July 2016 FAQs

What evidence is available for the use of fluorescein for gastrointestinal and genitourinary procedures?

Introduction

Fluorescein is a diagnostic dye that is approved for angiography or angioscopy of the retina.¹ When exposed to electromagnetic radiation or blue light (wavelength 465 to 490 nm), fluorescein produces a yellowish-green light (fluorescence, wavelength 520 to 530 nm). Fluorescein is poorly water soluble and highly protein bound, so it remains in the vasculature and does not penetrate epithelial tissue unless there is a break in the epithelial layer.² Therefore, after intravenous (IV) administration fluorescein can be used to visualize blood vessels and identify areas of tissue damage. Fluorescein has been used for diagnostic purposes in many settings including lymph node mapping, visualization of peripheral vasculature, neurosurgery, and dermatologic/cosmetic surgery. This article summarizes the published evidence for the use of fluorescein in the gastrointestinal (GI) and genitourinary (GU) tracts.

Assessment of bowel ischemia and viability

Multiple observational studies and case reports support the use of fluorescein for visualization of mesenteric and intestinal ischemia and viability.^3-8 In a prospective study without randomization, fluorescein 1000 mg given IV over 30 to 60 seconds, Doppler, and clinical judgment were compared for the assessment of viability of 71 ischemic bowel segments in 28 patients.⁵ The use of fluorescein was significantly more accurate than clinical judgment (100% vs 89 ± 9%, p<0.04) and had a significantly higher specificity, predictive value, and accuracy compared to Doppler (all p<0.05). A retrospective study of 186 patients who underwent aortic reconstruction and received fluorescein 500 to 1000 mg IV for the evaluation of colonic perforation during surgery found that fluorescein had a specificity of 100% for assessing colon perfusion.⁴ The authors concluded that fluorescein should be used to reduce the incidence of clinically significant ischemic colitis after aortic surgery. Another retrospective study of 16 patients who underwent second-look abdominal exploration for mesenteric ischemia found similar rates of accuracy and predictive value between fluorescein (56% and 60%, respectively) and pulse palpation/clinical judgment (50% and 63%, respectively).³ The fluorescein dose was not reported, which limits the extrapolation of these results.

Several cases report more definitive diagnoses or more conservative surgical outcomes after use of fluorescein.^6-8 The use of fluorescein 500 mg IV for assessment of bowel viability following laparoscopic gastric bypass allowed the patient in one case report to receive a limited bowel resection despite extensive bowel ischemia.⁶ In another case report, a section of ischemic bowel after appendectomy was identified with fluorescein (dose not specified) after clinical assessment did not produce a definitive conclusion about the presence of ischemia.⁸ A case report of fluorescein injection (dose not specified) during surgery for superior mesenteric artery repair/ligation confirmed a lack of intestinal ischemia and prevented revascularization and resection.⁷

Assessment of intestinal histology

Confocal laser endomicroscopy procedures
Confocal laser endomicroscopy (CLE) is a noninvasive method of visualizing cellular and vascular structures of the intestines and identifying neoplastic intestinal lesions through a process known as “virtual biopsy”.⁹ Fluorescein is used during CLE to facilitate the visualization of blood vessels. A prospective observational study in 16 patients who underwent CLE of the colon and received fluorescein 500 mg IV found that fluorescence was significantly increased (p<0.001) in patients with colonic adenomas compared to patients without adenoma, due to increased vascular permeability at the adenoma site. ¹⁰ In addition, the biopsy samples obtained during the CLE procedure retained the fluorescence after tissue processing and did not need additional staining prior to analysis. A similar prospective observational study in 35 patients found that the procedure had a sensitivity of 93.9% (95% confidence interval [CI] 85.4% to 97.6%) and specificity of 95.9% (95% CI 86.2% to 98.9%) for real-time adenoma diagnosis with an overall accuracy of 94.8% (95% CI 89.1% to 97.6%).¹¹ In a case report, signet ring cell carcinoma of the gastric antrum was successfully diagnosed using CLE with fluorescein 500 mg IV, which was administered after CLE alone did not result in a diagnosis.¹²

Fluorescein can also be used with CLE for non-neoplastic indications. A prospective observational study in 45 patients undergoing CLE of the colon who received fluorescein 10 mg/kg IV (up to 500 mg) reported the successful visualization of normal intestinal histopathology.¹³ Successful differentiation between ulcerative colitis and Crohn’s disease was reported in a prospective observational study of 79 patients who underwent colonoscopy for CLE and received fluorescein 500 mg IV.¹⁴ In separate case reports, ipilumab-induced colitis and intestinal healing post-recurrent Clostridium difficile infection were successfully diagnosed with fluorescein-assisted CLE (doses not specified).^15,16 In a prospective observational study in 63 patients, CLE with fluorescein 500 mg IV was used to diagnose Barrett’s esophagus and Barrett’s-associated neoplastic changes.¹⁷

Other procedures
Thirty three patients who had colonic polyps in a prospective observational study received fluorescein 1 mg/kg IV before colonoscopy.¹⁸ Compared to autofluorescence imaging without fluorescein, visualization with fluorescein had a higher specificity (16.7% vs 91.7%, p=0.004) and similar sensitivity for differentiating between neoplastic and non-neoplastic polyps. Compared to white light endoscopy, the use of fluorescein had a significantly higher sensitivity and specificity (both p=0.031) for identifying neoplastic polyps.

