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Introduction
Angina is first and foremost a pain signal that originates from the heart to reach the brain. Typically, angina is triggered by myocardial ischemia. In addition to advanced coronary artery disease (CAD), microvascular dysfunction and vasospastic angina are well-described etiologies of myocardial ischemia resistant to medical therapy ( Fig. 27.1 ). Angina is often simplified as the mere reflection of myocardial ischemia resulting from an imbalance between oxygen supply and demand ( Fig. 27.2 ). However, the poor correlation between angina and the extent of coronary disease suggests that there is more than fixed epicardial coronary stenoses and oxygen deprivation to refractory angina. Angina becomes refractory when defective neurologic, psychogenic, or mitochondrial functions overlap with tissue ischemia to inappropriately maintain or enhance a persistent cardiac pain syndrome. Refractory anginas are therefore not a single disease but rather a mosaic of different systemic dysfunctions. Success in the treatment of refractory angina is unlikely to be achieved by addressing myocardial ischemia alone. Instead, the contemporary treatment of refractory angina also specifically addresses the neurogenic, psychogenic, and mitochondrial components of angina and cardiac pain ( Fig. 27.3 ).
Angina can be considered refractory for several reasons. Refractory angina is a complex interaction between symptoms, myocardial perfusion, and coronary anatomy ( Fig. 27.4 ). In some cases, patients with advanced CAD unsuitable for revascularization will experience persistent angina despite optimal doses of β-blockers, calcium-channel blockers (CCBs), and long-acting nitrates. In other cases, angina caused by microvascular dysfunction or vasospasm can go unrecognized before a proper diagnosis is finally made and an adequate treatment is implemented. In North America alone, up to 500,000 Canadians and more than 1.8 million Americans are estimated to have refractory angina. In Europe and the United States, it is estimated that between 5% and 15% of patients undergoing cardiac catheterization have refractory angina. Whereas the annualized mortality rates among patients with refractory angina range between 2% and 4%, the rates of ischemic endpoints (myocardial infarction [MI], stroke, cardiovascular rehospitalization, and revascularization) are approximately 50% in the 3 years following the diagnosis. The management of refractory angina is challenging, yet the condition is insufficiently studied and poorly covered by national practice guidelines. In this review, we discuss the pharmacologic, noninvasive, and interventional treatments of refractory angina in the context of past, present, and future innovations likely to influence how we treat refractory angina for the years to come.
Drug Therapy
The approach to refractory angina varies across different regions in the world, reflecting the local regulatory, organizational, and financial culture. The choice of an add-on drug when symptoms persist despite β-blockers, CCBs, or long-acting nitrates can seem empirical, but some principles are available to help guide the selection of a new drug, such as the blood pressure (BP) and heart rate, the lack of tolerance to nitrates, and the presumptive defective system responsible for refractory angina. In a 2015 systematic review and meta-analysis, Belsey et al. studied the relative efficacy of adding ranolazine, trimetazidine, or ivabradine to patients with angina, despite treatment with β-blockers or CCBs (no comparative study was available for nicorandil) ( Fig. 27.5 ). The results suggest that the addition of ranolazine, trimetazidine, or ivabradine can delay the ischemic threshold and does improve the control of angina. The use of traditional therapies—β-blockers, nitrates, and CCBs—has been reviewed elegantly by Husted and Ohman (see also Chapter 20 ). This section will focus on the evidence supporting the use of add-on antianginal drugs in patients with refractory angina.
Late Sodium Current Inhibitors
The tradition of treating angina with late sodium (Na) current inhibitors dates back to the 1960s when amiodarone was used in Europe. Nowadays, amiodarone is anecdotally used for refractory angina. Ranolazine, another late Na current inhibitor, has been extensively studied for stable angina with obstructive CAD and is considered in certain regions of the world to be on par with long-acting nitrates, ivabradine, or nicorandil as a second-line treatment after β-blockers or nondihydropyridine CCBs. Ranolazine is well suited for patients with persistent symptoms despite maximal tolerable doses of first-line antianginal agents, as its anti-ischemic effect is not related to heart rate or systemic BP lowering. The reason ranolazine is effective is debated, but likely involves an improved excitation-contraction coupling at the ventricular level and/or improved usage of oxygen at the mitochondrial level. In the diseased heart, the exaggerated influx of Na + and calcium (Ca 2+ ) in the myocytes impairs relaxation, which increases diastolic stiffness and begets ischemia by preventing adequate ventricular perfusion. Ranolazine inhibits the late sodium current in cardiomyocytes and prevents the accumulation of Na + ions in the myocytes, which in return prompts the sodium/calcium exchanger to expel calcium outside the myocytes to improve diastolic relaxation and coronary perfusion. In experimental models, ranolazine also inhibits the β-oxidation of fatty acid in mitochondria. This inhibition favors the oxidation of glucose, which requires less oxygen to yield similar amounts of adenosine triphosphate (ATP) production.
