Sildenafil for pulmonary hypertension: when the risks outweigh the benefits

Relevance

Patients with residual pulmonary hypertension who have had successful heart valve surgery should not receive sildenafil.
This is evidenced by the results of the first randomized trial presented at the European Congress of Cardiology 2022. It is well known that the vasodilator sildenafil is widely used in the treatment of erectile dysfunction, but the drug is also effective in patients with pulmonary arterial hypertension.

Sildenafil

To diagnose erectile dysfunction, determine its possible causes and select adequate treatment, it is necessary to obtain a complete medical history and conduct a thorough physical examination. Erectile dysfunction treatments should be used with caution in patients with anatomical deformation of the penis (angulation, cavernous fibrosis, Peyronie's disease), or in patients with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia) (see section "Caution" ).

During post-marketing studies, cases of prolonged erection and priapism have been reported. If an erection persists for more than 4 hours, you should immediately seek medical help. If treatment for priapism is not carried out immediately, it can lead to damage to the tissue of the penis and irreversible loss of potency.

Medicines intended to treat erectile dysfunction should not be prescribed to men for whom sexual activity is undesirable.

Sexual activity poses a certain risk in the presence of heart disease, so before starting any therapy for erectile dysfunction, the doctor should refer the patient for an examination of the condition of the cardiovascular system. Sexual activity is not advisable in patients with heart failure, unstable angina, myocardial infarction or stroke in the past 6 months, life-threatening arrhythmias, hypertension (BP > 170/100 mm Hg) or hypotension (BP < 90/50 mm Hg) .) Taking sildenafil in such patients is contraindicated (see section “Contraindications”). Clinical studies have shown no difference in the incidence of myocardial infarction (1.1 per 100 people per year) or the incidence of cardiovascular mortality (0.3 per 100 people per year) in patients taking sildenafil compared with patients taking sildenafil. those receiving placebo.

Cardiovascular complications

During post-marketing use of sildenafil for the treatment of erectile dysfunction, adverse events such as severe cardiovascular complications (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension and hypotension) have been reported. which had a temporary association with the use of sildenafil. Most of these patients, but not all of them, had risk factors for cardiovascular complications. Many of these adverse events occurred shortly after sexual activity, and some of them occurred after taking sildenafil without subsequent sexual activity. It is not possible to establish a direct connection between the observed adverse events and these or other factors.

Hypotension

Sildenafil has a systemic vasodilating effect, leading to a transient decrease in blood pressure, which is not a clinically significant phenomenon and does not lead to any consequences in most patients. However, before prescribing sildenafil, the physician should carefully assess the risk of possible unwanted manifestations of the vasodilating effect in patients with relevant diseases, especially against the background of sexual activity. Increased susceptibility to vasodilators is observed in patients with obstruction of the left ventricular outflow tract (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as with the rare syndrome of multiple system atrophy, manifested by severe dysregulation of blood pressure from the autonomic nervous system.

Since the combined use of sildenafil and alpha-blockers may lead to symptomatic hypotension in selected sensitive patients, sildenafil should be administered with caution to patients taking alpha-blockers (see sections "Precautions" and "Interactions with other drugs"). To minimize the risk of postural hypotension in patients taking alpha-blockers, sildenafil should be started only after hemodynamic stability has been achieved in these patients. You should also consider the advisability of reducing the initial dose of sildenafil (see section "Dosage and Administration"). The physician should inform the patient what actions to take if symptoms of postural hypotension occur.