In a prospective nonrandomized study in 13 premature infants with suspected necrotizing enterocolitis, the use of fluorescein 14 mg/kg IV during laparoscopy allowed for accurate identification of ischemic bowel in 8 infants.¹⁹ In 3 of these patients, ischemic bowel was not found during standard laparoscopy but was identified with the use of fluorescein.

Miscellaneous gastrointestinal procedures

Visualization of bleeding/leakage
In case reports, fluorescein has been used to visualize bleeding or leakage at sites in the GI tract.^20-22 A case report describes the efficacy of fluorescein 500 mg injection mixed in 125 mL of fruit juice for the visualization of esophageal leak drained by tube thoracostomy.²⁰ The presence of fluorescence in the effluent confirmed the esophageal leak without the need for more invasive testing. Duodenal bleeding was diagnosed after the administration of fluorescein 500 mg IV in another case report.²¹ A case report noted the effectiveness of fluorescein 1000 mg via the intraarterial jejunal catheter for visualization of obscure GI bleeding from a small bowel arteriovenous malformation.²²  

Visualization during laparoscopic cholecystectomy
A case series reported the efficacy of fluorescein 7.5 mg/kg IV for visualization of the biliary system in 5 patients undergoing laparoscopic cholecystectomy.²³ The fluorescence lasted for the duration of the surgery in all 5 patients and may have prevented unintended injury to the bile duct during the surgical procedure.

Genitourinary procedures

Bladder procedures
Several studies and cases describe the use of fluorescein during bladder procedures.^24-26 In a prospective observational study of 15 patients who underwent bladder angiography for interstitial cystitis or transurethral resection of bladder tumors, the use of fluorescein 250 to 500 mg IV facilitated the visualization of bladder tumors.²⁶ Previously unrecognized pathologies were also identified in 2 patients due to the use of fluorescein (carcinoma in situ of the bladder neck and invasive bladder cancer). A prospective observational study in 27 patients reported the use of fluorescein for visualization of bladder neoplasia using CLE.²⁵ Patients received fluorescein 100 mg IV (n=10), intravesical administration of fluorescein 300 to 500 mg diluted in 0.9% sodium chloride (dilution volume not specified) instilled into the bladder via Foley catheter and left to dwell for 5 minutes (n=5), or administration by both routes (n=12). The authors reported notable differences between bladder tissue, low grade tumors, and high grade tumors in all patients. A case series of 12 patients reported the use of IV fluorescein for visualization of ureteral jets during cystoscopy.²⁴ Doses of 10 to 100 mg were used, but 3 patients experienced yellowing of the sclera and palms with the 100 mg dose so subsequent patients received lower doses (50 mg, 25 mg, or 10 mg).

Ovarian procedures
There is little data to support the use of fluorescein during ovarian procedures.^27,28 One case report describes the use of fluorescein 700 mg (10 mg/kg) IV to diagnose uterine tissue necrosis after uterine inversion, which led to the patient undergoing hysterectomy at the time of diagnosis rather than during a later procedure.²⁸ In a prospective observational study, 11 patients received fluorescein 500 mg IV during surgery for adnexal torsion to evaluate the viability of ovarian tissue after untwisting.²⁷ The use of fluorescein allowed 8 patients to retain the affected ovary after confirmation of tissue viability.

Conclusion

Numerous observational studies and case reports support the efficacy of single doses of fluorescein for diagnostic and interventional procedures of the GI and GU tracts that require enhanced visualization. However, the available studies are small, uncontrolled, and limited by heterogeneity in the procedures performed and assessment methods/outcomes used. None of the studies or case reports observed any major safety concerns with the use of fluorescein. A survey of 16 surgical centers that used fluorescein for CLE in 2272 patients noted only minor adverse events such as temporary yellow skin discoloration, nausea, erythema at the injection site, and transient decreases in blood pressure.²⁹ Green-colored urine has also been reported.²⁵ Overall, these limited efficacy reports suggest that fluorescein is a useful diagnostic aid in many procedures of the GI and GU tracts, with no major safety concerns in this setting. Prospective studies with comparisons to other diagnostic dyes are needed to further establish the efficacy, safety, and place in therapy for fluorescein.