Ranolazine improves total exercise duration and increases ischemic threshold in patients with chronic stable angina. In the Combination Assessment of Ranolazine In Stable Angina (CARISA) trial, ranolazine (750 mg or 1000 mg for 12 weeks) compared to a placebo on top of amlodipine, atenolol, or diltiazem increased total exercise duration and times to angina and to ischemia (1 mm ST-segment depression). Ranolazine decreased angina (by approximately one episode per week) and reduced the use of nitroglycerin. Similar results were observed in the Efficacy of Ranolazine in Chronic Angina (ERICA) trial, where ranolazine (500 mg twice daily) or placebo for 1 week, followed by ranolazine (1000 mg twice daily) or placebo for 6 weeks, was added to amlodipine. In the Type 2 Diabetes Evaluation of Ranolazine in Subjects with Chronic Stable Angina (TERISA) trial, patients with type 2 diabetes mellitus and persistent angina despite one or two antianginal drugs experienced fewer angina episodes per week compared to placebo (3.8 vs. 4.3 episodes; p < 0.01) and consumed less sublingual nitroglycerin (1.7 vs. 2.1 doses; p < 0.01).
In a post hoc subgroup analysis of the Metabolic Efficiency with Ranolazine for Less Ischemia in Non–ST-Segment Elevation Acute Coronary Syndromes (MERLIN-TIMI 36) trial, 3565 participants who had a history of chronic angina prior to their index acute coronary syndrome experienced a significant reduction of the primary endpoint (cardiovascular death, MI, and recurrent ischemia) with ranolazine compared to placebo (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75–0.97; p = 0.02). This reduction was mostly driven by a drop in the number of recurrent ischemic episodes (HR, 0.78; 95% CI, 0.67–0.91; p < 0.01). Similar results were observed when the analysis was restricted to patients with a history of moderate-to-severe angina before enrollment (HR, 0.75; 95% CI, 0.63–0.91; p < 0.01), but ranolazine had no impact on the occurrence of cardiovascular death or MI. This antiischemic effect persisted in a 30-day landmark analysis, for up to a year (HR, 0.80; 95% CI, 0.67–0.96; p = 0.02). Of note, patients in this substudy were treated with 2.9 antianginal agents on average over the entire duration of the follow-up.
The favorable results seen in the MERLIN subgroup analysis fueled the enthusiasm for the Ranolazine in patients with incomplete revascularization after percutaneous coronary intervention (PCI) (RIVER-PCI) trial, which assessed whether ranolazine 1000 mg twice daily was superior to placebo in 2651 participants with a history of chronic angina and incomplete revascularization post-PCI (residual lesions with diameter stenosis ≥ 50% in large coronary artery) at preventing the occurrence of ischemia-driven hospitalization with or without revascularization. Over a median follow-up of 643 days, the primary endpoint occurred in 345 participants (26%) assigned to ranolazine versus 364 participants (28%) assigned to placebo (HR, 0.95; 95% CI, 0.82–1.10; p = 0.48). Of note, the treatment effect of ranolazine for the primary endpoint remained the same in participants prescribed two to three anti-ischemic drugs, such as β-blockers, CCBs, or long-acting nitrates (HR, 1.04; 95% CI, 0.82–1.32; p interaction = 0.36). A safety subgroup analysis suggested that patients older than 75 years of age experienced higher rates of major adverse cardiovascular events (MACE) when given ranolazine compared to placebo. In this population, ranolazine provided no additional benefit to angina-related quality of life compared to placebo, as quality of life improved drastically in both groups following the PCI. Overall, patients enrolled in RIVER-PCI had a low angina burden at baseline and follow-up, leaving little room for the quantification of an improvement, once the effect of the index PCI and the regression to the mean were taken into account.
