October 2011 FAQs
October 2011 FAQs
When should parenteral nutrition be initiated in critically ill patients?
When should parenteral nutrition be initiated in critically ill patients?
Critically ill patients often develop nutritional deficits secondary to both an increase in caloric requirements associated with the catabolic stress response and a decrease in oral intake.1,2 Nutrition support is used in this patient population to maintain lean body mass and support the immune system through prevention of oxidative cellular injury.2 Enteral nutrition is recognized as the preferred method of nutrition in intensive care unit (ICU) patients with inadequate oral intake.2,3 However, many patients do not reach their caloric requirements using only enteral nutrition.1 Parenteral nutrition is often used when caloric requirements cannot be met by enteral nutrition alone. The optimal time for initiation of parenteral nutrition, however, is controversial.
Clinical Practice Guidelines
Patients at risk for starvation could benefit from early parenteral nutrition because underfeeding critically ill patients has been associated with longer duration of mechanical ventilation and increased risk of infection and death.4 Conversely, early initiation of parenteral nutrition in critically ill patients has been associated with increased risk of nosocomial infection and mortality, possibly associated with poorly controlled hyperglycemia or parenteral administration.5 Disagreement between major nutrition organizations only adds to the difficulty of the clinician's decision regarding the best time to initiate parenteral nutrition. The European Society for Clinical Nutrition and Metabolism (ESPEN) recommends early initiation of parenteral nutrition in critically ill patients, while the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) supports late initiation of parenteral nutrition.2,6
The ESPEN guidelines on parenteral nutrition in intensive care patients recommend initiating parenteral nutrition within 24 to 48 hours in all patients not expected to have normal nutrition within 3 days if the patient is unable to tolerate enteral nutrition.6 This recommendation is based upon a meta-analysis by Simpson et al, which reviewed 9 studies and found reduced mortality in critically ill patients receiving early parenteral nutrition compared with delayed enteral nutrition.7 The ESPEN guidelines also reference a study of 300 postoperative patients who were randomized to either total parenteral nutrition (TPN) starting the first day following surgery or glucose alone for up to 15 days following surgery. 8 Although overall mortality was not different between the glucose and TPN groups in this study, complicated patients with inadequate oral intake after 14 days had increased morbidity and mortality in the glucose-alone group compared to the TPN group. Despite the fact that 60% of patients in the study were able to eat within 8 to 9 days following surgery with no difference in outcome with TPN versus glucose in these patients, the authors emphasized the increased mortality seen with delayed initiation of TPN in the subgroup of complicated patients. They discussed the difficulty of identifying these patients who are at high-risk for inadequate oral intake following surgery, and therefore concluded that late initiation of TPN results in increased morbidity and mortality in postoperative patients.
The A.S.P.E.N. guidelines for nutrition support in the critically ill patient do not recommend initiating parenteral nutrition until after 7 days of hospitalization, with the exception of patients who have baseline malnutrition.2 This recommendation is based on the results of 2 meta-analyses. Braunschweig et al reviewed 27 studies with a total of 1,828 patients and concluded that parenteral nutrition is associated with higher rates of infection compared with standard care (i.e., no nutrition support) in most patients except those patients malnourished at baseline who had higher mortality and increased rates of infection with standard care.9 Heyland et al reviewed 26 studies with a total of 2,211 critically ill patients and found TPN had no effect on mortality compared to standard care, although it reduced rate of complications in malnourished patients. 10
The optimal time to initiate parenteral nutrition in critically ill patients remains uncertain. The Early versus Late Parenteral Nutrition in Critically Ill Adults (EPaNIC) Study, published in the New England Journal of Medicine in July 2011, revealed pertinent new data on this issue.1
The EPaNIC study was a prospective, multicenter, randomized controlled trial.1 Patients were enrolled from August 2007 to November 2010 and randomized to either early or late initiation of parenteral nutrition. The early initiation group received glucose 20% solution intravenously with a total energy intake target of 400 kcal per day on ICU day 1 and 800 kcal per day on day 2. Parenteral nutrition was initiated on day 3 to reach 100% of the caloric goal using both enteral and parenteral nutrition. Patients in the late initiation group received glucose 5% solution intravenously and enteral nutrition with a total volume equal to that of the parenteral nutrition in the early initiation group. Parenteral nutrition was initiated on day 8 if the patient could not reach caloric goals on enteral nutrition alone. Both groups were supplemented with parenteral trace elements, minerals, and vitamins. Patients were given continuous insulin infusions, adjusted to a blood glucose goal of 80 to 110 mg/dL.