References
1.    Ak-Fluor [package insert]. Lake Forest, IL: Akorn Inc; 2011.
2.    Roberts HW, Donati-Bourne JF, Wilson VL, Wilton JC. The use of live fluorescence staining techniques in surgery: a review. J Invest Surg. 2013;26(5):283-293.
3.    Ballard JL, Stone WM, Hallett JW, Pairolero PC, Cherry KJ. A critical analysis of adjuvant techniques used to assess bowel viability in acute mesenteric ischemia. Am Surg. 1993;59(5):309-311.
4.    Bergman RT, Gloviczki P, Welch TJ, et al. The role of intravenous fluorescein in the detection of colon ischemia during aortic reconstruction. Ann Vasc Surg. 1992;6(1):74-79.
5.    Bulkley GB, Zuidema GD, Hamilton SR, O'Mara CS, Klacsmann PG, Horn SD. Intraoperative determination of small intestinal viability following ischemic injury: a prospective, controlled trial of two adjuvant methods (Doppler and fluorescein) compared with standard clinical judgment. Ann Surg. 1981;193(5):628-637.
6.    Gribar SC, Hamad GG. Ischemic bowel after laparoscopic Roux-en-Y gastric bypass: limited resection based on fluorescein assessment of bowel viability. Surg Obes Relat Dis. 2007;3(5):561-563.
7.    Kopatsis A, D'Anna JA, Sithian N, Sabido F. Superior mesenteric artery aneurysm: 45 years later. Am Surg. 1998;64(3):263-266.
8.    Paral J, Cecka F, Chobola M. Fluorescein dye and ultraviolet light technique in diagnosis of small bowel ischaemia. ANZ J Surg. 2010;80(10):762-763.
9.    Gheonea DI, Saftoiu A, Ciurea T, Popescu C, Georgescu CV, Malos A. Confocal laser endomicroscopy of the colon. J Gastrointestin Liver Dis. 2010;19(2):207-211.
10.    Coron E, Mosnier JF, Ahluwalia A, et al. Colonic mucosal biopsies obtained during confocal endomicroscopy are pre-stained with fluorescein in vivo and are suitable for histologic evaluation. Endoscopy. 2012;44(2):148-153.
11.    Xie XJ, Li CQ, Zuo XL, et al. Differentiation of colonic polyps by confocal laser endomicroscopy. Endoscopy. 2011;43(2):87-93.
12.    Neumann H, Vieth M, Siebler J, Bernatik T, Neurath MF, Boxberger F. Fluorescein-aided endomicroscopy for detection of signet ring cell carcinoma. Endoscopy. 2011;43 Suppl 2 UCTN:E199-200.
13.    Odagi I, Kato T, Imazu H, Kaise M, Omar S, Tajiri H. Examination of normal intestine using confocal endomicroscopy. J Gastroenterol Hepatol. 2007;22(5):658-662.
14.    Tontini GE, Mudter J, Vieth M, et al. Confocal laser endomicroscopy for the differential diagnosis of ulcerative colitis and Crohn's disease: a pilot study. Endoscopy. 2015;47(5):437-443.
15.    Hundorfean G, Atreya R, Agaimy A, et al. Fluorescein-guided confocal laser endomicroscopy for the detection of ipilimumab-induced colitis. Endoscopy. 2012;44 Suppl 2 UCTN:E78-79.
16.    Hundorfean G, Agaimy A, Chiriac MT, et al. In vivo detection of mucosal healing-involved histiocytes by confocal laser endomicroscopy. World J Gastroenterol. 2012;18(32):4447-4449.
17.    Kiesslich R, Gossner L, Goetz M, et al. In vivo histology of Barrett's esophagus and associated neoplasia by confocal laser endomicroscopy. Clin Gastroenterol Hepatol. 2006;4(8):979-987.
18.    Lim LG, Bajbouj M, von Delius S, Meining A. Fluorescein-enhanced autofluorescence imaging for accurate differentiation of neoplastic from non-neoplastic colorectal polyps: a feasibility study. Endoscopy. 2011;43(5):419-424.
19.    Numanoglu A, Millar AJ. Necrotizing enterocolitis: early conventional and fluorescein laparoscopic assessment. J Pediatr Surg. 2011;46(2):348-351.
20.    Brevetti GR, Napierkowski MT, Maher JW. Assessment of esophageal leak with oral fluorescein. Am J Gastroenterol. 1997;92(1):165-166.
21.    McWhorter JH, Roe DC, Schneir ES. Fluorescein angioscopy in occult gastrointestinal hemorrhage. W V Med J. 1986;82(8):272-273.
22.    Ohri SK, Jackson J, Desa LA, Spencer J. The intraoperative localization of the obscure bleeding site using fluorescein. J Clin Gastroenterol. 1992;14(4):331-334.
23.    Mohsen AA, Elbasiouny MS, Fawzy YS. Fluorescence-guided laparoscopic cholecystectomy: a new technique for visualization of biliary system by using fluorescein. Surg Innov. 2013;20(2):105-108.
24.    Doyle PJ, Lipetskaia L, Duecy E, Buchsbaum G, Wood RW. Sodium fluorescein use during intraoperative cystoscopy. Obstet Gynecol. 2015;125(3):548-550.
25.    Sonn GA, Jones SN, Tarin TV, et al. Optical biopsy of human bladder neoplasia with in vivo confocal laser endomicroscopy. J Urol. 2009;182(4):1299-1305.
26.    Zimmern PE, Laub D, Leach GE. Fluorescein angiography of the bladder: technique and relevance to bladder cancer and interstitial cystitis patients. J Urol. 1995;154(1):62-65.
27.    McHutchinson LL, Koonings PP, Ballard CA, d'Ablaing G, 3rd. Preservation of ovarian tissue in adnexal torsion with fluorescein. Am J Obstet Gynecol. 1993;168(5):1386-1388.
28.    Romo MS, Grimes DA, Strassle PO. Infarction of the uterus from subacute incomplete inversion. Am J Obstet Gynecol. 1992;166(3):878-879.
29.    Wallace MB, Meining A, Canto MI, et al. The safety of intravenous fluorescein for confocal laser endomicroscopy in the gastrointestinal tract. Aliment Pharmacol Ther. 2010;31(5):548-552.

July 2016

The information presented is current as of May 27, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What is the evidence to support the new 2016 heart failure update and place in therapy of the new heart failure agents?

Heart failure is a disease state with significant morbidity and mortality that affects a significant number of the United States population.¹ It is estimated that there are 915,000 new cases of heart failure annually within the United States. Heart failure was mentioned as an attributed cause of mortality in over 300,000 cases in 2013 which is similar to the 287,000 heart failure deaths in 1995. The incidence of heart failure is approximately 10 per 1000 people among those aged 65 years and older.^1,2  The prevalence is predicted to grow by as much as 46% between 2012 and 2030, which will lead to more than 8 million adults with heart failure.¹ Heart failure is also a significant burden to healthcare and was responsible for over a million admissions in 2013. Total healthcare costs in 2013 due to heart failure were estimated to be $30.7 billion, 68% of which was due to direct medical costs. By 2030, it is projected that the total cost will reach $69.7 billion, a 127% increase.

