August 2011 FAQs
August 2011 FAQs
What is Rivaroxaban's (Xarelto) place in therapy?
What is Rivaroxaban's (Xarelto) place in therapy?
Rivaroxaban (Xarelto by Bayer; Janssen Pharmaceuticals) was approved by the Food and Drug Administration on July 1st as the first and only oral direct factor Xa inhibitor available in the United States .1 It is indicated for the prevention of deep vein thrombosis (DVT) in patients following knee or hip replacement surgery. Rivaroxaban works by competitively inhibiting free and clot-bound factor Xa, which is the coagulation factor at the convergence of the intrinsic and extrinsic pathways of the coagulation cascade.2 The recommended daily dose of rivaroxaban is 10 mg once daily, with or without food, for 35 days in patients undergoing hip replacement surgery and for 12 days inthose undergoing knee replacement surgery.1
Rivaroxaban is different from traditional oral agents such as warfarin in that it does not require any special monitoring or ongoing dose adjustments; however, some clinical considerations for this novel agent include avoidance in patients with severe renal impairment (creatinine clearance [CrCl] < 30 mL/min) and in those with moderate or severe hepatic impairment (Child-Pugh B or C).1 In addition, rivaroxaban is associated with numerous drug interactions via the P-glycoprotein (P-gp) and cytochrome (CYP) 3A4 pathways, and no antidote currently exists to reverse the anticoagulant effects of rivaroxaban.
Rivaroxaban has been studied for prevention of venous thromboembolism (VTE), treatment of VTE, and stroke prevention in patients with atrial fibrillation (AF); ongoing studies for patients with acute coronary syndromes also are under way.3 For prevention of VTE, rivaroxaban 10 mg once daily was compared with enoxaparin, either for hip replacement or knee replacement surgery, in 4 Phase III clinical trials known as the RECORD (Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Vein Thrombosis and Pulmonary Embolism) trials 1 through 4.4-7 Approval of rivaroxaban was based on data from the RECORD 1, 2, and 3 trials.1
In the RECORD 1, 2, and 3 trials, 4,487 patients were treated with rivaroxaban 10 mg/day and 4,524 were given subcutaneous (SC) enoxaparin 40 mg/day. 1 The RECORD 1 and 2 trials were conducted in patients undergoing hip replacement surgery. The mean duration of enoxaparin varied in these 2 trials (RECORD 1: 34 days; RECORD 2: 12 days); rivaroxaban was given for approximately 35 days in both studies.4,5 The results of both trials showed that use of rivaroxaban resulted in a significant relative risk reduction (RRR) for total VTE and major VTE events (proximal DVT, nonfatal pulmonary embolism [PE], or VTE-related death). In RECORD 1, total VTE occurred in 1.1% of rivaroxaban-treated patients versus 3.9% in the enoxaparin group (RRR 71%, 95% confidence interval [CI] 50-83, p<0.001), and in RECORD 2 these values were 2.0% versus 8.4%, respectively, (RRR 76%, 95% CI 59-86, p<0.001).1,4,5
The RECORD 3 trial was conducted in patients undergoing elective total knee replacement surgery and compared rivaroxaban 10 mg/day and SC enoxaparin 40 mg/day each given for a mean duration of 12 days.6 As with the data seen in the hip studies, use of rivaroxaban resulted in a significant RRR for total VTE and major VTE events. The rate of total VTE events was in 9.7% of rivaroxaban-treated patients versus 18.8% in the enoxaparin group (RRR 48%, 95% CI 34-60, p<0.001) and major VTE events occurred in 1.0% and 2.5% of the groups, respectively, (RRR 60%, 95% CI 14-81, p=0.024). 1,6 Similar results were observed in the RECORD 4 trial, which compared rivaroxaban 10 mg/day with SC enoxaparin 30 mg twice daily, both given for 10 to 14 days, after knee replacement surgery.7 In this trial, the rate of total VTE in rivaroxaban-treated patients was 6.9% versus 10.1% in the enoxaparin group (RRR 31.4%, 95% CI 7.5-49.1, p=0.0160).
In addition to the RECORD trials, results from studies such as the EINSTEIN-DVT and ROCKET AF (Rivaroxaban Once Daily Oral Direct Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) have been released.8,9 The EINSTEIN-DVT trial showed that rivaroxaban 15 mg twice daily for the first 3 weeks, followed by rivaroxaban 20 mg once daily thereafter for 3, 6, or 12 months, demonstrated noninferiority to the standard of care (i.e., initial enoxaparin treatment followed by warfarin for prevention of recurrent VTE) in patients with acute symptomatic DVTs.8 The 2 regimens had comparable safety profiles, with first major or clinically relevant non-major bleeding occurring in 8.1% of patients in both groups. When rivaroxaban 20 mg/day was continued for an additional 6 or 12 months in patients who completed an initial 6 to 12 months of treatment, more recurrent VTE events occurred in those given long-term placebo than active treatment (42 events vs. 8 events, p<0.001).
