Editorial
Use of nitrates in ischemic heart disease
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
Cocco Giuseppe†, Jerie Paul & Iselin Hans-Ulrich †
Cardiology Office -- Cardiology, CH-4310 Rheinfelden, Switzerland
1.
Introduction
2.
Short-acting nitrates
3.
Long-acting nitrates
4.
Contradicting data about long-term use of nitrates in stable ischemic heart disease
5.
Endothelial dysfunction and tolerance with long-acting nitrates
6.
Differences among long-acting nitrates
7.
Puzzling results
8.
Expert opinion
Short-acting nitrates are beneficial in acute myocardial ischemia. However, many unresolved questions remain about the use of long-acting nitrates in stable ischemic heart disease. The use of long-acting nitrates is weakened by the development of endothelial dysfunction and tolerance. Also, we currently ignore whether lower doses of transdermal nitroglycerin would be better than those presently used. Multivariate analysis data from large nonrandomized studies suggested that long-acting nitrates increase the incidence of acute coronary syndromes, while data from another multivariate study indicate that they have positive effects. Because of methodological differences and open questions, the two studies cannot be compared. A study in Japanese patients with vasospastic angina has shown that, when compared with calcium antagonists, long-acting nitrates do not improve long-term prognosis and that the risk for cardiac adverse events increases with the combined therapy. We have many unanswered questions. Keywords: glyceryl-trinitrate, isosorbide-5-mononitrate, isosorbide-dinitrate, nitrates, nitroglycerin, pentaerythritol tetranitrate Expert Opin. Pharmacother. [Early Online]
1.
Introduction
Nitrates have been on the market since 1882. In spite of different chemical structures (see Figure 1) their effects and complications are quite similar. In most countries, available nitrates are nitroglycerin and isosorbide nitrates (isosorbide5-mononitrate and isosorbide dinitrate). Their complex mechanisms of action were recently reviewed [1,2]. Shortly, nitrates induce vasodilation by nitric oxide/ cyclic guanosine cyclic monophosphate-mediated intracellular signaling, which leads to smooth muscle cell relaxation through activation of cyclic guanosine cyclic monophosphate-dependent protein kinase-I and decrease in intracellular Ca2+ levels (via inhibition of the inositol trisphosphate receptor-3--regulated Ca2+-channel, activation of K+-channels with subsequent inhibition of Ca2+-channels, and activation of the Ca2+-pump) as well as epigenetic mechanisms [1,2]. We review the clinical use of nitrates in ischemic heart disease (IHD) and underline open questions that arise from the use of long-acting nitrates. 2.
Short-acting nitrates
In acute myocardial ischemia, short-acting nitrates are therapeutically effective by dilating coronary arteries. Nitroglycerin (also called glyceryl-trinitrate) also affects the mitochondrial function and exerts an antiaggregant effect, which might contribute to its beneficial effect in the therapy of acute coronary syndromes [1,2]. Sublingual nitroglycerin is the standard initial therapy for effort and spastic angina: 0.3 -- 0.6 mg is used every 5 min until the pain goes or a maximum of 1.2 mg has been taken within 15 min [3]. Nitroglycerin spray has similar effects but acts more rapidly [1,4].
10.1517/14656566.2015.1052742 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
1
C. Giuseppe et al.
Nitroglycerin
O
O
–
N+ O
N+
Pentaerythritol tetranitrate O
O– O–
O O O
N+
O
O
O O
N+
O–
O –
O
O
Isosorbide-5 mononitrate
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
O–
O
O N+
N+
N+
O–
Isosorbide dinitrate
Figure 1. Chemical structures of nitrates.
Sublingual (or spray) nitroglycerin and sublingual isosorbide nitrates are strongly recommended prophylactically when angina can be expected, such as during physical activity, with emotional stress, sexual activity, after a meal and in colder weather. Their effect is considered important in the differential diagnosis of chest pain [1,4].
3.
Long-acting nitrates
Two well-designed studies have proven that the combination of hydralazine and isosorbide dinitrate is effective and reduces mortality in the therapy of congestive heart failure, particularly in Afro-American patients [5,6]. The use of long-acting nitrates in the therapy of stable IHD was established in old studies that do not satisfy modern requirements. It is known that none of the available longacting nitrates exerts 24-h antianginal and anti-ischemic therapeutic effects. In an excellent review, Mu¨nzel et al. [1] wrote that nitrates are a ‘third-line’ option in stable IHD, but the 2013 European Guidelines consider (class IIA, level B recommendation) longacting nitrates a ‘second-line’ option, equivalent to ivabradine, nicorandil (a drug with nitrate properties and K+/ATP-channel opener) and ranolazine. Indeed, long-acting nitrates are used in patients whose angina pectoris persists in spite of therapy with b-blockers and/or Ca2+ antagonists, and/or coronary 2
revascularization [3]. The safety of a combined therapy with Ca2+ antagonists and long-acting nitrates may be questioned.
Contradicting data about long-term use of nitrates in stable ischemic heart disease
4.