The primary endpoint was duration of dependency on intensive care.1 This assessment included the number of ICU days for both survivors and nonsurvivors and the time to discharge from the ICU. Safety endpoints included proportion of patients alive at discharge from the ICU in ≤8 days, rates of death in the ICU and the hospital, and rates of survival up to 90 days. Number of patients with new infection was measured as a secondary endpoint.
There were 4,640 patients included in the study.1 Late initiation of parenteral nutrition reduced ICU stay compared to early initiation. Median ICU stay was 3 days in the late initiation group versus 4 days with early initiation (p=0.02). The hazard ratio of earlier time to discharge from ICU (late initiation versus early) was 1.06 (95% CI 1.00-1.13; p=0.04). More patients with late initiation were discharged from the ICU within 8 days than early initiation (75.2% versus 71.7%; p=0.007). Rates of death were similar between groups: death in the ICU (6.1% versus 6.3%; p=0.76), death in the hospital (10.4% versus 10.9%; p=0.63), and death at 90 days (11.2% versus 11.2%; p=1). There were fewer new infections in the late initiation group (22.8% versus 26.2%; p=0.008).
Limitations of the study include the fact that patients were provided with tight glucose control and administration of micronutrients from day 1 in both study groups, which may not be applicable to clinical practice. In addition, patients and clinicians were not blind to treatment group, potentially introducing bias. Finally, patients in both groups were also fed enterally if tolerated.
The EPaNIC study demonstrated benefits with prolonging initiation of parenteral nutrition for critically ill patients.1 There were shorter ICU stays and fewer new infections in patients initiating parenteral nutrition after 7 days in the ICU compared to patients who initiated within 48 hours; however, mortality was not significantly different between the 2 groups. These results support waiting to initiate parenteral nutrition in ICU patients until after the first week. This recommendation is consistent with the current A.S.P.E.N. guidelines.2 Therefore, this study supports current practice in the United States and provides additional support for the current A.S.P.E.N. recommendation.
1. Casaer MP, Mesotten D, Hermans G, et al. Early versus late parenteral nutrition in critically ill adults. N Engl J Med. 2011;365(6):506-517.
2. McClave SA, Martindale RG, Vanek VW, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (ASPEN). J Parenter Enteral Nutr. 2009;33(3):277-316.
3. Kreymann KG, Berger MM, Deutz NEP, et al. ESPEN guidelines on enteral nutrition: intensive care. Clin Nutr. 2006;25(2):210-223.
4. Stapleton RD, Jones N, Heyland DK. Feeding critically ill patients: what is the optimal amount of energy? Crit Care Med. 2007;35(9 Suppl):S535-S540.
5. Sena MJ, Utter GH, Cuschiere J, et al. Early supplemental parenteral nutrition is associated with increased infectious complications in critically ill trauma patients. J Am Coll Surg. 2008;207(4):459-467.
6. Singer P, Berger NM, Van den Berghe G, et al. ESPEN guidelines on parenteral nutrition: intensive care. Clin Nutr. 2009;28(4):387-400.
7. Simpson F, Doig GS. Parenteral vs. enteral nutrition in the critically ill patient: a meta-analysis of trials using the intention to treat principle. Intensive Care Med. 2005;31(1):12-23.
8. Sandstrom R, Drott C, Hyltander A, et al. The effect of postoperative intravenous feeding (TPN) on outcome following major surgery evaluated in a randomized study. Ann Surg. 1993;217(2):185-195.
9. Braunschweig CL, Levy P, Sheean PM, Wang X. Enteral compared with parenteral nutrition: a meta-analysis. Am J Clin Nutr. 2001;74(4):534-542.
10. Heyland DK, MacDonald S, Keefe L, Drover JW. Total parenteral nutrition in the critically ill patient: a meta-analysis. JAMA. 1998;280(23):2013-2019.
Written by: Nicole Mueller, PharmD
What methods are available for reversal of dabigatran and rivaroxaban?
What methods are available for reversal of dabigatran and rivaroxaban?
