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Acute myocardial infarction associated with sildenafil
CORRESPONDENCE 1
2
Feenstra J, van Drie-Pierik FJHM, Laclé CF, Stricker BHCh. Acute myocardial infarction associated with sildenafil. Lancet 1998; 352: 957–58. National Cholesterol Education Program. Cholesterol lowering in the patient with coronary heart disease. Physician Monograph. Washington, DC: US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute, 1997. NIH publication no 97-3794.
Authors’ reply Sir—L López-Lázaro and colleagues comment on our case report of a patient who developed a myocardial infarction shortly after taking sildenafil. However, we think that their conclusion that our patient probably had hypercholesterolaemia is speculative and improbable. First, we stated that our patient had LDL cholesterol of 3·2 mmol/L, which is, in fact, below the accepted limit for initiation of drug therapy in patients with coronary heart disease. Second, plasma lipid values were measured in a blood sample obtained 9 h after hospital admission. Although plasma concentrations of total cholesterol and both LDL and HDL cholesterol indeed fall after acute myocardial infarction, Ryder 1 and Fyfe2 and their colleagues have shown that plasma lipid values can still accurately be assessed in the first 24–48 h after myocardial infarction. Since serum cholesterol was 4·3 mmol/L in our patient, which is substantially lower than the upper normal value of 5·2 mmol/L, it seems very unlikely that the patient had hypercholesterolaemia as a risk factor for myocardial infarction. *J Feenstra, R J H M van Drie-Pierik, C F Laclé, B H Ch Stricker Inspectorate for Health Care, Drug Safety Unit, PO Box 16119, 2500 BC Den Haag, Netherlands 1
2
Ryder REJ, Hayes TM, Mulligan IP, Kingswood JC, Williams S, Owens DR. How soon after myocardial infarction should plasma lipid values be assessed? BMJ 1984; 289: 1651–53. Fyfe T, Baxter RH, Cochran KM, Booth EM. Plasma lipid changes after myocardial infarction. Lancet 1971; ii: 997–1001.
Sir—J Feenstra and colleagues 1 report a patient who developed an acute myocardial infarction after taking one 50 mg sildenafil tablet. Erectile dysfunction is common in end-stage renal disease (ESRD) and treatment of this symptom has been limited. Since cardiovascular diseases are common in ESRD, an increased prevalence of sildenafil side-effects can be expected in this population.
THE LANCET • Vol 352 • December 12, 1998
We report a patient with chronic renal failure who presented with acute thrombosis of radial arteriovenous fistula after sildenafil consumption. A 54-year-old black man was seen at our clinic 3 days after occlusion of a left forearm arteriovenous fistula (AVF). He had been followed for 4 years for chronic renal failure related to a biopsy-proven chronic tubulointerstitial nephropathy without evidence of immunological infectious or toxic aetiology. Left-ventricular hypertrophy was also present, associated with hypertension requiring a triple-drug regimen. He had no history of smoking, diabetes mellitus, or hypercholesterolaemia. Despite good control of hypertension, renal insufficiency progressed and creatinine clearance reached 12 mL per min in September, 1998, leading to the development of an AVF. Echocardiography showed normal left-ventricular function and estimated cardiac index was 3·1 L min ⫺1 m⫺2. The vessels appeared healthy and a direct vascular anastomosis between left radial vein and artery was done. The patient was taught how to listen for AVF murmur and thrill. 3 weeks after surgery, AVF was well developed and judged functional. Because of intermittent erectile dysfunction associated with antihypertensive therapy (losartan 50 mg, amlodipine 10 mg, and furosemide 80 mg daily), sildenafil was prescribed by his general practitioner. Two 25 mg tablets were first used without improvement of sexual function, but the patient achieved brief sexual intercourse 1 h after taking a 50 mg tablet. 30 min after coitus, the patient had transient isolated forearm pain and could no longer feel the thrill from the fistula. At this time, he was free of chest pain, headache, nausea, and visual disturbances. Physical examination 3 days later was normal apart from complete AVF occlusion. Blood pressure was 124/88 mm Hg. Serum creatinine was stable (560 mol/L), plasma ionogram was normal, haemoglobin was 119 g/L without erythropoietin use. The electrocardiogram remained unchanged. The close temporal relation between sildenafil ingestion and AVF occlusion suggests that this drug was related to the acute vascular event. However, since this accident occurred after short sexual intercourse, sexual exertion cannot be excluded as a precipitating factor. Information from the manufacturers suggests an accumulation of sildenafil in patients with mild to moderate renal failure,