As summarized in Table 1, long-term therapy with nitroglycerin and isosorbide nitrates increases the oxidative stress, thus favoring endothelial dysfunction and microcoronary dysfunction. Multivariate analysis data from large nonrandomized studies [7] suggested that the long-term use of nitrates in IHD increases the incidence of acute coronary syndromes, thus worsening the prognosis. On the other hand, data from the GRACE registry from over 52,000 unselected patients with an acute coronary syndrome suggested that long-term therapy with nitrates is beneficial in this setting [8]: ST-Elevation Myocardial Infarction (STEMI) (which reflects chiefly transmural necrosis) was much more prevalent among nonchronic nitrate users; Non-ST-Elevation Myocardial infarction (NSTEMI) (which is typically associated with a smaller extent of myocyte death) largely prevailed among chronic nitrate users; episodes of acute coronary syndrome, which did not evolve to myocardial infarction (i.e., unstable angina), were significantly more likely to occur in chronic-nitrate users; lastly, nitrate users showed significantly lower release of biochemical markers of myocyte necrosis. This biochemical effect was not a passive reflection of the fact that in this
Expert Opin. Pharmacother. (2015) 16(11)
Use of nitrates in ischemic heart disease
Table 1. Different pharmacology and complications among nitrates.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
NTG
Biotransformation occurs in mitochondria (ALDH-2). It has an antiaggregant effect Intermittent therapy is accompanied by strong rebound effects Long-term treatment is associated with a strong increase in the expression of endothelin-1, mainly within the endothelial cell layer and the adventitia, and by a subsequent increase in the sensitivity of the vasculature to vasoconstricting agents such as phenylephrine and angiotensin II ISON Biotransformation does not occur in mitochondria. They lack antiaggregant effects With intermittent therapy there are minor rebound phenomena (due to the special pharmacokinetics) Long-term administration is associated with tolerance with superoxide production, oxidative stress (of cytosolic, extramitochondrial origin), renin production and plasma volume expansion. Intermittent therapy has been associated with endothelial dysfunction. Long-term treatment is associated with a strong increase in the expression of endothelin-1, mainly within the endothelial cell layer and the adventitia, and by a subsequent increase in the sensitivity of the vasculature to vasoconstricting agents such as phenylephrine and angiotensin II PTN Biotransformation occurs in mitochondria (ALDH-2). With intermittent therapy there are minor rebound phenomena It induces antioxidant defense protein heme-oxygenase 1 and increases the expression and formation of ferritin, which binds to iron and thus prevents hydroxyl radical formation, of the antioxidant molecule bilirubin, and the vasodilator carbon monoxide Long-term treatment is not associated with a strong increase in the expression of endothelin-1, and does not increase in the sensitivity of the vasculature to vasoconstricting agents such as phenylephrine and angiotensin II All nitrates induce vasodilation by nitric oxide/cyclic guanosine cyclic monophosphate-mediated intracellular signaling, which leads to smooth muscle cell relaxation through activation of cyclic guanosine cyclic monophosphate-dependent protein kinase-I and decrease in intracellular Ca2+ levels (via inhibition of the inositol trisphosphate receptor-3--regulated Ca2+-channel, activation of K+-channels with subsequent inhibition of Ca2+-channels, and activation of the Ca2+-pump) as well as epigenetic mechanisms [1,2].
population the acute coronary syndrome episode more frequently remained confined to unstable angina (in which no release is expected to occur), because the difference persisted when data were analyzed within the specific conditions of STEMI and NSTEMI, in both cases favoring nitrate users [8]. It is established that brief ischemic episodes with release of endogenous nitric oxide by nitric oxide synthase acting as a key event can precondition the heart toward a subsequent major ischemic episode, thereby reducing the extent of myocardial infarction. The GRACE authors selected experimental animal data, which show that preconditioning can be pharmacologically mimicked by pretreatment with nitrates, other nitric oxide donors or drugs that increase nitric oxide
availability, and hypothesize that in IHD long-acting nitrates induce a pharmacologic preconditioning effect [8]. Data from the GRACE study derive from a multivariate analysis. It is difficult to know if STEMI and NSTEMI patients had a comparable anatomic and functional cardiac pathology. Common experience says that these STEMI and NSTEMI rely on different cardiac pathologies, for example, extent and duration of coronary impairment. It might be asked whether longacting nitrates were similarly used in patients with different symptoms. In this case, the occurrence of STEMI/NSTEMI in acute coronary syndromes, which was detected in the GRACE study, might also be related to different cardiac pathologies and not only be due to the use/nonuse of longacting nitrates. The statistical method ’composite outcome measures’ is often used to collect data on outcomes, but it is proven that the findings may obfuscate data and lead to inaccurate conclusions [9]. To improve the validity of the analysis of long-term complications and poor outcomes in acute coronary syndrome, the ’weighted composite endpoints’ has been used [10]. Unfortunately, up to know this approach has not been used to assess outcomes in studies reporting outcomes with the long-term use of nitrates. It is also problematic to use experimental data from a relatively short term use of nitrates in animals to interpret results from long-term use of nitrates in humans. Other experimental data [1,11] have shown that nitrates treatment was associated with a strong increase in the expression of endothelin-1 and by a subsequent increase in the sensitivity of the vasculature to vasoconstricting agents such as phenylephrine and angiotensin II. These results cannot be used to support the hypothesis that the use of longacting nitrates may only exert a preconditioning effect in IHD. The final therapeutic effect would rather be a balance between positive and negative effects on the coronary circulation. Even disregarding the open questions about the negative [7] and positive studies [8] important methodological differences among these meta-analysis statistics do not allow comparing results. Finally, recent data open another question about the therapeutic advantages/disadvantage of long-term nitrates. One thousand four hundred and twenty-nine Japanese patients with chronic vasospastic angina were treated with Ca2+ antagonists and long-acting nitrates or nicorandil: when compared with Ca2+ antagonists alone, combined therapy with nitrates did not improve prognosis; on the contrary, the combined therapy increased the risk for cardiac adverse events, especially when transdermal nitroglycerin and nicorandil were used [12]. Vasospastic angina and microcoronary dysfunction are much more frequent in Japan than in other countries [13], and results in Japanese patients should not be directly extrapolated to non-Japanese patients. Nonetheless, the fact remains that in Japanese patients with stable vasospastic IHD the combined use of Ca2+ antagonists and long-acting nitrates increases the risk for cardiac events. This leads to the question whether the 2013 European Guidelines statement that ’long-acting
Expert Opin. Pharmacother. (2015) 16(11)
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C. Giuseppe et al.