The ROCKET AF trial showed superiority of rivaroxaban 20 mg/day or 15 mg/day for patients with moderate renal impairment compared with dose-adjusted warfarin in reducing the risk of stroke and noncentral nervous system systemic embolism in patients with AF.9 Rates of bleeding in this trial were similar to warfarin; however, bleeding events such as intracranial hemorrhage, critical organ bleeds, and bleeding-related death occurred more frequently in the warfarin group.
As with other anticoagulants, rivaroxaban has a boxed warning for occurrence of spinal/epidural hematoma in patients who are receiving neuraxial anesthesia or undergoing spinal puncture.1 In addition, the drug has warnings for serious and fatal bleeding and a risk of pregnancy-related hemorrhage. When compared with enoxaparin in the RECORD 1, 2, and 3 trials, the rates for a major bleeding event (rivaroxaban 0.3% vs. 0.2% enoxaparin), fatal bleeding event (rivaroxaban <0.1% vs. 0% enoxaparin), and any bleeding event (rivaroxaban 5.8% vs. 5.6% enoxaparin) were similar between groups.
Since rivaroxaban is a substrate for CYP3A4/5, CYP2J2, and the P-gp and ATP-binding cassette G2 transporters (ABCG2), drug interactions are a concern. 1 The labeling recommends the following:
§ Avoid concomitant use with combined P-gp and strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir)
§ Avoid concomitant use with combined P-gp and weak or moderate CYP3A4 inhibitors (e.g., erythromycin) in patients with renal impairment unless the benefit outweighs the bleeding risk
§ Avoid concomitant use with combined P-gp and strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin); or a dose increase of rivaroxaban can be considered (20 mg/day with food)
Rivaroxaban's Place in Therapy
Based on all the available data, rivaroxaban appears to be both safe and efficacious and offers patients a once daily oral alternative to low molecular weight heparins (LMWHs) and warfarin. Rivaroxaban may be a good option for patients who do not want to use SC injections of LMWHs for DVT prophylaxis posthip or knee replacement surgery or as an alternative to warfarin for longer-term management in patients with acute DVTs or for those with AF. Patients who have trouble keeping their INR within range as a result of dietary, drug interaction, or adherence issues may be ideal candidates for rivaroxaban as compared with warfarin.
Dabigatran (Pradaxa by Boehringer Ingelheim) is the other recently approved oral anticoagulant agent indicated to reduce the risk of stroke and systemic embolism in patients with nonvalvular AF.10 This agent has a different mechanism of action than rivaroxaban as it is a direct thrombin inhibitor. As of July 2011, no head-to-head studies have been conducted between dabigatran and rivaroxaban; however, key differences between these 2 agents include their labeled indications, twice daily dosing required for dabigatran versus once daily dosing with rivaroxaban, and fewer drug interactions with dabigatran. In addition, dabigatran can be given to patients with a CrCl between 15 and 30 mL/min at a reduced dose of 75 mg twice daily, whereas rivaroxaban is not recommended for patients with a CrCl <30 mL/min. As with rivaroxaban, dabigatran does not require any special monitoring, has no documented dietary restrictions, and has no known antidote to reverse its anticoagulant effects.
If rivaroxaban is used, clinicians must keep in mind the restrictions on its use in patients with severe renal and moderate to severe hepatic impairment, the potential for drug-drug interactions, the lack of a readily available antidote to reverse its effects, and the cost of this agent in comparison to generic agents such as warfarin and newer oral agents such as dabigatran.
1. Xarelto [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2011.
2. Abrams PJ, Emerson CR. Rivaroxaban: a novel, oral, direct factor Xa inhibitor. Pharmacotherapy. 2009;29(2):167-181.
3. Chen T, Lam S. Rivaroxaban: an oral direct factor Xa inhibitor for the prevention of thromboembolism. Cardiol Rev. 2009;17(4):192-197.
4. Eriksson BI, Borris LC, Friedman RJ, for the RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358(26):2765-2775.
5. Kakkar AK, Brenner B, Dahl OE, for the RECORD2 investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomized controlled trial. Lancet. 2008;372(9632):31-39.
6. Lassen MR, Ageno W, Borris LC, for the RECORD3 investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358(26):2776-2786.
7. Turpie AGG, Lassen MR, Davidson BL, for the RECORD4 investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomized trial. Lancet. 2009;373(9676):1673-1680.
8. EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-2510.
9. Johnson and Johnson. Rivaroxaban significantly reduces risk of stroke in patients with atrial fibrillation with comparable safety versus warfarin in pivotal Phase III study. http://www.jnj.com/connect/news/all/rivaroxaban-significantly-reduces-risk+of-stroke-in-patients-with-atrial-fibrillation-with-comparable-safety-vs-warfarin-in-pivotal-phase-3-study . Accessed July 6, 2011.
10. Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim; 2011.
Magnesium Sulfate Shortage-Are there effective and safe alternatives for the treatment of preeclampsia?
Magnesium Sulfate Shortage-Are there effective and safe alternatives for the treatment of preeclampsia?