Recently, 2 new anticoagulant agents-dabigatran and rivaroxaban-have been approved for use in the United States for reduction of the risk of stroke in association with atrial fibrillation (dabigatran) and for prophylaxis of deep vein thromboembolism in patients undergoing knee or hip replacement surgery (rivaroxaban).1,2 In addition to differing in labeled indications, the 2 agents differ in their mechanism of action. Dabigatran is a direct thrombin inhibitor, preventing the conversion of fibrinogen to fibrin and subsequent thrombus formation.1 Rivaroxaban is a factor Xa inhibitor, blocking an essential step in the coagulation cascade for thrombus formation.2 However, both agents are given in a fixed-dose regimen and do not require routine monitoring.3,4 In addition, unlike well-established anticoagulants such as warfarin and unfractionated heparin, there are no clear antidotes for reversal of the anticoagulant effects of either of these newer agents. Although both have relatively short half-lives (12 to 17 hours for dabigatran and 5 to 9 hours for rivaroxaban) there may be situations where urgent reversal of anticoagulant effects is needed (e.g., emergency surgery, overdose, or life-threatening bleeding).
Agents for reversal
Several publications are available with suggested approaches to reversal of the anticoagulant effects of dabigatran and rivaroxaban. Both recombinant factor VIIa (rFVIIa) and prothrombin complex concentrates (PCCs) have been suggested as agents for reversal for both dabigatran and rivaroxaban. van Ryn and colleagues conducted an in vitro study using rFVIIa and a PCC (FEIBA[a] to reverse the effects of high dose dabigatran in an animal model. 5 Following administration of dabigatran, rFVIIa (0.5 or 1 mg/kg) and FEIBA (50 or 100 U/kg) were both found to reduce bleeding time from 1455 seconds to less than 186 seconds. Use of rFVIIa also reduced activated prothrombin time (aPTT) from 58.8 seconds to ~ 30 seconds; however, FEIBA had no effect on aPTT.
Eerenberg conducted a double-blind crossover trial to assess the effects of PCCs[b] versus placebo in reversal of the effects of both dabigatran and rivaroxaban in healthy volunteers.6 Twelve healthy volunteers were randomized to either dabigatran (150 mg twice daily) or rivaroxaban (20 mg twice daily) for 2.5 days. On the third day, patients were given either a PCC or placebo (50 U/kg). The PCC used in this trial was Cofact, a nonactivated PCC containing factors II, VII, IX, and X. After 11 days, patients were crossed-over to the alternate anticoagulant treatment and the study procedures repeated. The results are given in the Table. Overall, PCC had a significant effect on normalizing elevated coagulation parameters following rivaroxaban but had no effects on abnormal coagulation parameters following dabigatran.
[a] FEIBA is an activated prothrombin complex concentrate, containing nonactivated factors I, IX, X, and activated factor VII.
[b] Prothrombin complex concentrates are generally classified as 4-factor and 3-factor concentrates. In the United States, only two PCCs are available (Profilnine and Bebulin), both of which are 3-factor concentrates and contain lower concentrations of factor VII as compared to 4-factor concentrates. Cofact, a 4-factor concentrate, is not available in the United States.
Table. Effects of PCC on anticoagulation with dabigatran and rivaroxaban.6
Anti-coagulant Reversal agent (change from posttreatment) Baseline (after anticoagulant treatment) Post-PCC treatment value PT aPTT ETPa TT ECT PT aPTT ETPa TT ECT Dabigatran NA 59.4 s 7.5 m >120 s 69 s NA 70.3 s 8.7 m Immeasurable prolongation 86 s Rivaroxaban 15.8 s NA 51% NA NA 12.8 sb NA 114%b NA
a Thrombin generation tests assess the change in the thrombin generation by treatment. In this study, the effects of treatment on thrombin generation (as endogenous thrombin potential [ETP]) were measured as lag time to thrombin generation for dabigatran and the potential (as percentage) for thrombin generation for rivaroxaban. Effective reversal of dabigatran would be indicated by a shorter lag time to thrombin generation and an increase in percentage of potential for rivaroxaban.
b Significant change from baseline.
aPTT, activated prothrombin time; ECT, ecarin clotting time; ETP, endogenous thrombin potential; NA, not applicable; PT, prothrombin time; TT, thrombin time.