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Table 2. Mechanisms inducing endothelial dysfunction with long-acting nitrates. Long-acting nitrates induce or worsen oxidative stress by Increasing intracellular superoxide Inactivating nitric oxide and formation of peroxinitrite Inducing nitric oxide synthase uncoupling Reducing nitric oxide signaling Inhibiting prostacyclin formation Stimulating endothelin expression Inhibiting the activity of soluble guanylate cyclase Long-acting nitrate drugs increase sympathetic activation and apocrine neurohormonal mechanisms by Increasing production of norepinephrine (also called noradrenalin or levarterenol) Increasing production of angiotensin II
nitrates can be used as a second-line option in combination with Ca2+ antagonists’ [3] is generally wise.
5. Endothelial dysfunction and tolerance with long-acting nitrates
Endothelial dysfunction is a complex pathology due to various mechanisms (see Table 2), which promote vasoconstriction and procoagulation [13-16] and is commonly present in IHD. Endothelial dysfunction results from vascular injury due to arteriosclerotic inducing factors, anticipates the angiographic documentation of anatomical lesions, and has been linked with adverse outcomes in many conditions [1,13-17]. As shown in Table 2, long-term use of nitrates increases/ induces endothelial oxidative stress, increases sympathetic activation and apocrine neurohormonal mechanisms and, therefore, has negative effects on endothelial dysfunction [1,11]. Nitrates tolerance is not the same phenomenon as endothelial dysfunction and was first mentioned in 1889, in the Brunton’s Textbook Pharmacology and Therapeutics. The pathophysiology of tolerance is not yet fully understood but it shares most of the known mechanisms that induce endothelial dysfunction [1,2,11]. We hypothesize that long-term use of nitrates may induce microcoronary dysfunction, a pathophysiologic phenomenon that is frequently found in patients with cardiac syndrome X [17]. This pathophysiologic mechanism may contribute to the occurrence of nitrates tolerance. Because of tolerance, in stable IHD, the therapeutic effects (hemodynamics, anginal pectoris and exercise capacity) of transdermal nitroglycerin and oral isosorbide nitrates (b.i.d. or t.i.d. administrations) are weakened [1-4]. Tolerance can be reduced either by drug-free phases or by slowly declining plasma nitrate levels at night before taking the morning dose of the medication. However, especially with transdermal nitroglycerin, the problem of rebound ischemia in the drugfree phase still remains [18]. 4
Details about endothelial dysfunction and tolerance with long-acting nitrates will be discussed in the following section. 6.
Differences among long-acting nitrates
Clinical complications of long-acting nitrates (transdermal nitroglycerin, isosorbide nitrates and pentaerythritol tetranitrate) are rather similar, with the exception of rebound phenomena, which are less manifest with isosorbide nitrates, probably due to the fact that changes in the bioavailability of orally administered isosorbide nitrates follow a shallower curve compared with that of transdermal on-off administration of nitroglycerin [1,18,19]. However, isosorbide nitrates do not reduce the clinical problems associated with the use of long-acting nitrates in stable IHD. Compared to nitroglycerin, isosorbide nitrates induce more endothelial dysfunction, tolerance, oxidative stress, renin production, plasma volume expansion, strong increase in the expression of endothelin-1 (mainly within the endothelial cell layer and the adventitia) and subsequent increase in the sensitivity of the vasculature to vasoconstricting agents such as phenylephrine and angiotensin II [1,2,11,20]. Isosorbide nitrates also increase vascular superoxide production, predominantly because of activation of the vascular nicotinamide adenine dinucleotide phosphate-oxidase and uncoupling of the endothelial nitric oxide synthase [1]. Different from nitroglycerin, isosorbide nitrates stimulate the phagocytic nicotinamide adenine dinucleotide phosphate oxidase, a phenomenon that is completely blocked by the endothelin receptor-blocker bosentan [1]. As summarized in Table 1, in nitroglycerin and isosorbide nitrates, the stimulation of autocrine neurohormonal and endothelin-1 vascular production follows different pathophysiologic mechanisms [1,2]. In contrast to nitroglycerin (and pentaerythritol tetranitrate), isosorbide nitrates are not bioactivated by mitochondrial aldehyde dehydrogenase family-2, and the nicotinamide adenine dinucleotide phosphate-oxidase activation is not dependent on the cross-talk between reactive oxygen species--producing mitochondria and the enzyme; therefore, mitochondrial oxidative stress plays a minor role, emphasizing that this mechanism is not a necessary component for the adverse effects of nitrates [1,2]. However, probably because of the absence of changes in mitochondrial reactive oxygen species production, isosorbide nitrates are devoid of protective preconditioning-mimetic and antiaggregant effects [1,2]. In most countries, pentaerythritol tetranitrate is no longer marketed. On the other hand, in healthy volunteers, chronic administration of pentaerythritol tetranitrate vasodilating potency was not reduced and oxidative stress or endothelial dysfunction was not induced [21]. Also, a 2-month therapy with t.i.d. pentaerythritol tetranitrate in patients with IHD increased responses to sublingual nitroglycerin without inducing endothelial dysfunction [22]. Perhaps, long-term use of
Expert Opin. Pharmacother. (2015) 16(11)
Use of nitrates in ischemic heart disease
pentaerythritol tetranitrate rather than other nitrates would induce less endothelial dysfunction and tolerance. 7.
Puzzling results
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A clear dose-response relationship between exercise capacity and different dosages of transdermal nitroglycerin was never established [1]. It has been proven [23] that low doses of transdermal nitroglycerin have similar hemodynamic effects as the higher ones that are usually used, with the advantage that they do no induce tolerance. Perhaps, endothelial dysfunction and nitrates tolerance result from too high therapeutic doses. 8.
