Volume 42, Issue 10, 19 November 2003, Pages 1855-1860 https://doi.org/10.1016/j.jacc.2003.09.023Get rights and content This study was designed to determine the time course of nitrate interaction with tadalafil, a phosphodiesterase 5 (PDE5) inhibitor with a half-life (t1/2) of 17.5 h. The PDE5 inhibitors augment the blood pressure (BP)-lowering effects of nitrates, yet the time course of this interaction is unclear. Recent guidelines from the American College of Cardiology/American Heart Association recommend that nitrates be withheld for 24 h after taking sildenafil (t1/2= 4 h). Male subjects (n = 150) received seven consecutive daily doses of placebo or tadalafil (20 mg). On day 7 and beyond, subjects received repeated doses of sublingual nitroglycerin (0.4 mg) after the last dose of placebo or tadalafil. After a 10- to 21-day washout period, subjects crossed over to either placebo or tadalafil, and nitrate dosing was repeated. In response to nitroglycerin at 4, 8, and 24 h, standing systolic BP fell below 85 mm Hg in more subjects on tadalafil compared with placebo (p < 0.05), with no difference in the response to nitroglycerin at 48, 72, and 96 h (p > 0.2). Similar observations were made for standing diastolic BP <45 mm Hg, decrease in systolic BP >30 mm Hg, and decrease in diastolic BP >20 mm Hg. Nitroglycerin also evoked greater mean maximal decreases in standing systolic BP at 8 and 24 h after taking tadalafil versus placebo (p < 0.02), with no significant difference at 48, 72, or 96 h (p > 0.49). The hemodynamic interaction between tadalafil and sublingual nitroglycerin lasted 24 h, but was not seen at 48 h and beyond. Similar to other PDE5 inhibitors, tadalafil should not be administered in combination with organic nitrates. cGMP cyclic guanosine monophosphate
As coprescribing drugs for erectile dysfunction and oral organic nitrates for ischemic heart disease (IHD) surged, cardiovascular adverse events did not significantly increase, a new study finds. The authors of the new research specifically examined how frequently phosphodiesterase type 5 (PDE5) inhibitors, such as Viagra, were prescribed. The U.S. Food and Drug Administration and the European Medicines Agency have warned that these drugs for erectile dysfunction are contraindicated for use with nitrates because of concerns about cardiovascular risks. "Small, randomized, pharmacologic studies have reported an amplified decrease in blood pressure during controlled coexposure with nitrates and [phosphodiesterase type 5 inhibitors], both in healthy participants and in participants with IHD," wrote lead author Anders Holt, MD, of Copenhagen University Hospital–Herlev and Gentofte and colleagues, in Annals of Internal Medicine. "Potentially, this increases the risk for vascular ischemic events including myocardial infarction and stroke." But there is a scarcity of real-world data showing that using both types of drugs together increases these risks, the researchers noted. To address this knowledge gap, Holt and colleagues conducted a retrospective study involving 249,541 Danish men with IHD. In this overall population, from 2000 to 2018, prescriptions for PDE5 inhibitors increased 10-fold, from 3.1 to 30.9 prescriptions per 100 persons per year. Within a subgroup of 42,073 patients continuously prescribed oral organic nitrates, PDE5-inhibitor prescriptions jumped twice that magnitude, from 0.9 to 19.7 prescriptions per 100 persons per year. Despite this surge in coprescribing, the investigators did not observe a significant increase in either of two composite measures of cardiovascular adverse events. The first composite included ischemic stroke, shock, cardiac arrest, myocardial infarction, or acute coronary arteriography (odds ratio, 0.58; 95% confidence interval, 0.28-1.13). The second composite included drug-related adverse events, angina pectoris, or syncope (OR, 0.73; CI, 0.40-1.32). Lead Author Speculates on Reasons for Findings"I propose several explanations [for these findings]," Holt said in an interview, "but I want to emphasize that our study does not contain any data to back it up. It is just speculation. First, the observed drop in blood pressure may not cause a condition for which patients seek a hospital. A drop in blood pressure has been shown in pharmacologic trials, but it might not translate to a real-life risk for cardiovascular outcomes. Second, patients could be well informed and adherent to guidance that the prescribing physician has provided. For example, patients are aware of the recommended pause in nitrate treatment before PDE5-inhibitor use and follow these recommendations. Third, nitrates are often taken in the morning, and with the careful assumption that most PDE5-inhibitor activities take place in the evening, the nitrates could be metabolized to a degree such that the synergistic interaction is negligible." Holt went on to suggest a novel clinical approach based on the new findings. "Coadministration should still be contraindicated due to the proven drop in blood pressure," he said. "However, perhaps physicians can allow for coprescription if patients are adequately informed." A qualitative study is needed to determine how patients and physicians discuss coprescription, including avoidance of coadministration, Holt added. Findings Call for a Reassessment of Whether the Contraindication is WarrantedRobert A. Kloner, MD, PhD, chief science officer and director of cardiovascular research at Huntington Medical Research Institutes in Pasadena, Calif., and professor of medicine at University of Southern California, Los Angeles, previously conducted research exploring drug interactions with PDE5 inhibitors, and in 2018, coauthored a literature review that concluded that PDE5 inhibitors and nitrates are contraindicated. But now, considering these new findings, Kloner is offering a fresh perspective. "This study is reassuring," Kloner said in an interview. "I think that it's time to reassess whether there should be an absolute contraindication, or this should be more of like a warning." He noted that in controlled studies, like the ones he previously conducted, PDE5 inhibitors and nitrates were administered "very close to each other, on purpose," yet this probably doesn't reflect typical practice, in which clinicians can guide usage based on durations of drug metabolism. "I think that physicians might be more comfortable now prescribing the drugs at the same time, but then telling patients that they shouldn't take the two drugs simultaneously; they should wait and take the nitrate 24 hours after the last Viagra, or the nitrate 48 hours after the last Cialis," Kloner said. "I suspect that that is happening. I suspect also the fact that people would be more likely to take the nitrate in the morning and the PDE5 inhibitor at night probably also contributes to the safety findings." Kloner noted that blood pressures vary throughout the day based on circadian rhythm, and that the body can adapt to some fluctuations without negative effects. There could still be some people who experience a drop in blood pressure and get sick from it from the two drugs interacting, but that's probably not that common, he said. The study was supported by several grants. The investigators disclosed relationships with Merck, BMS, Bayer, and others. Kloner consults for Sanofi. This story originally appeared on MDedge.com, part of the Medscape Professional Network.
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The combination of nitrates (and drugs such as nicorandil) with sildenafil is contraindicated. This combination must be avoided as it can produce significant hypotension and is potentially fatal. The guidance from the Committee on Safety of Medicines (CSM) regarding nitrates and sildenafil states (1):
The British Heart Foundation have addressed the use of GTN spray and nitrate tablets and phosphodiesterase (PDE5) inhibitors (sildenafil, tadalafil, verdenafil) (2):
The concurrent use of nicorandil and PDE5 inhibitors is also contraindicated (2,3) - this is due to the nitrate component of nicorandil. alpha blockers
Referral to specialist is appropriate if severe CVD which makes sexual activity unsafe or a situation when PDE5 inhibitor use contra- indicated (6)
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Reference: Last reviewed 01/2018 Links: |