Visual impairment

In rare cases, non-arteritic anterior ischemic optic neuropathy (NAIAON), a rare disease and cause of vision loss or reduction, has been reported during post-marketing use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors, including decreased papilledema/disc ratio (“congestive disc”), age over 50 years, diabetes mellitus, hypertension, coronary artery disease, hyperlipidemia, and smoking. An observational study assessed whether recent use of the PDE5 inhibitor class of drugs was associated with acute onset of NPINSID. Results indicate an approximately two-fold increase in the risk of NPINSID within 5 half-lives of PDE5 inhibitor use. Published literature estimates the annual incidence of NPINSID to be 2.5–11.8 cases per 100,000 men aged >50 years in the general population. In case of sudden loss of vision, patients should be advised to stop sildenafil therapy and consult a doctor immediately. Individuals who have already had a case of NPIND have an increased risk of recurrent NPIND. Therefore, the physician should discuss this risk with such patients, as well as discuss with them the potential for adverse effects from PDE5 inhibitors. PDE5 inhibitors, including sildenafil, should be used with caution in such patients and only in situations where the expected benefit outweighs the potential risk. In patients with episodes of NPINS with loss of vision in one eye, sildenafil is contraindicated (see section "Contraindications").

A small number of patients with hereditary retinitis pigmentosa have genetically determined dysfunction of retinal phosphodiesterases. There is no information on the safety of sildenafil in patients with retinitis pigmentosa, therefore sildenafil should not be used in such patients (see section "Contraindications").

Hearing impairment

Some post-marketing and clinical studies have reported cases of sudden deterioration or loss of hearing associated with the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors for sudden deterioration or loss of hearing. A cause-and-effect relationship between the use of PDE5 inhibitors and sudden hearing loss or deterioration has not been established. If there is a sudden deterioration in hearing or hearing loss while taking sildenafil, you should consult your doctor immediately.

Bleeding

Sildenafil enhances the antiplatelet effect of sodium nitroprusside (nitric oxide donor) on human platelets in vitro. There are no data on the safety of sildenafil in patients with a tendency to bleeding or exacerbation of gastric and duodenal ulcers, so sildenafil should be used with caution in these patients (see section "With caution"). The incidence of epistaxis in patients with PH associated with diffuse connective tissue diseases was higher (sildenafil - 12.9%, placebo - 0%) than in patients with primary pulmonary arterial hypertension (sildenafil - 3.0%, placebo - 2%). ,4%). Patients receiving sildenafil in combination with a vitamin K antagonist had a higher incidence of epistaxis (8.8%) than patients not taking a vitamin K antagonist (1.7%).

Use in conjunction with other means of treating erectile dysfunction

The safety and effectiveness of using sildenafil in combination with other PDE5 inhibitors or other drugs for the treatment of pulmonary arterial hypertension containing sildenafil (for example, Revazio) or other drugs for the treatment of erectile dysfunction have not been studied, therefore the use of such combinations is not recommended (see section "Contraindications").

Methods

In order to evaluate the effectiveness of sildenafil in patients with residual pulmonary hypertension after heart valve surgery, the SIOVAC study was performed. This was a multicenter, double-blind, placebo-controlled, parallel-group study.

Patients underwent cardiac catheterization to confirm pulmonary hypertension.

200 patients from 17 Spanish clinics were randomized 1:1 to sildenafil 40 mg three times daily (n=104) or placebo (n=96) for 6 months.

The patients underwent clinical, laboratory and instrumental examinations after 3 and 6 months of observation. The primary endpoint was a composite of death from all causes, hospitalization for heart failure, worsening exercise capacity, and self-reported worsening of well-being after initiation of therapy.

Sealex Sildenafil tablets 100 mg 1 piece ➤ instructions for use

To diagnose erectile dysfunction, determine its possible causes and select adequate treatment, it is necessary to obtain a complete medical history and conduct a thorough physical examination. Erectile dysfunction treatments should be used with caution in patients with anatomical deformation of the penis (angulation, cavernous fibrosis, Peyronie's disease), or in patients with risk factors for priapism (sickle cell anemia, multiple myeloma, leukemia) (see section "Caution" ).

Medicines intended to treat erectile dysfunction should not be prescribed to men for whom sexual activity is undesirable.

If an erection persists for more than 4 hours, you should seek medical help. If priapism therapy is not carried out in a timely manner, this can lead to damage to the tissue of the penis and irreversible loss of potency.