Expert opinion
We have learned important facts on the pharmacology of available nitrates [1,2,11]. Short-acting nitrates are beneficial in acute myocardial ischemia and reduce the occurrence of effort or stress-induced angina and ischemia [1,3,4]. None of the available nitrates exerts 24-h antianginal and anti-ischemic effects. Combined use of hydralazine and isosorbide dinitrate seems to be useful in the therapy of congestive heart failure, particularly in Afro-Americans [5,6]. The long-term use of transdermal nitroglycerin and oral isosorbide nitrates in IHD is weakened by the development of endothelial dysfunction and tolerance. Intermittent therapy reduces tolerance but, especially with transdermal nitroglycerin, rebound ischemia in the drug-free phase still remains a problem [18,19]. Long-acting isosorbide nitrates induce more endothelial dysfunction than transdermal nitroglycerin, and tolerance occurs with a similar frequency [11]. Also, as yet we do not know whether lower doses of transdermal nitroglycerin would be better than those presently used. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
..
2.
3.
Mu¨nzel T, Daiber A, Gori T, et al. More answers to the still unresolved question of nitrate tolerance. Eur Heart J 2013;34:2666-73 This paper explains the pharmacologic differences among available nitrates and give important information about their use in cardiology.
.
4.
Mu¨nzel T, Daiber A, Gori T. Nitrate therapy: new aspects concerning molecular action and tolerance. Circulation 2011;123:2132-44 Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of
..
We have conflicting data about the benefits/disadvantage derived from the use of long-acting nitrates in IHD. Multivariate analysis data [7] suggested that they increase the incidence of acute coronary syndromes (a negative effect) while data from the GRACE registry [8] indicate a positive effect in acute coronary syndromes. Important methodological differences among the two studies do not allow comparing results and in any case the statistical methods used to assess outcomes in cardiology are far from perfect [9,10]. Results from a recent study open another question about the use of long-acting nitrates. In Japanese patients with stable vasospastic IHD, the combined use of Ca2+ antagonists and long-acting nitrates increased the risk for cardiac events [12]. Is it perhaps unsafe to combine these agents in the longterm therapy of IHD? Therefore, we have discording data and new questions about the long-term use of transdermal nitroglycerin and oral isosorbide nitrate in IHD. A randomized study with pentaerythritol tetranitrate might be interesting, and alternative drugs with a different effect on nitric oxide might be useful.
Acknowledgment The authors thank Mrs Bugmann for her secretarial help.
Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Cardiology. Eur Heart J 2013;34:2949-03 This paper is the 2013 Guidelines of the ESC in the therapy of coronary artery disease and discusses the use of nitrates in this pathology.
5.
Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a veterans administration cooperative study. New Engl J Med 1986;314:1547-52
Qaseem A, Fihn SD, Dallas P, et al. Management of stable ischemic heart disease: summary of a clinical practice guideline from the American College of Physicians/American College of Cardiology Foundation/American Heart Association/American Association for Thoracic Surgery/Preventive Cardiovascular Nurses Association/ Society of Thoracic Surgeons. Ann Intern Med 2012;157:735-43 This paper explains the pharmacologic differences among available nitrates and give important information about their use in cardiology.
6.
Taylor AL, Ziesche S, Yancy C, et al. For the African-American Heart Failure Trial Investigators. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. New Engl J Med 2004;351:2049-57
7.
Nakamura Y, Moss AJ, Brown MW, et al. Long-term nitrate use may be deleterious in ischemic heart disease: a study using the database from two large-scale postinfarction studies. Multicenter myocardial ischemia research Group. Am Heart J 1999;138:577-85
8.
Ambrosio G, Flather MD, B€ohm M, et al. Chronic nitrate therapy is
Expert Opin. Pharmacother. (2015) 16(11)
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associated with different presentation and evolution of acute coronary syndromes: insights from 52.693 patients in the global registry of acute coronary events. Eur Heart J 2010;31:430-8 9.
10.
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
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12.
.
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6
Ciolino JD, Carter RE. Reanalysis or redefinition of the hypothesis? Eur Heart J 2015;36:340-1 Bakal JA, Roe MT, Ohman EM, et al. Applying novel methods to assess clinical outcomes: insights from the TRILOGY ACS trial. Eur Heart J 2015;36:385-92 Mu¨nzel T, Gori T, Bruno MR, Taddei S. Translational medicine: is oxidative stress a therapeutic target in cardiovascular disease? Eur Heart J 2010;31:2741-8 Takahashi JT, Nihei T, Tagaki Y, et al. Prognostic impact of chronic nitrate therapy in patients with vasospastic angina: multicenter registry study of the Japanese coronary spasm association. Eur Heart J 2015;36:228-37 The paper shows that combining calcium antagonists and nitrates in Japanese patient with stable spastic coronary artery disease is not effective and increases cardiovascular events. Niccoli G, Scalone G, Crea F. Acute myocardial infarction with no obstructive coronary atherosclerosis: mechanisms and management. Eur Heart J 2015;36:47581
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Endemann DH, Schiffrin EI. Endothelial dysfunction. JASN 2004;15:1983-92
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Feletou M, Vanhoutte PM. Endothelial dysfunction. a multifaceted disorder (The Wigger Award Lecture). Am J Physiology Heart Circ Physiol 2006;291:H985-02
16.
Gutierrez E, Flammer AJ, Lerman LO, et al. Endothelial dysfunction over the course of coronary artery disease. Eur Heart J 2013;34:3175-81
17.
Cocco G, Jerie P. Angina pectoris in patients without flow-limiting coronary artery disease (cardiac syndrome X). A forest of a variety of trees. Cardiol J 2015;In press
18.
Parker JD. Potential problems with intermittent nitrate therapy. Can J Cardiol 1996;12(Suppl C):22C-4C
19.
Parker JD. Counterregulatory responses: sustained-release isosorbide-5-mononitrate versus transdermal nitroglycerin. J Cardiovasc Pharmacol 1996;28:631-8
20.
Oelze M, Knorr M, Kr€oller-Sch€on S, et al. Chronic therapy with isosorbide-5-mononitrate causes endothelial dysfunction, oxidative stress, and a marked increase in endothelin-1 expression. Eur Heart J 2013;34:3206-16
21.