Ranolazine has been associated with favorable outcomes in small pilot studies of microvascular angina, and it was hypothesized that ranolazine could improve regional coronary in-flow in areas of myocardial ischemia. Bairey Merz et al. (2016) reported the results of a trial in participants with microvascular dysfunction but without obstructive CAD who were randomized to either short-term oral ranolazine 500 to 1000 mg twice daily for 2 weeks or placebo, then crossed over to the alternate treatment arm. The majority of patients were women treated with at least one antianginal drug, angiotensin converting enzyme inhibitors, and statins, and all participants had symptoms related to myocardial ischemia. Compared to placebo, ranolazine did not significantly improve the angina-related quality of life (measured by the Seattle Angina Questionnaire [SAQ]). In a mechanistic substudy, ranolazine failed to improve the myocardial perfusion reserve index (MPRI) measured by cardiac magnetic resonance imaging. One interesting finding was that the change in MPRI correlated with the change in SAQ score, suggesting that a modulation of microvascular dysfunction could lead to a new therapeutic avenue in patients with refractory angina. The suboptimal results in incompletely revascularized patients and those with microvascular disease might be a barrier to widespread use of ranolazine in this population.
Due to pharmacologic interaction, ranolazine should not be used concomitantly with nondihydropyridine CCBs, ketoconazole, or macrolide antibiotics.
Partial Fatty Acid Oxidation Inhibitors
Trimetazidine
Trimetazidine (TMZ) is frequently presented as the archetype of partial fatty acid oxidation (pFOX) inhibitors. TMZ is proposed to modulate the mitochondrial metabolism by blocking the long-chain 3-ketoacyl-CoA thiolase (KAT), a key enzyme in the β-oxidation of fatty acids. This blockade is thought to shift the mitochondrial substrate utilization toward glycolysis, which requires 10% to 15% less oxygen than the oxidation of fatty acid to yield the same energy. A partial inhibition of fatty acid oxidation has the potential to prevent the intracellular accumulation of lactate and protons, both of which are associated with impaired contraction–relaxation coupling in ischemic myocytes. Although appealing, this presumptive mechanism of action is challenged by evidence suggesting that TMZ does not alter metabolic substrate oxidation in the human cardiac mitochondria but rather acts via an unidentified intracardiac mechanism, possibly involving the adenosine monophosphate (AMP)-activated protein kinase (AMPK) and extracellular signal-related kinase (ERK) signaling pathway, and the activation of p38 mitogen-activated protein kinase and Akt signaling.
In the TRIMetazidine in POLand (TRIMPOL II) trial, 426 participants with stable CAD and an abnormal treadmill stress test despite metoprolol 50 mg twice daily were randomized to either TMZ (20 mg three times daily over 12 weeks) or matching placebo. TMZ markedly improved the time to ST-segment depression compared to placebo (+ 86 s vs. + 24 s; p < 0.01). Likewise, TMZ reduced the weekly angina count (– 1.9 episodes vs. – 0.9 episode; p < 0.01).
In a recent meta-analysis of 1628 participants involved in 13 randomized trials from 1997 to 2013, TMZ in addition to antianginal medication was shown to be superior to antianginal medications at reducing the weekly angina count (weighted mean difference [WMD] = –0.95 episode; 95% CI, –1.30 episode to –0.61 episode; p < 0.001), the weekly nitroglycerin use (WMD = –0.98; 95% CI, –1.44 to –0.52; p < 0.001), and the time to 1-mm ST-segment depression (WMD = 0.30; 95% CI, 0.17 to 0.43; p < 0.001). Of note, only four of the trials included in the pooled analyses were appropriately blinded. These results contradict a previous meta-analysis that detected no benefit. Importantly, TMZ has not been associated with a reduction in mortality or cardiovascular events. TMZ is associated with adverse extrapyramidal reactions such as restless leg syndrome and parkinsonism.
In summary, data supporting the use of TMZ are conflicting and further clinical trials are required. The European Medicines Agency (EMA) has restricted the use of TMZ as add-on therapy for patients who remain symptomatic or are intolerant to first-line antianginal treatments. The efficAcy and safety of Trimetazidine in Patients with angina pectoris having been treated by Percutaneous Coronary Intervention (ATPCI) trial (EudraCT Number: 2010-022134-89) is examining the efficacy of TMZ in patients with post-PCI angina. Results of this large trial are expected in 2017.