Other interventions have been suggested for overdoses of dabigatran and rivaroxaban. van Ryn and colleagues have developed an algorithm for treatment of bleeding with dabigatran.3 For mild bleeding, a delay in dosing or discontinuation of the drug has been suggested. For patients with moderate to severe bleeding, treatment recommendations include mechanical compression, surgical intervention, fluid replacement, transfusion, oral charcoal (for ingestions < 2 h before), and hemodialysis. Use of either PCC, FVIIa, and fresh frozen plasma have been suggested by van Ryn and other authors for life-threatening bleeding, as well as charcoal filtration and hemodialysis.3,7 The PCCs have also been suggested for reversal of rivaroxaban, by providing more factor X and Xa.4 However, there is little clinical evidence for these interventions.
Currently, there are no definitive treatments for reversal of the effects of dabigatran or rivaroxaban. One available clinical trial supports the use of PCCs for rivaroxaban-associated bleeding. However, data are limited. Treatment of excess bleeding due to either of these agents needs to be individualized, with close monitoring of patient response.
1. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc: 2011.
2. Xarelto [package insert]. Titusville, NJ; Janssen Pharmaceuticals; 2011.
3. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate-a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost. 2010;103(6):1116-1127.
4. DeLoughery T. Practical aspects of the oral new anticoagulants. Am J Hematol. 2011;86(7):586-590.
5. van Ryn J, Ruehl HD, Preipke H, Hauel N, Wienen W. Reversibility of the anticoagulant effect of high doses of the direct thrombin inhibitor dabigatran, by recombinant factor VIIA or activated prothrombin complex concentrate. Haematologica. 2008;93(Suppl 1):148.
6. Eerenberg E, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrates. Circulation. 2011. Doi. 10.1161/CirculationAHA.111.029017.
7. Watanabe M, Siddiqui F, Qureshi AI. Incidence and management of ischemic stroke and intracerebral hemorrhage in patients on dabigatran etexilate treatment. Neurocrit Care. 2011. Doi. 10.1007/s12028-011-9591-y.
Is there a difference between the nitroglycerin sublingual tablet and spray formulations for the treatment of angina?
Is there a difference between the nitroglycerin sublingual tablet and
spray formulations for the treatment of angina?
Angina is precipitated by a lack of oxygen reaching the heart due to a decrease in coronary blood flow, which can be caused by acute coronary syndromes, physical exertion, or coronary artery spasms.1 Symptoms of angina include sternal pressure (may be described as a burning sensation), pain that radiates to the jaw or arm, or shortness of breath. These symptoms typically last from 30 seconds to 30 minutes and are usually relieved with rest or nitroglycerin. Some patients experience frequent angina, which may not pose an immediate threat to the patient's health if symptoms resolve with rest and nitroglycerin; however, new onset angina or pain that does not resolve with these interventions can be a sign of a life-threatening myocardial infarction.
Sublingual tablet and lingual nitroglycerin spray formulations are approved by the Food and Drug Administration (FDA) for the treatment and prophylaxis of acute angina.2-4 Nitroglycerin is metabolized to nitric oxide, which acts as a potent vasodilator that relaxes smooth muscle. As a result, the vasodilation aids in the redistribution of blood to areas that experienced ischemia due to factors such as plaque lesion and thromboembolism obstruction, artery spasms, or an increased demand for cardiac output.1-4
The recommended dose of sublingual nitroglycerin tablets for acute angina is 0.3 to 0.6 mg dissolved under the tongue at symptom onset.2-4 Administration may be repeated at 5 minute intervals as needed for a maximum of 3 doses within 15 minutes. The recommended dose of lingual nitroglycerin spray is 1 to 2 sprays (0.4 to 0.8 mg) on or under the tongue. Repeat and maximum dosing is the same as indicated for the sublingual tablet. Both formulations may be used as prophylaxis 10 to15 minutes prior to engaging in activities that precipitate angina symptoms.3,4
Clinical Practice Guidelines
The clinical practice guidelines for unstable angina (UA) and non-ST-elevation myocardial infarction (NSTEMI) as well as the ST-elevation myocardial infarction (STEMI) guidelines developed by the American College of Cardiology (ACC) and the American Heart Association (AHA) address the use of nitroglycerin.5,6 Patients who have experienced angina in the past and have been prescribed nitroglycerin by their physician should take 1 sublingual dose at symptom onset. If the pain does not improve or worsens, immediate medical attention should be sought. If pain improves with 1 dose, the dose may be repeated as indicated in the FDA-approved labeling. If symptoms do not completely resolve after repeat doses, immediate medical attention is essential and intravenous nitroglycerin may be warranted. The UA/NSTEMI guidelines do not specify a dose for sublingual nitroglycerin; however, the STEMI guidelines recommend 0.4 mg. All patients with UA/NSTEMI or STEMI should have nitroglycerin sublingual tablets or spray prescribed for the treatment of future angina symptoms. The guidelines do not state a formulation preference.