Heart failure exists when the heart is unable to perform optimally either due to issues with contraction in patients with systolic heart failure, also known as heart failure with reduced ejection fraction (HFrEF) and/or relaxation in patients with diastolic heart failure, also referred to as heart failure with preserved ejection fraction (HFpEF).³ Heart failure with reduced ejection fraction is described most often as a left ventricular ejection fraction (LVEF) of 40% or less. The most common causes of HFrEF are myocardial infarction (MI), hypertension, diabetes, or dilated cardiomyopathies. The pathophysiology of heart failure involves a complex relationship between structural, functional, and biological factors.² A compensatory response to poor cardiac output results in the activation of endogenous neurohormones (e.g., norepinephrine, angiotensin II, aldosterone, and vasopressin) which play a major role in vasoconstriction, sodium-water retention, and ventricular remodeling leading to heart failure progression.^2,3 Treatment with the intent to antagonize these neurohormones has been shown to improve morbidity and mortality for heart failure patients.

The stages of heart failure have been described by the American College of Cardiology/ American Heart Association (ACC/AHA) task force.⁴ Stage A includes patients who are at high risk for heart failure but without any structural disease or symptoms. Stage B is for asymptomatic patients with existing structural heart disease. Stage C includes patients who have existing structural heart disease and with current or prior symptoms. Stage D is the most severe stage and describes patients with refractory heart failure which requires specialized interventions. While the ACC/AHA classification focuses on the development and progression of heart failure, the New York Heart Association (NYHA) classification system focuses more on exercise capacity and symptoms of the disease. Patients who fall into NYHA Class I have no limitation of physical activity. Class II describes symptoms of heart failure with ordinary physical activity, but none at rest. Class III is when a marked reduction in physical activity is noted, and less than ordinary physical activity results in symptoms. Class IV describes heart failure symptoms at rest or the inability to perform any physical activity without heart failure symptoms. Both classification systems may be used to guide treatment in patients with heart failure.

2013 Standards of Care for Heart Failure with Reduced Ejection Fraction

Pharmacological treatments which have been proven to improve morbidity and mortality for patients with HFrEF include agents which inhibit the renin-angiotensin system, beta-blockers, aldosterone antagonists, and a combination of hydralazine and nitrates in select patient populations. In 2013, the American College of Cardiology Foundation (ACCF) and the AHA published guidelines for the management of heart failure.⁴ It is recommended for patients in ACC/AHA stages B through D with a reduced LVEF to receive treatment with an angiotensin-converting enzyme (ACE) inhibitor. While the use of ACE inhibitors has the most robust mortality data in HFrEF patients with a history of MI or acute coronary syndrome (ACS), it is also recommended for all HFrEF patients in ACC/AHA stages B through D to prevent symptomatic heart failure. Patients who cannot tolerate ACE inhibitors can receive treatment with an angiotensin-II receptor blocker (ARB) instead. Beta-blockers are recommended for all patients with ACC/AHA stages C and D heart failure and for stage B patients with a history of MI or ACS. Aldosterone antagonists are recommended for ACC/AHA stage C patients with NYHA class II to IV heart failure and a LVEF of 35% or less. Additionally, aldosterone antagonists are recommended to reduce morbidity and mortality in patients who have LVEF 40% or less following an acute MI who develop heart failure symptoms or who have a history of diabetes mellitus. Since 2013, 2 new agents with novel mechanisms of action have been developed that provide additional morbidity and mortality benefit to patients with HFrEF, sacubutril/valsartan and ivabradine. The ACC, AHA, and Heart Failure Society of America (HFSA) have recently published a focused update which defines the place in therapy of these agents.⁵  The evidence that supports the inclusion of these 2 new agents into the guidelines is discussed below.

Sacubutril/Valsartan

Sacubutril/valsartan was approved by the Food and Drug Administration (FDA) in July 2015. The agent is a combination of valsartan, an ARB, and sacubutril, a neprilisyn inhibitor. Neprilisyn is an endopeptidase which degrades several vasoactive peptides, such as natriuretic peptides, bradykinin, and adrenomedullin.⁶ By inhibiting neprilisyn, levels of vasoactive peptides are increased which counteract the neurohormonal activation seen in heart failure. When used in combination with a renin-angiotensin inhibitor in experimental studies, beneficial effects were better than either agent alone. Sacubutril has been combined with an ARB instead of first-line ACE inhibitors because of the high rate of life-threatening angioedema seen when used with ACE inhibitors. Because of this, the concomitant use of sacubutril/valsartan and ACE inhibitors is contraindicated.⁷ Additionally, sacubutril/valsartan is contraindicated in patients who have any history of angioedema with an ACE inhibitor or ARB, with the concomitant use of aliskiren in patients with diabetes, or hypersensitivity to either agent.