Sexual activity poses a certain risk in the presence of heart disease, so before starting any therapy for erectile dysfunction, the doctor should refer the patient for an examination of the condition of the cardiovascular system. Sexual activity is undesirable in patients with heart failure, unstable angina, myocardial infarction or stroke in the last 6 months, life-threatening arrhythmias, arterial hypertension (BP >170/100 mm Hg) or hypotension (BP <90/50 mm Hg. Art.). Clinical studies have shown no difference in the incidence of myocardial infarction (1.1 per 100 people per year) or the incidence of cardiovascular mortality (0.3 per 100 people per year) in patients treated with sildenafil compared with patients treated with sildenafil. those receiving placebo.

Cardiovascular complications

During post-marketing use of sildenafil for the treatment of erectile dysfunction, adverse events such as serious cardiovascular events (including myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, hemorrhagic stroke, transient ischemic attack, hypertension and hypotension) have been reported. ), which had a temporary association with the use of sildenafil. Most of these patients, but not all of them, had risk factors for cardiovascular complications. Many of these adverse events occurred shortly after sexual activity, and some of them occurred after taking sildenafil without subsequent sexual activity. It is not possible to establish a direct connection between the observed adverse events and these or other factors.

Hypotension

Sildenafil has a systemic vasodilating effect, leading to a transient decrease in blood pressure, which is not a clinically significant phenomenon and does not lead to any consequences in most patients. However, before prescribing sildenafil, the physician should carefully assess the risk of possible undesirable manifestations of the vasodilating effect in patients with relevant diseases, especially against the background of sexual activity. Increased susceptibility to vasodilators is observed in patients with obstruction of the left ventricular outflow tract (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as with the rare syndrome of multiple system atrophy, manifested by severe dysregulation of blood pressure from the autonomic nervous system. Since the combined use of sildenafil and α-blockers can lead to symptomatic hypotension in some sensitive patients, the drug should be prescribed with caution to patients taking α-blockers (see section "Interaction with other drugs"). To minimize the risk of postural hypotension in patients taking α-blockers, sildenafil should be started only after hemodynamic stability has been achieved in these patients. You should also consider the advisability of reducing the initial dose of sildenafil (see section "Dosage and Administration"). The physician should inform patients about what actions to take if symptoms of postural hypotension occur.

Visual impairment

Rare cases of anterior non-arteritic ischemic optic neuropathy as a cause of deterioration or loss of vision have been reported with the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors such as optic disc excavation, age over 50 years, diabetes mellitus, hypertension, coronary artery disease, hyperlipidemia, and smoking. A small number of patients with hereditary retinitis pigmentosa have genetically determined dysfunction of retinal phosphodiesterases. There is no information on the safety of sildenafil in patients with retinitis pigmentosa.

Hearing impairment

Some post-marketing and clinical studies have reported cases of sudden deterioration or loss of hearing associated with the use of all PDE5 inhibitors, including sildenafil. Most of these patients had risk factors for sudden deterioration or loss of hearing. A cause-and-effect relationship between the use of PDE5 inhibitors and sudden hearing loss or deterioration has not been established. If there is a sudden deterioration in hearing or hearing loss while taking sildenafil, you should consult your doctor immediately.

Bleeding

Sildenafil enhances the antiplatelet effect of sodium nitroprusside, a nitric oxide donor, on human platelets in vitro. There are no data on the safety of sildenafil in patients with a tendency to bleeding or exacerbation of gastric and duodenal ulcers, so sildenafil should be used with caution in these patients (see section "With caution"). The incidence of epistaxis in patients with PH associated with diffuse connective tissue diseases was higher (sildenafil 12.9%, placebo 0%) than in patients with primary pulmonary hypertension (sildenafil 3.0%, placebo 2.4%). Patients receiving sildenafil in combination with a vitamin K antagonist had a higher incidence of epistaxis (8.8%) than patients not taking a vitamin K antagonist (1.7%).