Gori T, Al-Hesayen A, Jollife C, Parker JD. Comparison of the effects of pentaerythritol tetranitrate and
Expert Opin. Pharmacother. (2015) 16(11)
nitroglycerin on endothelium-dependent vasorelaxation in male volunteers. Am J Cardiol 2003;91:854-9 22.
Schnorbus B, Schiewe R, Ostad MA, et al. Effects of pentaerythritol tetranitrate and nitroglycerin on endothelial function in coronary artery disease: results of the penta study. Clin Res Cardiol 2010;99:115-24
23.
Uxa A, Thomas GR, Gori T, Parker JD. Standard versus low-dose transdermal nitroglycerin: differential effects on the development of tolerance and abnormalities of endothelial function. J Cardiovasc Pharmacol 2010;56:354-9
Affiliation
Cocco Giuseppe†1 MD FESC, Jerie Paul2 MD & Iselin Hans-Ulrich3 MD † Author for correspondence 1 Professor, Cardiology Office, Marktgasse 10 A, CH-4310 Rheinfelden, Switzerland Tel: +004161 831 45 55; Fax: +004161 833 97 56; E-mail: [email protected] 2 Cardiology Office, Marktgasse 10 A, CH-4310 Rheinfelden, Switzerland 3 President, Argovian Medical Association, Rheinfelden, Switzerland
Use of nitrates in ischemic heart disease
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
Cocco Giuseppe†, Jerie Paul & Iselin Hans-Ulrich †
Cardiology Office -- Cardiology, CH-4310 Rheinfelden, Switzerland
1.
Introduction
2.
Short-acting nitrates
3.
Long-acting nitrates
4.
Contradicting data about long-term use of nitrates in stable ischemic heart disease
5.
Endothelial dysfunction and tolerance with long-acting nitrates
6.
Differences among long-acting nitrates
7.
Puzzling results
8.
Expert opinion
Short-acting nitrates are beneficial in acute myocardial ischemia. However, many unresolved questions remain about the use of long-acting nitrates in stable ischemic heart disease. The use of long-acting nitrates is weakened by the development of endothelial dysfunction and tolerance. Also, we currently ignore whether lower doses of transdermal nitroglycerin would be better than those presently used. Multivariate analysis data from large nonrandomized studies suggested that long-acting nitrates increase the incidence of acute coronary syndromes, while data from another multivariate study indicate that they have positive effects. Because of methodological differences and open questions, the two studies cannot be compared. A study in Japanese patients with vasospastic angina has shown that, when compared with calcium antagonists, long-acting nitrates do not improve long-term prognosis and that the risk for cardiac adverse events increases with the combined therapy. We have many unanswered questions. Keywords: glyceryl-trinitrate, isosorbide-5-mononitrate, isosorbide-dinitrate, nitrates, nitroglycerin, pentaerythritol tetranitrate Expert Opin. Pharmacother. [Early Online]
1.
Introduction
Nitrates have been on the market since 1882. In spite of different chemical structures (see Figure 1) their effects and complications are quite similar. In most countries, available nitrates are nitroglycerin and isosorbide nitrates (isosorbide5-mononitrate and isosorbide dinitrate). Their complex mechanisms of action were recently reviewed [1,2]. Shortly, nitrates induce vasodilation by nitric oxide/ cyclic guanosine cyclic monophosphate-mediated intracellular signaling, which leads to smooth muscle cell relaxation through activation of cyclic guanosine cyclic monophosphate-dependent protein kinase-I and decrease in intracellular Ca2+ levels (via inhibition of the inositol trisphosphate receptor-3--regulated Ca2+-channel, activation of K+-channels with subsequent inhibition of Ca2+-channels, and activation of the Ca2+-pump) as well as epigenetic mechanisms [1,2]. We review the clinical use of nitrates in ischemic heart disease (IHD) and underline open questions that arise from the use of long-acting nitrates. 2.
Short-acting nitrates
In acute myocardial ischemia, short-acting nitrates are therapeutically effective by dilating coronary arteries. Nitroglycerin (also called glyceryl-trinitrate) also affects the mitochondrial function and exerts an antiaggregant effect, which might contribute to its beneficial effect in the therapy of acute coronary syndromes [1,2]. Sublingual nitroglycerin is the standard initial therapy for effort and spastic angina: 0.3 -- 0.6 mg is used every 5 min until the pain goes or a maximum of 1.2 mg has been taken within 15 min [3]. Nitroglycerin spray has similar effects but acts more rapidly [1,4].
10.1517/14656566.2015.1052742 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
1
C. Giuseppe et al.
Nitroglycerin
O
O
–
N+ O
N+
Pentaerythritol tetranitrate O
O– O–
O O O
N+
O
O
O O
N+
O–
O –
O
O
Isosorbide-5 mononitrate
Expert Opin. Pharmacother. Downloaded from informahealthcare.com by Nyu Medical Center on 06/08/15 For personal use only.
O–
O
O N+
N+
N+
O–
Isosorbide dinitrate
Figure 1. Chemical structures of nitrates.
Sublingual (or spray) nitroglycerin and sublingual isosorbide nitrates are strongly recommended prophylactically when angina can be expected, such as during physical activity, with emotional stress, sexual activity, after a meal and in colder weather. Their effect is considered important in the differential diagnosis of chest pain [1,4].
3.