The PARADIGM-HF (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilisyn Inhibitor] with ACE Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) Trial was a randomized, double-blind, parallel-group, active-control, two-arm, event-driven trial that compared the efficacy and safety of sacubutril/valsartan to enalapril in patients with HFrEF.⁸ Study participants included those who were 18 years or older in NYHA class II to IV, LVEF of 35% or less, serum brain natriuretic peptide (BNP) of at least 150 pg/mL (or n-terminal prohormone BNP [NT-proBNP] of at least 600 pg/mL) at screening or a BNP of at least 100 pg/mL (or NT-proBNP of at least 400 pg/mL) plus a hospitalization for heart failure within the last 12 months, and on a stable dose of a beta-blocker and ACE inhibitor or ARB equivalent to enalapril 10 mg daily.⁶ There were extensive exclusion criteria for the trial, some of which included systolic blood pressure less than 110 mmHg at screening, serum potassium greater than 5.2 mmol/L at screening, estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73m², and a history of angioedema or unacceptable side effects to ACE inhibitors or ARBs. The primary outcome of the study was a composite of death from cardiovascular causes or first hospitalization for heart failure. Secondary outcomes included time to death from any cause, change from baseline to 8 months in the Kansas City Cardiomyopathy Questionnaire (KCCQ; higher scores indicate fewer symptoms), the time to new onset atrial fibrillation, and the time to first occurrence of a decline in renal function (defined as end-stage renal disease or a decrease in the eGFR by at least 50% from randomization).

After patients completed 2 separate single-blind run-in periods with enalapril 10 mg twice daily followed by sacubutril/valsartan titrated to 200 mg twice daily, 8442 underwent randomization and received either enalapril 10 mg twice daily (n=4212) or sacubutril/valsartan 200 mg twice daily (n=4187).⁶ Patients were followed every 2 to 8 weeks for the first 4 months, then every 4 months thereafter with a median duration of follow up of 27 months. Dose reductions were allowed for adverse effects. Patients were well balanced between both groups; the average age was 63.8 years in both groups, with the majority being men (78.2%). Most patients were Caucasian (66%), and patients from western and central Europe represented slightly over 55% of the study participants in both arms. Over 90% of all patients in the study fell into either NYHA class II or III. Over 90% of patients were also taking a beta-blocker and using either an ACE inhibitor or ARB prior to screening. The average LVEF was 29.6% in the sacubutril/valsartan group and 29.4% in the enalapril group.

The primary outcome of composite cardiovascular death or hospital admission for heart failure was statistically significant with 21.8% events in the sacubutril/valsartan arm and 26.5% events in the enalapril arm (hazard ratio [HR] 0.80; 95% confidence interval [CI] 0.73 to 0.87; p<0.001).⁶ Subgroup analysis of the primary endpoint favored the combination treatment in most groups, except for patients 75 years and older, patients with NYHA class III or IV, and patients with no prior history of ACE inhibitor use in whom there were no statistically significant differences between treatment groups. Additionally, among the races analyzed (White, Black, Asian, Native American and Other), only Whites and patients classified as “other” demonstrated a significant difference in the primary endpoint with sacubutril/valsartan compared to enalapril.

Individually, each outcome was also statistically significant.⁶ Death from cardiovascular causes occurred in 13.3% of patients in the sacubutril/valsartan arm and 16.5% in patients treated with enalapril (HR 0.80, 95% CI 0.71 to 0.89; p<0.001) and first hospitalization for worsening heart failure was seen in 12.8% of patients receiving sacubutril/valsartan and 15.6% with enalapril (HR 0.79, 95% CI 0.71 to 0.89; p<0.001). Death from any cause was also significant, occurring in 17% of those receiving sacubutril/valsartan and 19.8% in those receiving enalapril (HR 0.84, 95% CI 0.76 to 0.93; p<0.001). The decrease in the KCCQ clinical summary score was smaller in the sacubutril/valsartan group compared to the enalapril group (p=0.001). New onset atrial fibrillation and decline in renal function were not found to be statistically significant. Significant adverse events that were observed in the trial included symptomatic hypotension (14% with sacubutril/valsartan vs 9.2% with enalapril; p<0.001), elevated serum creatinine of at least 2.5 mg/dL (3.3% with sacubutril/valsartan vs 4.5% with enalapril; p=0.007), serum potassium > 6 mmol/L (4.3% with sacubutril/valsartan vs 5.6% with enalapril; p<0.001), and cough (11.3% with sacubutril/valsartan vs 14.3% with enalapril; p<0.001). Patients receiving sacubutril/valsartan had more episodes of angioedema (0.45%) compared to the enalapril arm (0.24%), however this was not found to be statistically significant.

The authors of the study concluded that the outcomes of this study are clinically significant. For the first time since beta-blockers, a new novel mechanism of action has shown to have mortality benefit for patients with HFrEF.⁶ The use of sacubutril/valsartan not only reduced the risk of cardiovascular death or hospitalization due to heart failure but also all-cause mortality, with the number needed to treat to prevent one death from cardiovascular causes of 32 patients. This benefit was seen without a significant increase in adverse events when compared to enalapril, more patients had symptomatic hypotension, but this did not lead to a significantly different drop-out rate compared to enalapril (0.9% for sacubutril/valsartan vs 0.7% for enalapril; p=0.38).