Perhexiline Maleate
Perhexiline is one of the oldest known antianginal drugs and was extensively studied in the 1970s before β-blockers and CCBs became mainstream therapies. Despite its seeming efficacy, perhexiline was removed from the market in several countries due to cases of hepatotoxicity and neurotoxicity with chronic therapy, predominantly explained by drug accumulation in slow CYP2D6 metabolizers.
Perhexiline is a pFOX inhibitor that modulates mitochondrial metabolism by inhibiting the enzymes carnitine O -palmitoyltransferase (CPT) 1 and 2, which are responsible for the transfer of free fatty acids from the cytosol to the mitochondria. These effects are systemic and not limited to the heart. Similar to TMZ, perhexiline is thought to shift the mitochondrial substrate utilization toward glucose oxidation, which is more energy efficient as it requires less oxygen to produce the same amount of ATP. Based on stoichiometric models, an approximate 11% to 13% increase in oxygen efficiency would be expected by entirely blocking fatty acid metabolism in favor of an exclusive carbohydrate metabolism. In practice, a predominant mitochondrial carbohydrate oxidation has been reported to be at least 30% to 40% more efficient than free fatty acid oxidation. Animal metabolomic studies suggest that perhexiline may also favor lactate and amino acid uptake by the heart. Perhexiline is also a weak L-type CCB, a sodium channel blocker, and a vasodilator, but these possible antianginal properties have never been fully delineated.
In a systematic review counting 26 small, randomized, mostly cross-over, double-blind, controlled trials and 696 participants, perhexiline monotherapy was associated with a consistent reduction in the frequency of angina attacks and nitroglycerin consumption, although there were concerns around the quality of reporting of the available trials. In a small, double-blind, controlled crossover trial ( n = 17 participants), perhexiline was associated with a greater proportion (65%) of responders (measured by a reduction in angina as measured in a dedicated diary over 3 months) compared with placebo (18%, p < 0.05) in patients with refractory angina, despite the combination of β-blockers, nitrates, and CCBs. Likewise, all patients improved their performance on a treadmill stress test, compared with none when treated with placebo. Five of 17 (29%) patients developed significant side effects despite plasma concentration monitoring, including four cases of transient ataxia. Similar findings were reported in patients treated with adequate β-blockade. Of note, few trials have tested the efficacy of perhexiline at dosages deemed to be safe in most patients (100 to 200 mg/day). In a large 5-year retrospective series from two centers, perhexiline was associated with angina relief in most patients with otherwise refractory symptoms. However, the treatment was discontinued in 20% of patients due to side effects or out of safety concerns, despite careful therapeutic drug level monitoring.
Therapeutic plasma monitoring opens the door to the personalized perhexiline administration in selected cases to avoid excessive drug accumulation. Short-term dizziness, nausea, vomiting, lethargy, and tremors are acute adverse effects observed with perhexiline. Perhexiline may be safely started at a dose of 100 mg twice daily and monitored at 1, 4, and 8 weeks to maintain plasma concentrations between 0.15 and 0.60 mg/L. Perhexiline has been associated with occasional QT interval prolongation, especially in patients with K + -channel mutations (KCNQ1), and additional safety information will be required before it can be widely recommended in clinical practice. The genetic screening of allelic variants associated with slow cytochrome P450 2D6 hydroxylation may obviate the need for plasma monitoring in the future. Mutations in CYP2D6 are present in 7% to 10% of Caucasians versus 2% of African Americans and less than 1% in Chinese and Japanese populations. Perhexiline is used for refractory angina in Australia and New Zealand.