but there are no data for patients with severe renal failure or those on dialysis. Sildenafil acts at the corpora cavernosa level by inhibiting the breakdown of cyclic guanosine monophosphate (GMP) by a specific cyclic-GMP phosphodiesterase. 2 However, cyclic-GMP is also implicated in signalling pathways, including those for endogenous systemic vasodilators such as nitric oxide or atrial natriuretic peptide, two substances that are usually raised in patients with chronic renal failure. 3,4 Sildenafil has moderate vasodilator properties.2 Accumulation of the drug by reduced renal clearance could have enhanced this effect, increasing systemic vasodilation associated with antihypertensive treatment, and reducing blood flow in the vascular access leading to thrombosis. Our case, and the frequency of the underyling cardiovascular disease in a patient with chronic renal failure, suggest cautious use of sildenafil in ESRD patients. *Frank Martinez, Robert Maillet, Christophe Legendre, Claude Buisson Department of Nephrology, Hôpital SaintLouis, Paris; *Department of Nephrology, AURA, 75013 Paris, France; and Hôpital Armand Brillard, Nogent sur Marne 1
2
3
4
Feenstra J, van Drie-Pierik RJHM, Laclé CF, Stricker BHCh. Acute myocardial infarction associated with sildenafil. Lancet 1998; 352: 957–58. Goldstein I, Lue TF, Padman-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med 1998; 338: 1397–404. Rysz J, Luciak M, Kedziora J, Blaszczyk J, Sibinska E. Nitric oxide release in the peripheral blood during hemodialysis. Kidney Int 1997; 51: 294–300. De Nicola L, Bellizzi V, Cianciaruso B, et al. Pathophysiological role and diuretic efficacy of atrial natriuretic peptide in renal patients. J Am Soc Nephrol 1997; 8: 445–55.
ACE inhibitors and pneumonia in elderly people Sir—In hypertensive patients with stroke and silent aspirations, treatment with an inhibitor of angiotensin-converting enzyme (ACE) (imidapril hydrochloride) 1 led to increased concentrations of substance P and improvement in symptomless dysphagia.2 Symptomless dysphagia is one of the main causes of pneumonia in elderly people with stroke, and swallowing or the cough reflex can prevent aspiration pneumonia.3 An important reduction in substance
1937
2
Feenstra J, van Drie-Pierik FJHM, Laclé CF, Stricker BHCh. Acute myocardial infarction associated with sildenafil. Lancet 1998; 352: 957–58. National Cholesterol Education Program. Cholesterol lowering in the patient with coronary heart disease. Physician Monograph. Washington, DC: US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute, 1997. NIH publication no 97-3794.
Authors’ reply Sir—L López-Lázaro and colleagues comment on our case report of a patient who developed a myocardial infarction shortly after taking sildenafil. However, we think that their conclusion that our patient probably had hypercholesterolaemia is speculative and improbable. First, we stated that our patient had LDL cholesterol of 3·2 mmol/L, which is, in fact, below the accepted limit for initiation of drug therapy in patients with coronary heart disease. Second, plasma lipid values were measured in a blood sample obtained 9 h after hospital admission. Although plasma concentrations of total cholesterol and both LDL and HDL cholesterol indeed fall after acute myocardial infarction, Ryder 1 and Fyfe2 and their colleagues have shown that plasma lipid values can still accurately be assessed in the first 24–48 h after myocardial infarction. Since serum cholesterol was 4·3 mmol/L in our patient, which is substantially lower than the upper normal value of 5·2 mmol/L, it seems very unlikely that the patient had hypercholesterolaemia as a risk factor for myocardial infarction. *J Feenstra, R J H M van Drie-Pierik, C F Laclé, B H Ch Stricker Inspectorate for Health Care, Drug Safety Unit, PO Box 16119, 2500 BC Den Haag, Netherlands 1
2
Ryder REJ, Hayes TM, Mulligan IP, Kingswood JC, Williams S, Owens DR. How soon after myocardial infarction should plasma lipid values be assessed? BMJ 1984; 289: 1651–53. Fyfe T, Baxter RH, Cochran KM, Booth EM. Plasma lipid changes after myocardial infarction. Lancet 1971; ii: 997–1001.
Sir—J Feenstra and colleagues 1 report a patient who developed an acute myocardial infarction after taking one 50 mg sildenafil tablet. Erectile dysfunction is common in end-stage renal disease (ESRD) and treatment of this symptom has been limited. Since cardiovascular diseases are common in ESRD, an increased prevalence of sildenafil side-effects can be expected in this population.