Ivabradine

Ivabradine was approved by the FDA in April 2015 to reduce hospitalization for worsening heart failure. Ivabradine is an inhibitor of the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel, which results in inhibition of the I_f channel within the sinoatrial node. ^9,10 This selective mechanism of action results in a reduced heart rate without other cardiovascular effects such as decreased contractility, making it an ideal target for patients with HFrEF.¹¹ Ivabradine is contraindicated for use in patients with acute decompensated heart failure, blood pressure less than 90/50 mmHg, sick sinus syndrome, sinoatrial block, or third-degree AV block (unless a functioning demand pacemaker is present), resting heart rate of less than 60 bpm, severe hepatic impairment, pacemaker dependence (defined as a heart rate maintained exclusively by the pacemaker), and concomitant use of strong cytochrome P450 3A4 inhibitors.⁹

The SHIFT (Systolic Heart Failure Treatment with the I_f Inhibitor Ivabradine Trial) was a randomized, multinational, event-driven, double-blind, placebo-controlled, parallel-group trial that compared ivabradine to placebo in 6505 patients with moderate-to-severe heart failure and left-ventricular systolic dysfunction.¹⁰  Study participants included adults with stable symptomatic chronic heart failure, LVEF less than or equal to 35%, a hospital admission for worsening heart failure within the previous year, and patients had to be in normal sinus rhythm with a resting heart rate (HR) of 70 beats per minute (bpm) or higher based on a 12-lead electrocardiogram on 2 separate visits prior to randomization. Pertinent exclusion criteria included recent MI within the last 2 months, atrial fibrillation or atrial flutter, symptomatic hypotension, and ventricular or atrioventricular pacing active for 40% or more of the day. Concomitant drug therapy with non-dihydropyridine calcium channel blockers, class I antiarrhythmic agents, and strong cytochrome P450 3A4 inhibitors was not allowed at inclusion or during the study.

Patients were randomized at day 0 to either ivabradine (n=3241) starting at 5 mg twice daily or a matching placebo (n=3264).¹⁰ At day 14, doses were titrated up to to 7.5 mg twice daily if the resting HR was greater than 60 bpm; if the resting heart rate was between 50 to 60 bpm, the dose remained at 5 mg twice daily. For patients who had a resting HR less than 50 bpm or had symptomatic bradycardia, the dose was decreased to 2.5 mg twice daily. Beginning at day 28, follow-up visits were every 4 months until completion and doses were titrated at these visits similar to the day 14 follow-up.  For patients receiving 2.5 mg twice daily, if resting HR was less than 50 bpm or symptomatic bradycardia occurred, treatment was stopped. The median duration for follow up was 22.9 months. The primary endpoint of this study was a composite of cardiovascular death or hospital admission for worsening heart failure. Secondary endpoints included a composite of cardiovascular death or hospital admission for patients receiving at least 50% of a target beta-blocker dose at randomization, all-cause mortality, cardiovascular death, admission for worsening heart failure, all-cause hospital admission, cardiovascular admission, death from heart failure, and a composite of cardiovascular death, hospital admission for worsening heart failure, or admission for non-fatal MI.

The average age of study participants was slightly over 60 years in both groups.¹⁰ Males accounted for about 75% of all study participants. Caucasians encompassed 89% of the total patient population within both groups. Average resting heart rate prior to randomization was 79.7 bpm in the ivabradine group and 80.1 bpm in the placebo group. Ninety-nine percent of patients in both groups were classified in either NYHA class II or III with an average LVEF of 29%. Beta-blockers were used in 89% and 90% of patients in the ivabradine and placebo group, respectively. Prior to randomization, 56% percent of patients within both groups were taking at least 50% of a target beta-blocker dose and 26% were receiving the target dose of a beta-blocker in each group.

The primary endpoint was met by 24% of patients within the ivabradine group and 29% of patients in the placebo group (HR 0.82, 95% CI 0.75 to 0.90; p<0.0001). This outcome was driven largely by hospital admissions for worsening heart failure (16% with ivabradine versus 21% with placebo [HR 0.74; 95% CI 0.66 to 0.83; p<0.0001]) rather than cardiovascular death (14% with ivabradine versus 15% with placebo [HR 0.91, 95% CI 0.80 to1.03; p=0.128]). The primary outcome was significant for all prespecified subgroups except for patients who had a baseline resting heart rate less than 77 bpm and patients 65 years and older. All-cause hospital admissions was found to be statistically significant, which occurred in 38% of patients receiving ivabradine versus 42% of patients receiving placebo (HR 0.89, 95% CI 0.82 to 0.96; p=0.003). The use of ivabradine resulted in statistically fewer deaths from heart failure (3%) versus placebo (5%; HR 0.74, 95% CI 0.58 to 0.94; p=0.014) and fewer cardiovascular admissions with ivabradine (30%) versus placebo (34%; HR 0.85, 95% CI 0.78 to 0.92). All-cause mortality was not statistically significantly different between groups. A similar number of patients reported adverse events (75% ivabradine and 74% placebo). Patients receiving ivabradine had significantly more symptomatic bradycardia (5% versus 1%, p<0.0001), asymptomatic bradycardia (6% versus 1%, p<0.0001), and phosphenes or enhanced brightness in a restricted area of the visual field (3% versus 1%, p<0.0001). Although not found to be statistically significant, more patients taking ivabradine had blurred vision (1% versus <1%) and atrial fibrillation (9% versus 8%). The number of patients who dropped out due to adverse events was similar between both groups. 