There have been several clinical trials comparing the efficacy and safety of nitroglycerin sublingual tablets to a spray formulation. A summary of the available trials is provided in the table below.
Table 1. Clinical trials evaluating nitroglycerin sublingual tablet and spray formulations. 7-10
Citation Vandenburg 19867 Wight 19928 Ducharme 19999 Chien 200010 Study Design RCT Duration: 8 weeks Prospective trial Duration: 8 weeks RCT Duration: 1 dose R, XO Duration: treadmill exercise test Patient Population 352 patients (126 females and 226 males; 95% Caucasian) who had a mean angina duration of 4.7 years and a mean frequency of 7 angina attacks/week 783 patients (372 patients ≥ 65 years old and 411 < 65 years old) 20 healthy volunteers (8 females and 12 males; average age of 33) with no known risk factors for CAD 30 CAD patients (5 females and 25 males; average age of 59.4 +/- 8.5 years) with > 50% stenosis in a major artery Subjects had a history of angina, angiography confirmed CAD, and a positive treadmill exercise test Interventions 0.5 mg NTG sublingual tablets 0.4 mg spray 0.5 mg NTG sublingual tablets 0.4 mg spray 0.4 mg NTG sublingual tablets 0.4 mg spray 0.6 mg NTG sublingual tablets 0.4 mg spray Adverse Effects No headache: 58% spray vs. 38% tablet (p < 0.001) Taste disturbance: 4 spray vs. 0 tablet No statistically significant difference in number of events between treatment groups Headache: Fewer spray patients had complaints Taste disturbance: 7 spray vs. 2 tablet Not evaluated No statistically significant difference in number of events between treatment groups Hypotension, dizziness, and headache experienced more frequently with tablets Two tablet patients withdrew from the study due to severe headache Results Pain symptoms were "helped a lot": 80% spray vs. 60% tablet (p < 0.001) Chest pain relief within 1 minute: 70% spray vs. 38% tablet (p < 0.001) Majority of patients in both groups reported that the formulation was convenient to use Number of patients helped with their symptoms: 75% spray vs. 64% tablet (p < 0.05) Relief of symptoms within 1 minute: 62% spray vs. 36% tablet (p < 0.001) Statistically significant reduction in frequency of angina attacks compared to baseline with the spray (p < 0.05) but not with the tablet Tablet: onset and peak effect at 3 minutes with a 5.94 +/- 1.07% diameter increase compared to baseline (p = 0.003); vasodilatory response not statistically significant at 10 minutes compared to baseline Spray: onset of effect at 2 minutes, peak effect at 3 minutes with an 11.27 +/- 1.51% diameter increase compared to baseline (p = 0.0001); vasodilatory response remained statistically significant at 15 minutes compared to baseline No statistically significant difference in maximum vasodilatory response (9 .67 +/- 2.49% tablet vs. 13.32 +/- 1.69% spray; p = 0.25) No statistically significant difference in duration of exercise (399.1+/- 99.8 seconds with spray vs. 408.5 +/- 91.1 seconds with tablets; p = 0.26) No statistically significant difference in time to development of ischemia (355.4 +/-111.2 seconds with spray vs. 336.9 +/- 152.1 seconds with tablets; p = 0.30) Heart rate and systolic blood pressure were higher with spray vs. tablets with a difference of 6.42 bpm (p = 0.009) and 14.64 mm Hg between treatments (p = 0.005)
Abbreviations: bpm=beats per minute; CAD=coronary artery disease; mm Hg=millimeters of mercury; NTG=nitroglycerin; R=randomized; RCT=randomized controlled trial; XO=crossover trial.