THE LANCET • Vol 352 • December 12, 1998
We report a patient with chronic renal failure who presented with acute thrombosis of radial arteriovenous fistula after sildenafil consumption. A 54-year-old black man was seen at our clinic 3 days after occlusion of a left forearm arteriovenous fistula (AVF). He had been followed for 4 years for chronic renal failure related to a biopsy-proven chronic tubulointerstitial nephropathy without evidence of immunological infectious or toxic aetiology. Left-ventricular hypertrophy was also present, associated with hypertension requiring a triple-drug regimen. He had no history of smoking, diabetes mellitus, or hypercholesterolaemia. Despite good control of hypertension, renal insufficiency progressed and creatinine clearance reached 12 mL per min in September, 1998, leading to the development of an AVF. Echocardiography showed normal left-ventricular function and estimated cardiac index was 3·1 L min ⫺1 m⫺2. The vessels appeared healthy and a direct vascular anastomosis between left radial vein and artery was done. The patient was taught how to listen for AVF murmur and thrill. 3 weeks after surgery, AVF was well developed and judged functional. Because of intermittent erectile dysfunction associated with antihypertensive therapy (losartan 50 mg, amlodipine 10 mg, and furosemide 80 mg daily), sildenafil was prescribed by his general practitioner. Two 25 mg tablets were first used without improvement of sexual function, but the patient achieved brief sexual intercourse 1 h after taking a 50 mg tablet. 30 min after coitus, the patient had transient isolated forearm pain and could no longer feel the thrill from the fistula. At this time, he was free of chest pain, headache, nausea, and visual disturbances. Physical examination 3 days later was normal apart from complete AVF occlusion. Blood pressure was 124/88 mm Hg. Serum creatinine was stable (560 mol/L), plasma ionogram was normal, haemoglobin was 119 g/L without erythropoietin use. The electrocardiogram remained unchanged. The close temporal relation between sildenafil ingestion and AVF occlusion suggests that this drug was related to the acute vascular event. However, since this accident occurred after short sexual intercourse, sexual exertion cannot be excluded as a precipitating factor. Information from the manufacturers suggests an accumulation of sildenafil in patients with mild to moderate renal failure,
but there are no data for patients with severe renal failure or those on dialysis. Sildenafil acts at the corpora cavernosa level by inhibiting the breakdown of cyclic guanosine monophosphate (GMP) by a specific cyclic-GMP phosphodiesterase. 2 However, cyclic-GMP is also implicated in signalling pathways, including those for endogenous systemic vasodilators such as nitric oxide or atrial natriuretic peptide, two substances that are usually raised in patients with chronic renal failure. 3,4 Sildenafil has moderate vasodilator properties.2 Accumulation of the drug by reduced renal clearance could have enhanced this effect, increasing systemic vasodilation associated with antihypertensive treatment, and reducing blood flow in the vascular access leading to thrombosis. Our case, and the frequency of the underyling cardiovascular disease in a patient with chronic renal failure, suggest cautious use of sildenafil in ESRD patients. *Frank Martinez, Robert Maillet, Christophe Legendre, Claude Buisson Department of Nephrology, Hôpital SaintLouis, Paris; *Department of Nephrology, AURA, 75013 Paris, France; and Hôpital Armand Brillard, Nogent sur Marne 1
2
3
4
Feenstra J, van Drie-Pierik RJHM, Laclé CF, Stricker BHCh. Acute myocardial infarction associated with sildenafil. Lancet 1998; 352: 957–58. Goldstein I, Lue TF, Padman-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. N Engl J Med 1998; 338: 1397–404. Rysz J, Luciak M, Kedziora J, Blaszczyk J, Sibinska E. Nitric oxide release in the peripheral blood during hemodialysis. Kidney Int 1997; 51: 294–300. De Nicola L, Bellizzi V, Cianciaruso B, et al. Pathophysiological role and diuretic efficacy of atrial natriuretic peptide in renal patients. J Am Soc Nephrol 1997; 8: 445–55.
ACE inhibitors and pneumonia in elderly people Sir—In hypertensive patients with stroke and silent aspirations, treatment with an inhibitor of angiotensin-converting enzyme (ACE) (imidapril hydrochloride) 1 led to increased concentrations of substance P and improvement in symptomless dysphagia.2 Symptomless dysphagia is one of the main causes of pneumonia in elderly people with stroke, and swallowing or the cough reflex can prevent aspiration pneumonia.3 An important reduction in substance
1937