The authors of this trial concluded the use of ivabradine achieved significance of its primary outcome largely driven by fewer hospital admissions for heart failure and heart failure death, which were seen within the first 3 months of the trial.¹⁰ The population that was enrolled received treatment according to evidence-based guidelines with the majority of patients receiving both a beta-blocker and ACE inhibitor or ARB. The subgroup analysis showed that patients with a baseline resting heart rate of 77 bpm or greater had more benefit from ivabradine versus those with a lower baseline resting heart rate. The authors concluded that patients who confer the most benefit from ivabradine are those who receive the largest reduction in resting heart rate, which correlates with those that have higher baseline resting heart rates. Although almost 90% of all patients were using concomitant beta-blockers, there was a low incidence of bradycardia, and only 1% of patients withdrew due to this adverse event. Ivabradine may offer an alternative mechanism of lowering heart rate and improving morbidity and mortality in HFrEF who cannot achieve target doses of a beta-blocker and have a higher resting HR.

Conclusion

Based on the evidence from the PARADIGM-HF and SHIFT trials, the ACC/AHA/HFSA recently published an update to the 2013 guidelines which provides recommendations for implementation of these agents in therapy.⁵ For patients with Stage C HFrEF with chronic symptomatic HFrEF in NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement with sacubutril/valsartan is recommended to further reduce morbidity and mortality. This recommendation is a class I recommendation (strong), with B-R level of evidence, meaning that the evidence is of moderate-quality with support from 1 or more RCTs or meta-analysis of moderate-quality RCTs. If patients have a history of angioedema, sacubutril/valsartan is not recommended based on consensus expert opinion. Hypotension, angioedema, and renal insufficiency are the main adverse effects associated with sacubutril/valsartan.

Ivabradine is recommended for patients with NYHA class II or III HFreF (LVEF of 35% or less), who are receiving guideline-directed evaluation and management, including a beta-blocker at maximum tolerated doses and are in sinus rhythm with a resting heart rate of at least 70 bpm. This is a class IIa recommendation (weak), with B-R level of evidence.  Adverse effects that have occurred more frequently with ivabradine compared to placebo include bradycardia and vision changes. As clinical uptake of these recommendations progresses and clinical experience with these agents increases, more data will be available that may modify these current recommendations.

References

1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics – 2016 update:  a report from the American Heart Association. Circulation. 2016;133(4):e38-e360.
2. Jessup M. Brozena S. Heart failure. N Engl J Med. 2003;348(20):2007-2018.
3. Parker RB, Nappi JM, Cavallari LH. Chronic heart failure. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach. 9^th ed. New York, NY: McGraw-Hill; 2014. http://accesspharmacy.mhmedical.com.proxy.cc.uic.edu/content.aspx?bookid=689&Sectionid=45310471. Accessed June 15,2016.
4. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA Guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):e240-327.
5. Yancy CW, Jessup M, Bozkurt B, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure. Circulation. 2016 May 20. [epub ahead of print]
6. McMurray JJ. Packer M. Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993-1004.
7. Entresto [package insert]. East Hanover, NJ: Novartis AG; 2015.
8. McMurray JJ, Packer M, Desai AS, et al. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: a rationale for and design of the prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial (PARADIGM-HF). Eur J Heart Fail. 2013;15(9):1062–1073.
9. Corlanor [package insert]. Thousand Oaks, CA: Amgen Inc.; 2015.
10. Swedberg K, Komajda M, Bohm M, et al. Ivabridine and outcomes in heart failure (SHIFT): a randomised placebo-controlled study. Lancet. 2010;376(9744):875-885.
11. Bohm M, Swedberg K, Komajda M, et al. Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet. 2010;376(9744):886-894.

July 2016

Prepared by:
Mike Schmidt, PharmD
PGY1 Pharmacy Practice Resident
College of Pharmacy
University of Illinois at Chicago

The information presented is current as of June 15, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What is the comparative evidence on use of IV acetaminophen versus oral acetaminophen? 

Background

In 2010, the Food and Drug Administration approved intravenous (IV) acetaminophen (Ofirmev®) in the United States.^1,2 This agent has been available in Europe since 2002. Intravenous acetaminophen carries indications for mild to moderate pain and fever, and the dosing is very similar to oral acetaminophen.³ In fact, the conversion from IV acetaminophen to oral acetaminophen is one to one in patients who weigh 50 kg or more. Intravenous acetaminophen achieves up to a 70% higher maximum plasma concentration than oral acetaminophen after administration, but overall exposure is similar between the 2 formulations. Moreover, the IV formulation reaches this maximal concentration faster than either oral or rectal formulations.⁴ Both rectal and oral acetaminophen formulations are pregnancy category B, while IV acetaminophen carries the pregnancy category C designation because this formulation has not been studied in pregnant women.^3,4 Intravenous acetaminophen can be used in children 2 years and older while the oral and rectal acetaminophen formulations can be prescribed to children younger than this age.

Intravenous acetaminophen, however, possesses several disadvantages. This formulation may lead to infections, phlebitis, and irritation due to the IV route of administration.² The agent can be administered only as a 15 minute infusion, which is a much longer administration time than the oral or rectal formulations.^2,3  Clinical trials that led to approval of IV acetaminophen were all placebo-controlled. Another concern is the increasing price of IV acetaminophen. One source discusses tripling of the price from $12.43 per vial in January 2013 to $35.40 per vial in May 2014, which resulted in a $160,555 cost increase for hip, knee, or spine surgeries for each hospital with significant utilization of IV acetaminophen.⁵ Due to these disadvantages, controversy exists regarding appropriate use of IV acetaminophen compared to oral and rectal formulations. The goal of this article is to discuss comparative evidence of IV acetaminophen versus oral acetaminophen.

