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He has stable angina, having chest pain with exercise. He uses sublingual nitroglycerin (SL NTG prn) about three times a month. His blood pressure is 140/70 mm Hg. His pulse is 60 beats per minute. His current medications are lisinopril, atorvastatin, aspirin, and SL NTG tablets as needed.
What would you recommend?
A. No sildenafil; refer to urologist for other ED options.
B. Okay to use sildenafil if greater than 6 hours from NTG use.
C. Recommend tadalafil.
Is coprescribing nitrates and phosphodiesterase inhibitors safe?
The FDA warns against the use of phosphodiesterase inhibitors in patients taking nitrates. Combining nitrates with phosphodiesterase type 5 (PDE5) inhibitors is contraindicated because of a synergistic blood pressure lowering effect.1 This warning/contraindication was based on theoretical concerns, as well as concern that of the first 130 deaths reported in patients who took sildenafil, 16 of the patients also were taking nitrates.2
Parker and colleagues studied the safety of giving IV nitroglycerin to patients with coronary artery disease (CAD) who have taken sildenafil.3 The study was a randomized, placebo-controlled, crossover trial. Participants received sildenafil 100 mg or placebo, then received intravenous NTG. Patients who received sildenafil had a 4-6 mm Hg systolic BP drop compared with those who took the placebo. There was no difference in severe events between the sildenafil and placebo groups. The blood levels of nitroglycerin in this study were very likely much higher than the levels that occur with SL NTG.
A recent study by Holt et al. looked at overall cardiovascular outcomes with coprescribing nitrates and phosphodiesterase inhibitors.4 The study was a case crossover design, using a nationwide Danish health registry over the period of 2000-2018. In 2000, the rate of coprescribing of phosphodiesterase inhibitors in ischemic heart disease patients on nitrates was .9 per 100 persons/year and rose to 19.5 prescriptions per 100 persons/year in 2018. During this same time, no statistically significant association was found between the coprescription of nitrates with PDE5 inhibitors and the risk for MI, cardiac arrest, syncope, stroke, or an adverse drug event.
Does nitroglycerin response help determine cause of chest pain?
Nitroglycerin response has long been used as a clinical indicator on whether a patient’s chest pain is cardiac or not. Eric A. Shry, MD, and his colleagues looked at the usefulness of nitroglycerin response in the treatment of chest pain as a predictor of ischemic chest pain in an emergency department setting.5
The study was a retrospective review of 223 patients who presented to the emergency department over a 5-month period with ongoing chest pain. They looked at patients who had ongoing chest pain in the emergency department, received nitroglycerin, and did not receive any therapy other than aspirin within 10 minutes of receiving nitroglycerin. Response to the drug was compared with the final diagnosis of cardiac versus noncardiac chest pain.
Of the patients with a final determination of cardiac chest pain, 88% had a nitroglycerin response, whereas 92% of the patients with noncardiac chest pain had a nitroglycerin response (P = .50).
Deborah B. Diercks, MD, and her colleagues looked at improvement in chest pain scores in the emergency department in patients treated with nitroglycerin and whether it correlated with a cardiac etiology of chest pain.6 The study was a prospective, observational study of 664 patients in an urban tertiary care emergency department over a 16-month period. An 11-point numeric chest pain scale was assessed and recorded by research assistants before and 5 minutes after receiving nitroglycerin. The scale ranged from 0 (no pain) to 10 (worst pain imaginable).
A final diagnosis of a cardiac etiology for chest pain was found in 18% of the patients in the study. Of the patients who had cardiac-related chest pain, 20% had no reduction in pain with nitroglycerin, compared with 19% of the patients without cardiac-related chest pain.
A complete or significant reduction in chest pain occurred with nitroglycerin in 31% of patients with cardiac chest pain and 27% of the patients without cardiac chest pain (P = .76).
Nitroglycerin response does not appear to be helpful in distinguishing cardiac from noncardiac chest pain, but a study by His and colleagues offers an interesting twist.7
The authors of this research studied 118 patients looking to see if the side effect of headache with nitroglycerin was more common in patients who did not have CAD than in those who did. All the patients had a varying degree of relief of chest pain with NTG administration within 10 minutes. In patients with normal coronary arteries or minimal CAD, 73% had headache caused by NTG, whereas in patients with obstructive CAD, only 23% had headache after NTG use.
Take-home messages
- Short acting nitroglycerin may not be a contraindication for phosphodiesterase inhibitor use.
- More data are still needed.
- Nitroglycerin response does not help distinguish chest pain from CAD from noncardiac causes.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.