Use in conjunction with other means of treating erectile dysfunction

The safety and effectiveness of sildenafil in combination with other drugs for the treatment of erectile dysfunction have not been studied, therefore the use of such combinations is not recommended (see section "Contraindications").

results

• At 6 months of follow-up, 33 patients (33%) in the sildenafil group, compared with 14 patients (15%) in the control group, showed worsening (odds ratio for improvement, 0.39; 95% CI, 0.22-0 .67; p<0.001).
• Noteworthy was the 2-fold increase in the risk of hospitalization for decompensated heart failure in patients receiving sildenafil.
• 3 patients in the sildenafil group died, while 2 deaths occurred in the control group (p=0.63).
• Serious clinical events—death and rehospitalization for heart failure—occurred earlier and more frequently during sildenafil therapy (hazard ratio, 2.0; 95% CI, 1.0-4.0; p=0.044).

Principal investigator Dr Javier Bermejo (Madrid, Spain) noted that long-term use of sildenafil in patients with residual pulmonary hypertension and valvular heart disease should be avoided. At the same time, it is necessary to conduct studies that will propose strategies for the prevention and treatment of this complication in patients with valvular pathology.

Source:

ESC congress news. 29 August 2022.

Sildenafil in the treatment of erectile dysfunction in cardiac patients

Makushin Dmitry Gennadievich – Candidate of Medical Sciences, Head. urological department of the West Siberian Medical Center of the Federal State Budgetary Institution of Healthcare of the Federal Medical and Biological Agency of Russia, assistant of the Department of Faculty Surgery with a course of urology of the Federal State Budgetary Educational Institution of Higher Education Omsk State Medical University

Treatment of patients with erectile dysfunction (ED) is one of the most pressing problems of modern urology. Phosphodiesterase type 5 (PDE5) inhibitors are highly effective and safe oral medications for the treatment of ED and are recommended as first-line treatments [1–4]. The number of patients taking these drugs continues to increase in parallel with the rising prevalence of ED. The widespread use of PDE-5 inhibitors in clinical practice began after the appearance of the drug sildenafil in 1998, which is currently characterized as the most fully studied drug of this group.

Sildenafil, under conditions of sexual stimulation, restores impaired erectile function by increasing blood flow in the penis. It is known that the physiological mechanism of erection involves the release of nitric oxide (NO) in the corpus cavernosum due to sexual arousal. NO activates the enzyme guanylate cyclase, which leads to increased concentrations of cyclic guanosine monophosphate (cGMP). In turn, cGMP causes relaxation of the smooth muscles of the blood vessels and, accordingly, blood flow into the cavernous body of the penis. Sildenafil is a selective inhibitor of cGMP-specific PDE5, which causes the breakdown of cGMP in the corpus cavernosum of the penis. Sildenafil does not have a direct relaxing effect on the smooth muscles of the corpus cavernosum, but it enhances the relaxing effect of NO and increases blood flow in the penis. When the NO–cGMP chain is activated, which is observed during sexual stimulation, inhibition of PDE5 leads to an increase in the level of cGMP in the corpus cavernosum.

Sildenafil is the “gold standard” in the treatment of ED; it is highly effective and reliable, easy to use, and has a low number of side effects [5, 6]. It has been established that sildenafil provides 20 times (other PDE-5 inhibitors: vardenafil - only 7.5 times, tadalafil - only 1.4 times) greater penetration ability than placebo [7]. The main side effects - transient - occur, as a rule, when using a dosage of 100 mg and are characterized by slight or moderate severity (headache, redness of the face and neck, nasal congestion, dyspepsia), which does not require discontinuation of the drug [6, 8].