Long-acting nitrates
Two well-designed studies have proven that the combination of hydralazine and isosorbide dinitrate is effective and reduces mortality in the therapy of congestive heart failure, particularly in Afro-American patients [5,6]. The use of long-acting nitrates in the therapy of stable IHD was established in old studies that do not satisfy modern requirements. It is known that none of the available longacting nitrates exerts 24-h antianginal and anti-ischemic therapeutic effects. In an excellent review, Mu¨nzel et al. [1] wrote that nitrates are a ‘third-line’ option in stable IHD, but the 2013 European Guidelines consider (class IIA, level B recommendation) longacting nitrates a ‘second-line’ option, equivalent to ivabradine, nicorandil (a drug with nitrate properties and K+/ATP-channel opener) and ranolazine. Indeed, long-acting nitrates are used in patients whose angina pectoris persists in spite of therapy with b-blockers and/or Ca2+ antagonists, and/or coronary 2
revascularization [3]. The safety of a combined therapy with Ca2+ antagonists and long-acting nitrates may be questioned.
Contradicting data about long-term use of nitrates in stable ischemic heart disease
4.
As summarized in Table 1, long-term therapy with nitroglycerin and isosorbide nitrates increases the oxidative stress, thus favoring endothelial dysfunction and microcoronary dysfunction. Multivariate analysis data from large nonrandomized studies [7] suggested that the long-term use of nitrates in IHD increases the incidence of acute coronary syndromes, thus worsening the prognosis. On the other hand, data from the GRACE registry from over 52,000 unselected patients with an acute coronary syndrome suggested that long-term therapy with nitrates is beneficial in this setting [8]: ST-Elevation Myocardial Infarction (STEMI) (which reflects chiefly transmural necrosis) was much more prevalent among nonchronic nitrate users; Non-ST-Elevation Myocardial infarction (NSTEMI) (which is typically associated with a smaller extent of myocyte death) largely prevailed among chronic nitrate users; episodes of acute coronary syndrome, which did not evolve to myocardial infarction (i.e., unstable angina), were significantly more likely to occur in chronic-nitrate users; lastly, nitrate users showed significantly lower release of biochemical markers of myocyte necrosis. This biochemical effect was not a passive reflection of the fact that in this
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Use of nitrates in ischemic heart disease
Table 1. Different pharmacology and complications among nitrates.
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NTG
Biotransformation occurs in mitochondria (ALDH-2). It has an antiaggregant effect Intermittent therapy is accompanied by strong rebound effects Long-term treatment is associated with a strong increase in the expression of endothelin-1, mainly within the endothelial cell layer and the adventitia, and by a subsequent increase in the sensitivity of the vasculature to vasoconstricting agents such as phenylephrine and angiotensin II ISON Biotransformation does not occur in mitochondria. They lack antiaggregant effects With intermittent therapy there are minor rebound phenomena (due to the special pharmacokinetics) Long-term administration is associated with tolerance with superoxide production, oxidative stress (of cytosolic, extramitochondrial origin), renin production and plasma volume expansion. Intermittent therapy has been associated with endothelial dysfunction. Long-term treatment is associated with a strong increase in the expression of endothelin-1, mainly within the endothelial cell layer and the adventitia, and by a subsequent increase in the sensitivity of the vasculature to vasoconstricting agents such as phenylephrine and angiotensin II PTN Biotransformation occurs in mitochondria (ALDH-2). With intermittent therapy there are minor rebound phenomena It induces antioxidant defense protein heme-oxygenase 1 and increases the expression and formation of ferritin, which binds to iron and thus prevents hydroxyl radical formation, of the antioxidant molecule bilirubin, and the vasodilator carbon monoxide Long-term treatment is not associated with a strong increase in the expression of endothelin-1, and does not increase in the sensitivity of the vasculature to vasoconstricting agents such as phenylephrine and angiotensin II All nitrates induce vasodilation by nitric oxide/cyclic guanosine cyclic monophosphate-mediated intracellular signaling, which leads to smooth muscle cell relaxation through activation of cyclic guanosine cyclic monophosphate-dependent protein kinase-I and decrease in intracellular Ca2+ levels (via inhibition of the inositol trisphosphate receptor-3--regulated Ca2+-channel, activation of K+-channels with subsequent inhibition of Ca2+-channels, and activation of the Ca2+-pump) as well as epigenetic mechanisms [1,2].
population the acute coronary syndrome episode more frequently remained confined to unstable angina (in which no release is expected to occur), because the difference persisted when data were analyzed within the specific conditions of STEMI and NSTEMI, in both cases favoring nitrate users [8]. It is established that brief ischemic episodes with release of endogenous nitric oxide by nitric oxide synthase acting as a key event can precondition the heart toward a subsequent major ischemic episode, thereby reducing the extent of myocardial infarction. The GRACE authors selected experimental animal data, which show that preconditioning can be pharmacologically mimicked by pretreatment with nitrates, other nitric oxide donors or drugs that increase nitric oxide
availability, and hypothesize that in IHD long-acting nitrates induce a pharmacologic preconditioning effect [8]. Data from the GRACE study derive from a multivariate analysis. It is difficult to know if STEMI and NSTEMI patients had a comparable anatomic and functional cardiac pathology. Common experience says that these STEMI and NSTEMI rely on different cardiac pathologies, for example, extent and duration of coronary impairment. It might be asked whether longacting nitrates were similarly used in patients with different symptoms. In this case, the occurrence of STEMI/NSTEMI in acute coronary syndromes, which was detected in the GRACE study, might also be related to different cardiac pathologies and not only be due to the use/nonuse of longacting nitrates. The statistical method ’composite outcome measures’ is often used to collect data on outcomes, but it is proven that the findings may obfuscate data and lead to inaccurate conclusions [9]. To improve the validity of the analysis of long-term complications and poor outcomes in acute coronary syndrome, the ’weighted composite endpoints’ has been used [10]. Unfortunately, up to know this approach has not been used to assess outcomes in studies reporting outcomes with the long-term use of nitrates. It is also problematic to use experimental data from a relatively short term use of nitrates in animals to interpret results from long-term use of nitrates in humans. Other experimental data [1,11] have shown that nitrates treatment was associated with a strong increase in the expression of endothelin-1 and by a subsequent increase in the sensitivity of the vasculature