The results of these 4 clinical trials demonstrate that nitroglycerin lingual spray formulation has a faster onset, longer duration, and fewer adverse events compared to sublingual tablets.7-10 The spray offered relief within 1 minute for a greater number of patients in the studies conducted by Wight and colleagues and Vandenburg and colleagues.7,8 According to the study by Ducharme, the duration of vasodilatory response was greater with spray compared to tablets, with a statistically significant difference from baseline remaining at 15 minutes.9 In regards to safety and adverse effects, several of the studies reported that headache was experienced more frequently in patients with sublingual tablet administration.7,8,10
Although clinical trials were able to identify subtle differences between nitroglycerin tablet and spray formulations, there are numerous limitations to these studies.7-10 All 4 clinical trials were not blinded; thus, there is a risk of potential bias. In addition, all 4 clinical trials were conducted in outpatients and, therefore, may not be relevant to patients with acute coronary syndromes in the inpatient or emergency department setting. Two of the studies had very small patient populations and other studies do not necessarily reflect the population that uses nitroglycerin for relief of angina.7-10 For example, Ducharme and colleagues conducted a study in 20 young, healthy patients with no known risks for coronary artery disease.9 In addition, the inclusion and exclusion criteria for subjects were not provided by the authors for several studies, which makes it difficult to directly apply the study findings to clinical practice.7-9 Also, the dosing for the sublingual tablets was higher than that of the spray formulations in 3 of the clinical trials.7,8,10
Other factors to consider when choosing between formulations include patient preference and convenience. For example, in patients who experience dry mouth, the spray formulation may be a better alternative, since the dissolution of the spray is not dependent upon patient saliva.11 In patients who are elderly and frail, the sublingual tablet may be a better alternative because these patients may not have the capability or coordination needed to press down on a plunger to administer the spray. The spray can be administered quickly with a lower adverse effect profile; however, the tablet may be more discrete for administration and helps avoid an adverse effect of bitter taste, which has been reported with the spray formulation in clinical trials.7,8
Clinical trials have shown that nitroglycerin spray provides faster angina relief with fewer treatment-associated adverse events when compared to the sublingual tablets. However, the trials available have many limitations and the clinical implications are unclear. Therefore, there is no compelling evidence to support the use of one nitroglycerin formulation over another in the treatment of angina.
1. Talbert RL. Ischemic heart disease. In: Diprio JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York, NY: McGraw-Hill; 2011. Available at: http://www.accesspharmacy.com.proxy.cc.uic.edu/content.aspx?aID=7971879 . Accessed September 1, 2011.
2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard Inc.; 2011. http://clinicalpharmacology-ip.com.proxy.cc.uic.edu/default.aspx . Accessed September 1, 2011.
3. Micromedex Healthcare Series [database online]. Greenwood Village, CO: Thomas Rueters (Healthcare), Inc.; 2011. http://www.thomsonhc.com/micromedex2/librarian. Accessed September 1, 2011.
4. Wickersham RM, ed. Drug Facts and Comparisons. St. Louis, MO: Wolters Kluwer Health; 2011. http://online.factsandcomparisons.com/index.aspx . Accessed September 1, 2011.
5. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 2002 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction). Circulation. 2007;116(7):e148-e304.
6. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). Circulation. 2004;110(9):e82-e292.
7. Vandenburg MJ, Wight LJ, Griffiths GK, Brandman S. Sublingual nitroglycerin or spray in the treatment of angina. Br J Clin Pract. 1986;40(12):524-527.
8. Wight LJ, Vandenburg MJ, Potter CE, Freeth CJ. A large scale comparative study in general practice with nitroglycerin spray and tablet formulations in elderly patients with angina pectoris. Eur J Clin Pharmacol. 1992;42(3):341-342.
9. Ducharme A, Dupuis J, McNicoll S, Harel F,Tardif J. Comparison of nitroglycerin lingual spray and sublingual tablet on time of onset and duration of brachial artery vasodilation in normal subjects. Am J Cardiol. 1999;84(8):952-954.
10. Chien K, Sung F, Chao C, Su T, Chen M, Lee Y. A randomized crossover evaluation of antianginal efficacy and safety of nitrolingual-spray and nitroglycerin tablet form in coronary artery disease patients. Cardiology. 2000;93(3):137-141.
11. Sato H, Koretsune Y, Tanihuchi T, et al. Studies on the response of nitroglycerin oral spray compared with sublingual tablets for angina pectoris patients with dry mouth. A multicenter trial. Arzneimittelforschung. 1997;47(2):128-131.
Written by: Donna Faber, PharmD candidate, class of 2012