References
1. Schwartz BG, Kloner RA. Drug interactions with phosphodiesterase-5 inhibitors used for the treatment of erectile dysfunction or pulmonary hypertension. Circulation. 2010;122:88-95.
2. Kloner RA, Zusman RM. Cardiovascular effects of sildenafil citrate and recommendations for its use. Am J Cardiol. 1999 Sep 9;84(5B):11N-17N.
3. Parker JD et al. Safety of intravenous nitroglycerin after administration of sildenafil citrate to men with coronary artery disease: A double-blind, placebo-controlled, randomized, crossover trial. Crit Care Med. 2007;35:1863-8.
4. Holt A et al. Adverse events associated with coprescription of phosphodiesterase type inhibitors and oral organic nitrates in male patients with ischemic heart disease. Ann Intern Med. 2022 Jun;175(6):774-82.
5. Shry EA et al. Usefulness of the response to sublingual nitroglycerin as a predictor of ischemic chest pain in the emergency department. Am J Cardiol. 2002 Dec 1;90(11):1264-6.
6. Diercks DB et al. Changes in the numeric descriptive scale for pain after sublingual nitroglycerin do not predict cardiac etiology of chest pain. Ann Emerg Med. 2005 Jun;45(6):581-5.
7. His DH et al. Headache response to glyceryl trinitrate in patients with and without obstructive coronary artery disease. Heart 2005;91:1164-6.
He has stable angina, having chest pain with exercise. He uses sublingual nitroglycerin (SL NTG prn) about three times a month. His blood pressure is 140/70 mm Hg. His pulse is 60 beats per minute. His current medications are lisinopril, atorvastatin, aspirin, and SL NTG tablets as needed.
What would you recommend?
A. No sildenafil; refer to urologist for other ED options.
B. Okay to use sildenafil if greater than 6 hours from NTG use.
C. Recommend tadalafil.
Is coprescribing nitrates and phosphodiesterase inhibitors safe?
The FDA warns against the use of phosphodiesterase inhibitors in patients taking nitrates. Combining nitrates with phosphodiesterase type 5 (PDE5) inhibitors is contraindicated because of a synergistic blood pressure lowering effect.1 This warning/contraindication was based on theoretical concerns, as well as concern that of the first 130 deaths reported in patients who took sildenafil, 16 of the patients also were taking nitrates.2
Parker and colleagues studied the safety of giving IV nitroglycerin to patients with coronary artery disease (CAD) who have taken sildenafil.3 The study was a randomized, placebo-controlled, crossover trial. Participants received sildenafil 100 mg or placebo, then received intravenous NTG. Patients who received sildenafil had a 4-6 mm Hg systolic BP drop compared with those who took the placebo. There was no difference in severe events between the sildenafil and placebo groups. The blood levels of nitroglycerin in this study were very likely much higher than the levels that occur with SL NTG.
A recent study by Holt et al. looked at overall cardiovascular outcomes with coprescribing nitrates and phosphodiesterase inhibitors.4 The study was a case crossover design, using a nationwide Danish health registry over the period of 2000-2018. In 2000, the rate of coprescribing of phosphodiesterase inhibitors in ischemic heart disease patients on nitrates was .9 per 100 persons/year and rose to 19.5 prescriptions per 100 persons/year in 2018. During this same time, no statistically significant association was found between the coprescription of nitrates with PDE5 inhibitors and the risk for MI, cardiac arrest, syncope, stroke, or an adverse drug event.
Does nitroglycerin response help determine cause of chest pain?
Nitroglycerin response has long been used as a clinical indicator on whether a patient’s chest pain is cardiac or not. Eric A. Shry, MD, and his colleagues looked at the usefulness of nitroglycerin response in the treatment of chest pain as a predictor of ischemic chest pain in an emergency department setting.5
The study was a retrospective review of 223 patients who presented to the emergency department over a 5-month period with ongoing chest pain. They looked at patients who had ongoing chest pain in the emergency department, received nitroglycerin, and did not receive any therapy other than aspirin within 10 minutes of receiving nitroglycerin. Response to the drug was compared with the final diagnosis of cardiac versus noncardiac chest pain.
Of the patients with a final determination of cardiac chest pain, 88% had a nitroglycerin response, whereas 92% of the patients with noncardiac chest pain had a nitroglycerin response (P = .50).