Mildronate
Mildronate (better known as meldonium) has recently drawn a lot of attention after the suspension of a high-profile tennis player for doping. Mildronate indirectly acts as a pFOX inhibitor by blocking the enzyme γ-butyrobetaine hydroxylase (GGBH), which catalyses the biosynthesis of carnitine. Carnitine is essential for the transfer of long-chain fatty acids across the mitochondrial inner membrane for oxidation and ATP synthesis. Mildronate also inhibits the activity of carnitine acetyltransferase (CAT), an enzyme that regulates the level of acetyl coenzyme A (acetyl-CoA) in the mitochondria, which plays a key role in several aspects of intermediary metabolism, including the oxidation of free fatty acids. In the phase II dose-finding MILSS (a dose-dependent improvement in exercise tolerance in patients with stable angina treated with mildronate) trial, 512 patients with chronic stable Canadian Cardiovascular Society (CCS) class II–III angina, despite β-blockers (> 94%), long-acting nitrates (> 70%), or CCB (35–50%), were blindly randomized to either mildronate (one of four doses: 100 mg, 300 mg, 1000 mg, or 3000 mg) or placebo for 12 weeks. Mildronate resulted in a dose-related improvement in total exercise duration, as measured on a standard bicycle ergometer. Patients assigned to the 1000-mg dose (given as 500 mg twice daily) obtained the best effect compared to placebo (+35.2 s ± 53.3 s vs. –7.1 s ± 81.8 s, p = 0.002). No significant difference in the time to onset of angina was noted between the groups. Mildronate was developed in the former Soviet Union for the treatment of MI and stroke and has never been approved elsewhere. Mildronate is conceptually interesting for refractory angina, but insufficient evidence exists to support its use in clinical practice.
Nitric Oxide Donors
Nicorandil
Nicorandil is a coronary vasodilator with cardioprotective properties. The nicotinamide-nitrate ester acts as an ATP-sensitive potassium channel (KATP) opener at the mitochondrial level to mimic ischemic preconditioning and prepare the myocytes against injury. Similar to long-acting nitrates, nicorandil is a nitric oxide (NO) donor which directly vasodilates coronary arteries. Unlike nitrates however, nicorandil does not impair endothelial function and is not associated with tachyphylaxis and tolerance. Besides vasodilation, some evidence suggests that nicorandil may also have an intrinsic analgesic activity and may reduce the nociceptive response to angina. Likewise, nicorandil may also improve the myocardial fatty acid metabolism. For these reasons, nicorandil is conceptually appealing in patients with severe angina and advanced CAD, and in patients with vasospastic angina.
Nicorandil exerts effects similar to β-blockers, long-acting nitrates, and CCBs in patients with stable CAD with no other background treatment. The Impact Of Nicorandil in Angina (IONA) trial compared nicorandil versus placebo in 5126 patients with chronic angina despite nitrates (87%), β-blockers (57%), or CCBs (55%). Nicorandil reduced the combined occurrence of cardiovascular death, nonfatal MI, or unplanned admissions to hospital for chest pain (13.1% vs. 15.5%; p = 0.02) and confirmed the cardioprotective effect of nicorandil in patients with CAD. From this trial, no data were reported on the effect of nicorandil on angina symptoms or quality of life. At 6 months, 29.6% of patients assigned to nicorandil discontinued their study drug due to adverse effects, compared with 19.5% in patients assigned to placebo. No study has yet described the potential merit of nicorandil in patients with refractory angina despite classical antianginal drugs administered at maximal tolerable dose.
The European Society of Cardiology (ESC) practice guidelines recommend nicorandil as a second-line treatment for the relief of angina/ischemia (class IIa indication), on par with long-acting nitrates, ivabradine, and ranolazine, according to heart rate, BP, and tolerance. Surprisingly, no studies have been reported that describe the efficacy of nicorandil in an add-on role in angina. Nicorandil is only available by special-access programs run by regulatory agencies in Canada and the United States. As is the case with all NO donors, nicorandil can cause headaches and hypotension. Not infrequently, nicorandil can induce oral, anal, or gastrointestinal ulceration, which typically subsides upon drug discontinuation.
Molsidomine
Molsidomine is similar to long-acting nitrates, both in terms of mechanism of action and efficacy. Molsidomine mediates its effect via NO and increases myocardial perfusion by vasodilating the coronary arterial system, and reduces oxygen demand by increasing the peripheral venous capacitance, cardiac preload, and wall tension. Like long-acting nitrates, molsidomine could also be associated with tachyphylaxis and tolerance.