to vasoconstricting agents such as phenylephrine and angiotensin II. These results cannot be used to support the hypothesis that the use of longacting nitrates may only exert a preconditioning effect in IHD. The final therapeutic effect would rather be a balance between positive and negative effects on the coronary circulation. Even disregarding the open questions about the negative [7] and positive studies [8] important methodological differences among these meta-analysis statistics do not allow comparing results. Finally, recent data open another question about the therapeutic advantages/disadvantage of long-term nitrates. One thousand four hundred and twenty-nine Japanese patients with chronic vasospastic angina were treated with Ca2+ antagonists and long-acting nitrates or nicorandil: when compared with Ca2+ antagonists alone, combined therapy with nitrates did not improve prognosis; on the contrary, the combined therapy increased the risk for cardiac adverse events, especially when transdermal nitroglycerin and nicorandil were used [12]. Vasospastic angina and microcoronary dysfunction are much more frequent in Japan than in other countries [13], and results in Japanese patients should not be directly extrapolated to non-Japanese patients. Nonetheless, the fact remains that in Japanese patients with stable vasospastic IHD the combined use of Ca2+ antagonists and long-acting nitrates increases the risk for cardiac events. This leads to the question whether the 2013 European Guidelines statement that ’long-acting
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Table 2. Mechanisms inducing endothelial dysfunction with long-acting nitrates. Long-acting nitrates induce or worsen oxidative stress by Increasing intracellular superoxide Inactivating nitric oxide and formation of peroxinitrite Inducing nitric oxide synthase uncoupling Reducing nitric oxide signaling Inhibiting prostacyclin formation Stimulating endothelin expression Inhibiting the activity of soluble guanylate cyclase Long-acting nitrate drugs increase sympathetic activation and apocrine neurohormonal mechanisms by Increasing production of norepinephrine (also called noradrenalin or levarterenol) Increasing production of angiotensin II
nitrates can be used as a second-line option in combination with Ca2+ antagonists’ [3] is generally wise.
5. Endothelial dysfunction and tolerance with long-acting nitrates
Endothelial dysfunction is a complex pathology due to various mechanisms (see Table 2), which promote vasoconstriction and procoagulation [13-16] and is commonly present in IHD. Endothelial dysfunction results from vascular injury due to arteriosclerotic inducing factors, anticipates the angiographic documentation of anatomical lesions, and has been linked with adverse outcomes in many conditions [1,13-17]. As shown in Table 2, long-term use of nitrates increases/ induces endothelial oxidative stress, increases sympathetic activation and apocrine neurohormonal mechanisms and, therefore, has negative effects on endothelial dysfunction [1,11]. Nitrates tolerance is not the same phenomenon as endothelial dysfunction and was first mentioned in 1889, in the Brunton’s Textbook Pharmacology and Therapeutics. The pathophysiology of tolerance is not yet fully understood but it shares most of the known mechanisms that induce endothelial dysfunction [1,2,11]. We hypothesize that long-term use of nitrates may induce microcoronary dysfunction, a pathophysiologic phenomenon that is frequently found in patients with cardiac syndrome X [17]. This pathophysiologic mechanism may contribute to the occurrence of nitrates tolerance. Because of tolerance, in stable IHD, the therapeutic effects (hemodynamics, anginal pectoris and exercise capacity) of transdermal nitroglycerin and oral isosorbide nitrates (b.i.d. or t.i.d. administrations) are weakened [1-4]. Tolerance can be reduced either by drug-free phases or by slowly declining plasma nitrate levels at night before taking the morning dose of the medication. However, especially with transdermal nitroglycerin, the problem of rebound ischemia in the drugfree phase still remains [18]. 4
Details about endothelial dysfunction and tolerance with long-acting nitrates will be discussed in the following section. 6.
Differences among long-acting nitrates
Clinical complications of long-acting nitrates (transdermal nitroglycerin, isosorbide nitrates and pentaerythritol tetranitrate) are rather similar, with the exception of rebound phenomena, which are less manifest with isosorbide nitrates, probably due to the fact that changes in the bioavailability of orally administered isosorbide nitrates follow a shallower curve compared with that of transdermal on-off administration of nitroglycerin [1,18,19]. However, isosorbide nitrates do not reduce the clinical problems associated with the use of long-acting nitrates in stable IHD. Compared to nitroglycerin, isosorbide nitrates induce more endothelial dysfunction, tolerance, oxidative stress, renin production, plasma volume expansion, strong increase in the expression of endothelin-1 (mainly within the endothelial cell layer and the adventitia) and subsequent increase in the sensitivity of the vasculature to vasoconstricting agents such as phenylephrine and angiotensin II [1,2,11,20]. Isosorbide nitrates also increase vascular superoxide production, predominantly because of activation of the vascular nicotinamide adenine dinucleotide phosphate-oxidase and uncoupling of the endothelial nitric oxide synthase [1]. Different from nitroglycerin, isosorbide nitrates stimulate the phagocytic nicotinamide adenine dinucleotide phosphate oxidase, a phenomenon that is completely blocked by the endothelin receptor-blocker bosentan [1]. As summarized in Table 1, in nitroglycerin and isosorbide nitrates, the stimulation of autocrine neurohormonal and endothelin-1 vascular production follows different pathophysiologic mechanisms [1,2]. In contrast to nitroglycerin (and pentaerythritol tetranitrate), isosorbide nitrates are not bioactivated by mitochondrial aldehyde dehydrogenase family-2, and the nicotinamide adenine dinucleotide phosphate-oxidase activation is not dependent on the cross-talk between reactive oxygen species--producing mitochondria and the enzyme; therefore, mitochondrial oxidative stress plays a minor role, emphasizing that this mechanism is not a necessary component for the adverse effects of nitrates [1,2]. However, probably because of the absence of changes in mitochondrial reactive oxygen species production, isosorbide nitrates are devoid of protective preconditioning-mimetic and antiaggregant effects [1,2]. In most countries, pentaerythritol tetranitrate is no longer marketed. On the other hand, in healthy volunteers, chronic administration of pentaerythritol tetranitrate vasodilating potency was not reduced and oxidative stress or endothelial dysfunction was not induced [21]. Also, a 2-month therapy with t.i.d. pentaerythritol tetranitrate in patients with IHD increased responses to sublingual nitroglycerin without inducing endothelial dysfunction [22]. Perhaps, long-term use of
Expert Opin. Pharmacother. (2015) 16(11)
Use of nitrates in ischemic heart disease
pentaerythritol tetranitrate rather than other nitrates would induce less endothelial dysfunction and tolerance. 7.