Deborah B. Diercks, MD, and her colleagues looked at improvement in chest pain scores in the emergency department in patients treated with nitroglycerin and whether it correlated with a cardiac etiology of chest pain.6 The study was a prospective, observational study of 664 patients in an urban tertiary care emergency department over a 16-month period. An 11-point numeric chest pain scale was assessed and recorded by research assistants before and 5 minutes after receiving nitroglycerin. The scale ranged from 0 (no pain) to 10 (worst pain imaginable).
A final diagnosis of a cardiac etiology for chest pain was found in 18% of the patients in the study. Of the patients who had cardiac-related chest pain, 20% had no reduction in pain with nitroglycerin, compared with 19% of the patients without cardiac-related chest pain.
A complete or significant reduction in chest pain occurred with nitroglycerin in 31% of patients with cardiac chest pain and 27% of the patients without cardiac chest pain (P = .76).
Nitroglycerin response does not appear to be helpful in distinguishing cardiac from noncardiac chest pain, but a study by His and colleagues offers an interesting twist.7
The authors of this research studied 118 patients looking to see if the side effect of headache with nitroglycerin was more common in patients who did not have CAD than in those who did. All the patients had a varying degree of relief of chest pain with NTG administration within 10 minutes. In patients with normal coronary arteries or minimal CAD, 73% had headache caused by NTG, whereas in patients with obstructive CAD, only 23% had headache after NTG use.
Take-home messages
- Short acting nitroglycerin may not be a contraindication for phosphodiesterase inhibitor use.
- More data are still needed.
- Nitroglycerin response does not help distinguish chest pain from CAD from noncardiac causes.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.
References
1. Schwartz BG, Kloner RA. Drug interactions with phosphodiesterase-5 inhibitors used for the treatment of erectile dysfunction or pulmonary hypertension. Circulation. 2010;122:88-95.
2. Kloner RA, Zusman RM. Cardiovascular effects of sildenafil citrate and recommendations for its use. Am J Cardiol. 1999 Sep 9;84(5B):11N-17N.
3. Parker JD et al. Safety of intravenous nitroglycerin after administration of sildenafil citrate to men with coronary artery disease: A double-blind, placebo-controlled, randomized, crossover trial. Crit Care Med. 2007;35:1863-8.
4. Holt A et al. Adverse events associated with coprescription of phosphodiesterase type inhibitors and oral organic nitrates in male patients with ischemic heart disease. Ann Intern Med. 2022 Jun;175(6):774-82.
5. Shry EA et al. Usefulness of the response to sublingual nitroglycerin as a predictor of ischemic chest pain in the emergency department. Am J Cardiol. 2002 Dec 1;90(11):1264-6.
6. Diercks DB et al. Changes in the numeric descriptive scale for pain after sublingual nitroglycerin do not predict cardiac etiology of chest pain. Ann Emerg Med. 2005 Jun;45(6):581-5.
7. His DH et al. Headache response to glyceryl trinitrate in patients with and without obstructive coronary artery disease. Heart 2005;91:1164-6.
He has stable angina, having chest pain with exercise. He uses sublingual nitroglycerin (SL NTG prn) about three times a month. His blood pressure is 140/70 mm Hg. His pulse is 60 beats per minute. His current medications are lisinopril, atorvastatin, aspirin, and SL NTG tablets as needed.
What would you recommend?
A. No sildenafil; refer to urologist for other ED options.
B. Okay to use sildenafil if greater than 6 hours from NTG use.
C. Recommend tadalafil.
Is coprescribing nitrates and phosphodiesterase inhibitors safe?
The FDA warns against the use of phosphodiesterase inhibitors in patients taking nitrates. Combining nitrates with phosphodiesterase type 5 (PDE5) inhibitors is contraindicated because of a synergistic blood pressure lowering effect.1 This warning/contraindication was based on theoretical concerns, as well as concern that of the first 130 deaths reported in patients who took sildenafil, 16 of the patients also were taking nitrates.2
Parker and colleagues studied the safety of giving IV nitroglycerin to patients with coronary artery disease (CAD) who have taken sildenafil.3 The study was a randomized, placebo-controlled, crossover trial. Participants received sildenafil 100 mg or placebo, then received intravenous NTG. Patients who received sildenafil had a 4-6 mm Hg systolic BP drop compared with those who took the placebo. There was no difference in severe events between the sildenafil and placebo groups. The blood levels of nitroglycerin in this study were very likely much higher than the levels that occur with SL NTG.