Sildenafil has proven itself well in patients with ED caused by the presence of diabetes mellitus type 1 and 2, men with coronary heart disease (CHD) and arterial hypertension (AH), including against the background of hemodialysis and the use of drugs of different groups necessary for therapy underlying disease. At the same time, overall satisfaction with taking sildenafil was high (41, 78 and 100%, respectively, for severe, moderate and mild ED) in men with neurogenic, diabetic, psychogenic and vascular disorders (56, 58, 89, 86%, respectively) [9 ]. Sildenafil therapy improves the quality of life of both the patients themselves and their partners [10–12].

The dose of sildenafil is selected by titration, starting with 50 mg, followed by dose modification (either decreasing to 25 mg or increasing to 100 mg) depending on the effect and tolerability. Sildenafil is taken once a day, 1 hour before intended sexual intercourse. The effect of the drug begins 40–60 minutes after administration and lasts for 3–5 hours, and according to some data, up to 12 hours [5, 13, 14].

It is necessary to highlight two relevant aspects that arise when treating ED in a cardiac patient:

1) the possible impact of the resumption of sexual activity caused by taking sildenafil on the course of the patient’s pathology from the cardiovascular system;

2) possible drug interaction of sildenafil with drugs for the treatment of concomitant somatic pathologies.

To standardize the medical approach to the problem of sexual activity and cardiac risk, the American College of Cardiology and the American Heart Association developed recommendations regarding the prescription of sildenafil to cardiac patients [15], which formed the basis of the “Princeton Consensus” on the treatment of sexual dysfunction in patients with cardiovascular diseases ( CVD) [16].

In accordance with this consensus document, patients with CVD are divided into low, medium and high risk groups (see table).
In case of low risk, resumption of sexual activity or treatment of sexual dysfunction is considered safe; in case of average risk, additional examination is necessary before resuming sexual activity; in case of high risk, correction of the condition associated with CVD is required. Algorithm for determining the risk of sexual activity in CVD (Princeton Consensus) [16]

European guidelines for the treatment of stable coronary artery disease (ESC, 2013) note that ED is closely associated with cardiovascular risk factors and is more common among patients with coronary artery disease. The common denominator between ED and CAD is endothelial dysfunction and the use of a number of antihypertensive drugs, such as β-blockers and thiazide diuretics, which increase the risk of developing ED [17].

Lifestyle changes and pharmacological interventions, including weight loss, exercise training, smoking cessation and statin use, improve ED [18]. Pharmacological therapy with PDE-5 inhibitors (sildenafil and other drugs in this group) is effective, safe and well tolerated in men with stable coronary artery disease [17, 19]. Low-risk patients can usually receive PDE5 inhibitors without the need for cardiac evaluation. However, the use of NO donors, e.g. all nitroglycerin preparations, as well as isosorbide dinitrate and isosorbide mononitrate, is an absolute contraindication to the use of PDE-5 inhibitors due to the risk of a synergistic effect in the form of vasodilation, leading to arterial hypotension and hemodynamic collapse [16, 17, 20]. If a patient experiences chest pain while taking a PDE5 inhibitor, nitrates should not be prescribed in the first 24 hours (sildenafil, vardenafil) or the first 48 hours (tadalafil) [16, 21]. Nicorandil, due to its nitrate component, when interacting with sildenafil, can also lead to severe arterial hypotension.

In patients with hypertension and ED, it is better not to use thiazide diuretics and non-selective β-blockers (β-blockers), but to give preference to calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), which do not have a significant effect on the sexual sphere, or receptor blockers to angiotensin II (ARB), which can even slightly increase sexual activity in men [22–25].

Sildenafil is safe and effective in patients taking a variety of medications, including multiple antihypertensive medications, other cardiac medications, and antidiabetic medications [8]. Thiazide, loop and potassium-sparing diuretics, ACE inhibitors, CCBs, β-AB, warfarin, acetylsalicylic acid do not affect the pharmacokinetics of sildenafil.

Sildenafil may enhance the hypotensive effects of CCBs, β-ABs, and ACE inhibitors. When used simultaneously, it increases the effectiveness of hypoglycemic agents. With the simultaneous use of sildenafil and α-blockers, including doxazosin, especially during the first 4 hours after taking sildenafil, a pronounced decrease in blood pressure and orthostatic hypotension may be observed.