Evidence

The number of studies that have compared IV acetaminophen to the oral formulation that report patient outcomes is extremely limited. The majority of trials focusing on IV acetaminophen are single-center and have small sample sizes.⁴ Several comparative studies showed differences in postoperative acetaminophen concentrations between formulations but patient outcomes were not studied.^2,6,7

Table 1 lists the comparative studies that included patient outcomes within their endpoints. The trial performed by Pettersson and others in patients undergoing coronary bypass grafting was the first trial to show a potential benefit of IV acetaminophen over the oral formulation for reduction of opioid use.⁸ However, the clinical significance for the difference in the amount of rescue opioids used is questionable as the mean opioid dose was 17.4 mg in the IV acetaminophen group and 22.1 mg in the oral acetaminophen group.^2,8 Ketobemidone, which is similar to morphine, was the opioid utilized as a rescue medication post-operatively. This agent is not available in the United States, and therefore, the applicability of the study results to the United States population may be limited. About 65% of patients enrolled in the study experienced  breakthrough pain, which also brings to question the efficacy of the protocol involving acetaminophen for pain control in patients with coronary bypass grafting.⁴

Other trials listed within Table 1 show similar outcomes with oral versus IV acetaminophen.^9-11 The trial by Brett and colleagues showed statistically significant differences for acetaminophen levels post-procedure for 2 formulations but the difference in mean pain scores, use of postoperative fentanyl, and the time spent in the recovery area did not reach statistical significance.¹² The other 2 trials showed similar pain scores or mean morphine equivalent dose of opioids between oral and IV acetaminophen groups.^9,10 In fact, the trial in children undergoing clefting procedure revealed that administration of oral acetaminophen led to a faster ability to tolerate feedings compared to the administration of IV acetaminophen but statistical significance was not reported.⁹

A recent systematic review by Jibril and colleagues attempted to define the role of IV acetaminophen in comparison to oral acetaminophen.² The systematic review included 6 randomized trials that measured efficacy, safety, or pharmacokinetic outcomes between the 2 formulations. The data synthesis did not find any differences in efficacy between IV and oral acetaminophen, and safety was difficult to assess due to lack of consistency in safety outcomes among included trials.  The IV formulation displayed greater bioavailability than oral acetaminophen but pharmacokinetic differences did not result in significant differences in efficacy. Therefore, the authors concluded that the current literature does not support use of IV acetaminophen when patients are able to tolerate oral formulation.  

Conclusion

Although IV acetaminophen reaches a higher maximum concentration at a faster rate than oral acetaminophen after administration, the currently available literature does not support that IV acetaminophen results in better patient outcomes than oral acetaminophen. The comparative trials between IV and oral acetaminophen are low quality due to small sample size and single-center design. Numerous drawbacks exist with IV acetaminophen including high cost and risk for infections, phlebitis, and irritation. Therefore, IV acetaminophen should be reserved for patients unable to tolerate oral intake, otherwise, oral acetaminophen is the preferred agent.

Table 1. Comparative studies of IV acetaminophen versus oral acetaminophen that report efficacy as part of outcomes.^8-11

References

1.         Drugs@FDA [database online]. Silver Spring, MD: Food and Drug Administration; 2016. https://www.accessdata.fda.gov/scripts/cder/drugsatfda/. Accessed June 23, 2016.

2.         Jibril F, Sharaby S, Mohamed A, Wilby KJ. Intravenous versus oral acetaminophen for pain: systematic review of current evidence to support clinical decision-making. Can J Hosp Pharm. 2015;68(3):238-247.

3.         Ofirmev [package insert]. San Diego, CA: Cadence Pharmaceuticals; 2013.

4.         Yeh YC, Reddy P. Clinical and economic evidence for intravenous acetaminophen. Pharmacotherapy. 2012;32(6):559-579.

5.         Poeran J, Babby J, Rasul R, Mazumdar M, Memtsoudis SG, Reich DL. Tales from the Wild West of US drug pricing: the case of intravenous acetaminophen. Reg Anesth Pain Med. 2015;40(3):284-286.

6.         van der Westhuizen J, Kuo PY, Reed PW, Holder K. Randomised controlled trial comparing oral and intravenous paracetamol (acetaminophen) plasma levels when given as preoperative analgesia. Anaesth Intensive Care. 2011;39(2):242-246.

7.         Singla NK, Parulan C, Samson R, et al. Plasma and cerebrospinal fluid pharmacokinetic parameters after single-dose administration of intravenous, oral, or rectal acetaminophen. Pain Pract. 2012;12(7):523-532.

8.         Pettersson PH, Jakobsson J, Owall A. Intravenous acetaminophen reduced the use of opioids compared with oral administration after coronary artery bypass grafting. J Cardiothorac Vasc Anesth. 2005;19(3):306-309.

9.         Nour C, Ratsiu J, Singh N, et al. Analgesic effectiveness of acetaminophen for primary cleft palate repair in young children: a randomized placebo controlled trial. Paediatr Anaesth. 2014;24(6):574-581.

10.       Fenlon S, Collyer J, Giles J, et al. Oral vs intravenous paracetamol for lower third molar extractions under general anaesthesia: is oral administration inferior? Br J Anaesth. 2013;110(3):432-437.

11.       Brett CN, Barnett SG, Pearson J. Postoperative plasma paracetamol levels following oral or intravenous paracetamol administration: a double-blind randomised controlled trial. Anaesth Intensive Care. 2012;40(1):166-171.

12.       Skolnick BE, Mathews DR, Khutoryansky NM, Pusateri AE, Carr ME. Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects. Blood. 2010;116(5):693-701.

July 2016

The information presented is current as of June 23, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.