A recent study by Holt et al. looked at overall cardiovascular outcomes with coprescribing nitrates and phosphodiesterase inhibitors.4 The study was a case crossover design, using a nationwide Danish health registry over the period of 2000-2018. In 2000, the rate of coprescribing of phosphodiesterase inhibitors in ischemic heart disease patients on nitrates was .9 per 100 persons/year and rose to 19.5 prescriptions per 100 persons/year in 2018. During this same time, no statistically significant association was found between the coprescription of nitrates with PDE5 inhibitors and the risk for MI, cardiac arrest, syncope, stroke, or an adverse drug event.
Does nitroglycerin response help determine cause of chest pain?
Nitroglycerin response has long been used as a clinical indicator on whether a patient’s chest pain is cardiac or not. Eric A. Shry, MD, and his colleagues looked at the usefulness of nitroglycerin response in the treatment of chest pain as a predictor of ischemic chest pain in an emergency department setting.5
The study was a retrospective review of 223 patients who presented to the emergency department over a 5-month period with ongoing chest pain. They looked at patients who had ongoing chest pain in the emergency department, received nitroglycerin, and did not receive any therapy other than aspirin within 10 minutes of receiving nitroglycerin. Response to the drug was compared with the final diagnosis of cardiac versus noncardiac chest pain.
Of the patients with a final determination of cardiac chest pain, 88% had a nitroglycerin response, whereas 92% of the patients with noncardiac chest pain had a nitroglycerin response (P = .50).
Deborah B. Diercks, MD, and her colleagues looked at improvement in chest pain scores in the emergency department in patients treated with nitroglycerin and whether it correlated with a cardiac etiology of chest pain.6 The study was a prospective, observational study of 664 patients in an urban tertiary care emergency department over a 16-month period. An 11-point numeric chest pain scale was assessed and recorded by research assistants before and 5 minutes after receiving nitroglycerin. The scale ranged from 0 (no pain) to 10 (worst pain imaginable).
A final diagnosis of a cardiac etiology for chest pain was found in 18% of the patients in the study. Of the patients who had cardiac-related chest pain, 20% had no reduction in pain with nitroglycerin, compared with 19% of the patients without cardiac-related chest pain.
A complete or significant reduction in chest pain occurred with nitroglycerin in 31% of patients with cardiac chest pain and 27% of the patients without cardiac chest pain (P = .76).
Nitroglycerin response does not appear to be helpful in distinguishing cardiac from noncardiac chest pain, but a study by His and colleagues offers an interesting twist.7
The authors of this research studied 118 patients looking to see if the side effect of headache with nitroglycerin was more common in patients who did not have CAD than in those who did. All the patients had a varying degree of relief of chest pain with NTG administration within 10 minutes. In patients with normal coronary arteries or minimal CAD, 73% had headache caused by NTG, whereas in patients with obstructive CAD, only 23% had headache after NTG use.
Take-home messages
- Short acting nitroglycerin may not be a contraindication for phosphodiesterase inhibitor use.
- More data are still needed.
- Nitroglycerin response does not help distinguish chest pain from CAD from noncardiac causes.
Dr. Paauw is professor of medicine in the division of general internal medicine at the University of Washington, Seattle, and he serves as third-year medical student clerkship director at the University of Washington. He is a member of the editorial advisory board of Internal Medicine News. Dr. Paauw has no conflicts to disclose. Contact him at imnews@mdedge.com.
References
1. Schwartz BG, Kloner RA. Drug interactions with phosphodiesterase-5 inhibitors used for the treatment of erectile dysfunction or pulmonary hypertension. Circulation. 2010;122:88-95.
2. Kloner RA, Zusman RM. Cardiovascular effects of sildenafil citrate and recommendations for its use. Am J Cardiol. 1999 Sep 9;84(5B):11N-17N.
3. Parker JD et al. Safety of intravenous nitroglycerin after administration of sildenafil citrate to men with coronary artery disease: A double-blind, placebo-controlled, randomized, crossover trial. Crit Care Med. 2007;35:1863-8.
4. Holt A et al. Adverse events associated with coprescription of phosphodiesterase type inhibitors and oral organic nitrates in male patients with ischemic heart disease. Ann Intern Med. 2022 Jun;175(6):774-82.
5. Shry EA et al. Usefulness of the response to sublingual nitroglycerin as a predictor of ischemic chest pain in the emergency department. Am J Cardiol. 2002 Dec 1;90(11):1264-6.
6. Diercks DB et al. Changes in the numeric descriptive scale for pain after sublingual nitroglycerin do not predict cardiac etiology of chest pain. Ann Emerg Med. 2005 Jun;45(6):581-5.
7. His DH et al. Headache response to glyceryl trinitrate in patients with and without obstructive coronary artery disease. Heart 2005;91:1164-6.