A meta-analysis based on 67 placebo-controlled studies generated a database of 39,277 men treated with sildenafil 50 and 100 mg. The analysis did not find a cause-and-effect relationship with taking the drug and the development of cardiovascular complications, priapism, ischemic optic neuropathy, hearing loss or undesirable effects of interaction with drugs from other groups. The safety profiles in men who used sildenafil against the background of moderate impairment of liver and kidney function and in other patients with ED did not have significant differences [26].

The pharmacokinetic interaction of PDE-5 inhibitors with drugs from other groups is most often realized at the metabolic level in the system of oxidative enzymes of cytochromes P-450. Sildenafil is metabolized mainly by the liver microsomal isoenzymes CYP3A4 (main pathway) and CYP2C9 (additional pathway) [14, 27].

The metabolism of PDE-5 inhibitors in the liver is slowed down as part of their pharmacokinetic drug interaction with drugs that are inhibitors of the CYP3A4 enzyme. The most clinically significant inhibitory effect on CYP3A4 is exerted by drugs for the treatment of HIV (HIV protease inhibitors - ritonavir, saquinavir, indinavir, atazanavir), macrolide antibiotics (erythromycin, clarithromycin), antifungal drugs from the azole group (ketoconazole, itraconazole). Substances that inhibit CYP3A4 activity are also found in grapefruit and pomelo juice. Isoenzyme inhibitors reduce metabolism and increase the concentration of sildenafil in the blood, therefore, when taking the above drugs, treatment with sildenafil begins with a dose of 25 mg.

Inducers of the CYP3A4 isoenzyme include carbamazepine, phenytoin, phenobarbital (barbiturates), silymarin, St. John's wort, ursodeoxycholic acid, rifampicin, rifabutin. When taking PDE5 inhibitors and these drugs in combination, it may be necessary to increase the dose of sildenafil to improve erectile function.

In recent years, publications have appeared on the effectiveness and safety of daily use of PDE-5 inhibitors, and the advantages of this regimen compared to the traditional on-demand administration of drugs of this group. Daily use of PDE5 inhibitors has been shown to improve the quality of sexual life of both partners, may be effective in patients who have not responded to on-demand therapy, and in some men may help restore erectile function [28]. Six months later, after 12 months of daily dosing of sildenafil 50 mg at night, men initially presenting with mild to moderate vascular ED maintained normal erectile function [29].

One of the main issues of rational pharmacotherapy is the choice between the original drug and the generic. The goal of generic drugs is not to replace or displace original drugs from the pharmaceutical market, but to increase the availability of medicines for all segments of the population. Today, in most developed countries, generics have turned from the “Cinderella” of the pharmaceutical market into its most important component. The importance of generics lies primarily in the fact that they bring benefits to society at lower costs than in the case of original drugs [30, 31].

Currently, there are high-quality generic drugs on the market, used not only in the Russian Federation market, but also in Europe and the USA. Such drugs include sildenafil preparations manufactured by JSC KRKA, d.d., Novo Mesto, Slovenia, (hereinafter referred to as the KRKA company) - Vizarsin® and Vizarsin® Ku-tab®. KRKA's generic drugs are based on our own innovative synthesis procedures. All KRKA drugs are manufactured in compliance with strict rules and requirements for the production of medicines and in accordance with international GMP (Good Manufacturing Practice) standards, and also have certificates of conformity with the European Pharmacopoeia.

Vizarsin® and Vizarsin® Ku-tab® should be taken approximately 1 hour before sexual activity and no more than once a day. Visarsin® Qu-tab® is available in a form unique to sildenafil - a white tablet with a mint taste, soluble in the oral cavity [32].

Close interaction between a urologist and a therapist/cardiologist at the stage of providing primary specialized and health care will improve the efficiency of medical care and improve the quality of life of cardiology patients with erectile dysfunction.

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