafil has also been associated with atrial fibrillation in susceptible patients.26,27 One case reports that a 41-year-old man had sustained monomorphic VT after taking 100 mg of sildenafil.28 He was not taking any other medication, had no history of cardiac disease, and no family history of sudden cardiac death or long QT syndrome. Cardiac work-up of ischemia was unremarkable. An electrophysiologic study was performed and revealed that stimulation at the right ventricular apex and outflow tract induced 10 beats of nonsustained VT with alternating morphology. The patient subsequently had another electrophysiologic study done after 100 mg of sildenafil and this time nonsustained VT of 24 beats with identical morphology to the VT from admission was induced and subsequently an automated implantable cardioverter-defibrillator (AICD) was placed.
Sildenafil citrate at supratherapeutic plasma concentrations may increase the inducibility of ventricular arrhythmias in patients with systolic HF, CKD, and hepatic dysfunction and in those patients particularly vulnerable to drug accumulation. At what plasma concentration does the myocardium become susceptible remains unknown and the exact electrophysiologic mechanism remains speculative as the few preclinical investigations have been discordant. One group showed that sildenafil may accelerate cardiac repolarization and shorten the APD through blocking the ICa,L.16 Conversely, another laboratory showed that APD and cardiac repolarization is actually prolonged, primarily through blocking the fast component (IKr) of the delayed rectifier potassium current.15 Preclinical research is still needed before any conclusion can be made on any mechanism, but enough data do exist showing that at extremely high (tens to hundred times) unbound plasma concentration levels, the myocardium likely becomes more vulnerable to ventricular arrhythmias. Furthermore, sildenafil increases sympathetic modulation through its reflexive vasodilatory action and such an increase in sympathetic activation in HF patients could also be a mechanism for fatal ventricular arrhythmias. Additionally, sildenafil, vardenafil, and tadalafil all have variable levels of PDE-5 selectivity and, at higher plasma concentrations, have some cross-reactivity with PDE-3, thereby increasing intracellular cAMP levels, which also increases automaticity.
We would hypothesize that our case represents the typical case of a patient hospitalized with NYHA class III or IV HF, and World Health Organization (WHO) group II PAH who was not a candidate for mechanical assist device or cardiac transplantation. We propose that, similar to a large number of patients in the PDE-3 inhibitor studies, our patient with low LVEF, PAH, and CKD experienced 3 episodes of sudden death. Based on our case and discussion, we would like to pose several important questions regarding the use of PDE-5 inhibitors in patients with CHF. There are no accepted guidelines on their use in patients with decompensated HF. These suggestions are the guidelines we have established for our own program: (1) Should PDE-5 inhibitors be used in patients with CHF and preserved LVEF? The literature and our own experience support the safety and efficacy of PDE-5 inhibitors in this patient population. (2) Should PDE-5 inhibitors be used at all in patients with low LVEF and WHO group II PAH especially with CKD? We would not begin these patients on PDE-5 inhibitors but rather a combination of hydralazine and isordil with dosing guidelines from the African American Heart Failure Trial (A-HeFT).29 (3) Should patients with a low ejection fraction and PAH have an AICD placed? We bring these patients into the hospital and, using PDE-3 inhibitors or nesiritide, attempt to reduce pulmonary vascular resistance and then place an AICD. Furthermore, we would like to raise several important questions for the HF specialist regarding the use of PDE-5 inhibitors in CHF. (1) Should PDE-5 inhibitors be used at all in patients with WHO group II PAH and low LVEF, especially those with CKD? (2) Should patients with reactive PAH and low LVEF have an AICD in place prior to starting a PDE-5 inhibitor? After all, the patient with systolic dysfunction is already at risk for sudden death. It also raises the problem of placing an AICD in a patient with severe PAH and the increased risk of the procedure. (3) There is discussion that the original doses of the PDE-3 inhibitors were too high. Perhaps the starting dose of sildenafil at 20 mg, thrice daily is also too high? In any event, with the lessons learned from the PDE-3 trials, the ventricular dysrhythmia potential of the patient with low LVEF and the known pharmacologic effects of sildenafil, great caution should be used in starting a patient with low LVEF and pulmonary hypertension on sildenafil. Therefore, we should proceed with great caution and care when and if we design clinical trials in HF using PDE-5 inhibitors, paying very close attention to electrical activity and ventricular dysrhythmias.
Disclosures: The authors disclose that they have no conflicts of interest.