Molsidomine has not been tested in refractory angina. Two different formulations of molsidomine (8 mg twice daily vs. 16 mg daily) were compared to a placebo in a randomized trial of 533 patients with new onset angina pectoris where β-blockers, CCBs, and long-acting nitrates were prescribed. Both formulations of molsidomine were better than placebo at reducing the weekly angina count (2.3 ± 3.2 episodes vs. 3.8 ± 3.7 episodes, p < 0.001) and reducing the use of short-acting nitrates, and resulted in a significantly improved total exercise duration. In the 2015 Effect of Molsidomine on the Endothelial Dysfunction in Patients with Angina Pectoris (MEDCORE) randomized controlled trial (RCT), molsidomine 16 mg once a day for 12 months as an add-on treatment to best of care medical therapy failed to improve endothelial dysfunction over placebo in patients who underwent a PCI for stable angina pectoris. In real-world settings, molsidomine is well tolerated with only 9.1% of patients treated over the course of 1 year reporting drug-related adverse events (mostly headaches and hypotension). Given the lack of evidence specific to refractory angina and the lack of safety data, molsidomine should probably be used cautiously in this population.
l -Arginine
The amino acid l -arginine is transformed by the NO synthases into NO, which mediates the endothelium-dependent vasodilatation. Supplemental oral l -arginine (1 g TID) improves small-vessel coronary endothelial function in healthy individuals. Whereas l -arginine has been shown to be better than a placebo at improving the total exercise duration on treadmill stress test in patients with stable CAD, it has not been adequately investigated in refractory angina. In a small factorial trial, Ruel et al. suggested that l -arginine (6 g per day) may potentiate the effect of vascular endothelial growth factor (VEGF)-165 plasmid DNA in patients with advanced CAD. Participants who received the combination of VEGF-165 plasmid DNA and l -arginine had improved anterior wall perfusion on positron emission tomography.
I (f) Current Inhibitors
Ivabradine selectively inhibits the I (f) current which regulates the intrinsic chronotropic properties of the pacemaker cells in the sinoatrial node and lowers the heart rate. Ivabradine does not reduce BP nor does it exert a negative effect on the excitability of the heart and the conductive properties of the atrioventricular (AV) node.
In the Efficacy and Safety of Ivabradine on Top of Atenolol in Stable Angina Pectoris (ASSOCIATE) trial, ivabradine up to 7.5 mg twice daily for 4 months was superior to placebo at improving the total exercise duration compared to placebo (+24.3 s ± 65.3 s vs. 7.7 s ± 63.8 s; p < 0.001) in patients with persistent angina despite atenolol 50 mg daily. In small pilot trials performed in patients suffering microvascular angina, ivabradine (5 mg twice daily) has been superior to placebo at improving angina-related quality of life. Ivabradine did not improve cardiovascular outcomes in patients with stable CAD and left ventricular systolic dysfunction. However in the ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL) trial, the subgroup of participants who had limiting angina at baseline experienced a 24% reduction in cardiovascular death and hospitalization for MI or heart failure (HF). The majority of these patients were treated with β-blockers and long-acting nitrates.
In the Study assessInG the morbidity-mortality beNefits of the I (f) inhibitor ivabradine in patients with coronarY artery disease (SIGNIFY) trial, a dose of ivabradine adjusted to reach a heart rate of 55 to 60 beats per minute (bpm) on top of guideline-directed medical therapy was not superior to placebo at improving the occurrence of cardiovascular death or MI in 19,102 patients with stable CAD and a heart rate of 70 bpm or greater (6.8% vs. 6.4%, respectively; HR, 1.08; 95% CI, 0.96–1.20; p = 0.20; median follow-up of 27.8 months). In the subgroup of patients with symptomatic angina (CCS class II or higher), a greater proportion of ivabradine-treated patients experienced an improvement in their CCS angina class (24.0% vs. 18.8%, p = 0.01). Despite these favorable findings, ivabradine was associated with a small yet significant increase in cardiovascular death and MI (HR, 1.18; 95% CI, 1.03–1.35; p interaction = 0.02) in this subgroup. Based on these results, caution has been advised regarding the prescription of ivabradine in patients with angina without HF. Ivabradine might be considered in individuals with a heart rate of 70 bpm or greater who do not tolerate doses of β-blockers or when CCBs are contraindicated. Ivabradine has also been associated with new-onset atrial fibrillation, bradycardia, and blurred vision.
Miscellaneous Pharmacologic Agents
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