Puzzling results
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A clear dose-response relationship between exercise capacity and different dosages of transdermal nitroglycerin was never established [1]. It has been proven [23] that low doses of transdermal nitroglycerin have similar hemodynamic effects as the higher ones that are usually used, with the advantage that they do no induce tolerance. Perhaps, endothelial dysfunction and nitrates tolerance result from too high therapeutic doses. 8.
Expert opinion
We have learned important facts on the pharmacology of available nitrates [1,2,11]. Short-acting nitrates are beneficial in acute myocardial ischemia and reduce the occurrence of effort or stress-induced angina and ischemia [1,3,4]. None of the available nitrates exerts 24-h antianginal and anti-ischemic effects. Combined use of hydralazine and isosorbide dinitrate seems to be useful in the therapy of congestive heart failure, particularly in Afro-Americans [5,6]. The long-term use of transdermal nitroglycerin and oral isosorbide nitrates in IHD is weakened by the development of endothelial dysfunction and tolerance. Intermittent therapy reduces tolerance but, especially with transdermal nitroglycerin, rebound ischemia in the drug-free phase still remains a problem [18,19]. Long-acting isosorbide nitrates induce more endothelial dysfunction than transdermal nitroglycerin, and tolerance occurs with a similar frequency [11]. Also, as yet we do not know whether lower doses of transdermal nitroglycerin would be better than those presently used. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.
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Mu¨nzel T, Daiber A, Gori T, et al. More answers to the still unresolved question of nitrate tolerance. Eur Heart J 2013;34:2666-73 This paper explains the pharmacologic differences among available nitrates and give important information about their use in cardiology.
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Mu¨nzel T, Daiber A, Gori T. Nitrate therapy: new aspects concerning molecular action and tolerance. Circulation 2011;123:2132-44 Montalescot G, Sechtem U, Achenbach S, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of
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We have conflicting data about the benefits/disadvantage derived from the use of long-acting nitrates in IHD. Multivariate analysis data [7] suggested that they increase the incidence of acute coronary syndromes (a negative effect) while data from the GRACE registry [8] indicate a positive effect in acute coronary syndromes. Important methodological differences among the two studies do not allow comparing results and in any case the statistical methods used to assess outcomes in cardiology are far from perfect [9,10]. Results from a recent study open another question about the use of long-acting nitrates. In Japanese patients with stable vasospastic IHD, the combined use of Ca2+ antagonists and long-acting nitrates increased the risk for cardiac events [12]. Is it perhaps unsafe to combine these agents in the longterm therapy of IHD? Therefore, we have discording data and new questions about the long-term use of transdermal nitroglycerin and oral isosorbide nitrate in IHD. A randomized study with pentaerythritol tetranitrate might be interesting, and alternative drugs with a different effect on nitric oxide might be useful.
Acknowledgment The authors thank Mrs Bugmann for her secretarial help.
Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Cardiology. Eur Heart J 2013;34:2949-03 This paper is the 2013 Guidelines of the ESC in the therapy of coronary artery disease and discusses the use of nitrates in this pathology.
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Cohn JN, Archibald DG, Ziesche S, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a veterans administration cooperative study. New Engl J Med 1986;314:1547-52
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Ambrosio G, Flather MD, B€ohm M, et al. Chronic nitrate therapy is
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Ciolino JD, Carter RE. Reanalysis or redefinition of the hypothesis? Eur Heart J 2015;36:340-1 Bakal JA, Roe MT, Ohman EM, et al. Applying novel methods to assess clinical outcomes: insights from the TRILOGY ACS trial. Eur Heart J 2015;36:385-92 Mu¨nzel T, Gori T, Bruno MR, Taddei S. Translational medicine: is oxidative stress a therapeutic target in cardiovascular disease? Eur Heart J 2010;31:2741-8 Takahashi JT, Nihei T, Tagaki Y, et al. Prognostic impact of chronic nitrate therapy in patients with vasospastic angina: multicenter registry study of the Japanese coronary spasm association. Eur Heart J 2015;36:228-37 The paper shows that combining calcium antagonists and nitrates in Japanese patient with stable spastic coronary artery disease is not effective and increases cardiovascular events. Niccoli G, Scalone G, Crea F. Acute myocardial infarction with no obstructive coronary atherosclerosis: mechanisms and management. Eur Heart J 2015;36:47581
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Gori T, Al-Hesayen A, Jollife C, Parker JD. Comparison of the effects of pentaerythritol tetranitrate and
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nitroglycerin on endothelium-dependent vasorelaxation in male volunteers. Am J Cardiol 2003;91:854-9 22.
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Affiliation
Cocco Giuseppe†1 MD FESC, Jerie Paul2 MD & Iselin Hans-Ulrich3 MD † Author for correspondence 1 Professor, Cardiology Office, Marktgasse 10 A, CH-4310 Rheinfelden, Switzerland Tel: +004161 831 45 55; Fax: +004161 833 97 56; E-mail: [email protected] 2 Cardiology Office, Marktgasse 10 A, CH-4310 Rheinfelden, Switzerland 3 President, Argovian Medical Association, Rheinfelden, Switzerland