American Regent had temporarily suspended distribution of most intravenous electrolytes which has resulted in a national shortage of magnesium sulfate. Both APP and Hospira produce magnesium sulfate and have experienced manufacturing delays and back orders that may continue for an undetermined period. 1
Preeclampsia is a common complication of pregnancy and occurs in 5% to 7% of pregnant women.2 Preeclampsia is more common in first pregnancies, women over 35, those with chronic hypertension, nephropathy or diabetes, women carrying more than a singleton pregnancy, African-American women, and obese patients.3 It is defined as hypertension (>140/90 mm Hg) with proteinuria (>300 mg/protein on a 24-hour urine collection) after 20 weeks of gestation in a female with previously normal blood pressure. Patients with preeclampsia may also develop severe headache, abdominal pain, visual disturbances, elevated liver enzymes, low platelet count (< 100 x 109 per dL), and fetal growth restriction.
Preeclampsia may also occur in women with chronic hypertension.3 Often this presents as a rapid increase in blood pressure in early gestation , new onset proteinuria or worsening of proteinuria or development of HELLP syndrome (Hemolysis, Elevated Liver enzymes and Low Platelets). Reports indicate that 10% to 20% of women with severe preeclampsia may develop HELLP syndrome.4,5 Severe preeclampsia can result in new-onset seizures (eclampsia), stroke, intracranial hemorrhage, preterm delivery, and increased mortality for both the mother and infant.
Magnesium sulfate versus other agents
Intravenous magnesium sulfate is the first-line agent for seizure prevention and treatment in preeclampsia/eclampsia. There have been numerous reports of the treatment of preeclampsia that compare magnesium sulfate with placebo and with other anticonvulsants. In a recent meta-analysis that included 15 trials and over 11,000 patients, magnesium sulfate was shown to reduce the risk of eclampsia by 50% when compared to placebo or no anticonvulsant. 6 There was also a reduction in the risk of placental abruption. The analysis also compared magnesium sulfate to phenytoin in 4 trials of 2,343 women, to diazepam in 2 trials, and in single trials against nimodipine, methyl dopa, and nitrates. Magnesium sulfate decreased the risk of eclampsia (relative risk [RR] 0.08, 95% confidence interval [CI] 0.01 to 0.60) compared to phenytoin when data from 3 of these trials were assessed. Data with diazepam was not sufficient to draw any conclusions; there were only 66 patients randomized to receive diazepam or magnesium sulfate in the 2 trials. The risk of eclampsia was lower for women allocated to magnesium sulfate compared to nimodipine (RR 0.33, 95% CI 0.14 to 0.77). The single trials for methyl dopa and nitrates were also too small to draw any reliable conclusions. A recent search of PubMed revealed that there are no data to suggest that other magnesium salts may be used for preeclampsia.
Recommendations for preeclampsia/eclampsia
The most recent guidelines on hypertensive disorders in pregnancy, including preeclampsia, are from the Society of Obstetricians and Gynecologists of Canada.7 Magnesium sulfate is the first-line agent, although phenytoin or benzodiazepines have been used with limited success if there is a contraindication to or failure of magnesium. The recommendation of magnesium sulfate as a first-line agent is consistent with the 2002 American College of Obstetrics and Gynecology (ACOG) guidelines.3
In addition, pregnant women with elevated blood pressure should be treated with appropriate antihypertensive agents to maintain blood pressure within a normal range.3 Urgent therapy is recommended for diastolic blood pressure of 105 to 110 mm Hg or higher. Agents that are used for treatment of hypertensive urgency in pregnancy are shown in Table 1.
Table 1 . Antihypertensive treatment for preeclampsia. 3
Agent Dose Hydralazine 5 to 10 mg intravenous (IV) push every 15 to 20 minutes until desired effect. Labetalol Give 20 mg IV push. A second IV dose of 40 mg can be given after 10 minutes if no effects are seen. Then 80 mg IV every 10 minutes to maximum dose of 220 mg.
There are some additional steps that can be taken to reduce the risk of preeclampsia. Pregnant women with low dietary intake of calcium, defined as <600 mg/day, should receive supplemental calcium of at least 1 g/day.7 The addition of calcium supplements has been shown to reduce the risk of preeclampsia and preterm delivery. The addition of low-dose aspirin should be considered pre-pregnancy or by 16 weeks gestation in women with low calcium, with therapy continued until delivery.7 There is no evidence for any short or long term adverse effects on the fetus in this population.
Women with preeclampsia should be carefully monitored and receive intravenous magnesium sulfate as first-line for prevention and treatment of severe preeclampsia/eclampsia. Since there are no agents that have been shown to be as effective as magnesium sulfate in preventing eclampsia, it is important for hospital pharmacies to maintain an adequate supply of magnesium sulfate for use in severe preeclampsia.
Recommendations for conserving magnesium sulfate supplies:
- Until the current drug shortage is resolved, limit the use of magnesium sulfate to patients with preeclampsia/eclampsia.
- Remove magnesium sulfate from floor-stock in all areas except labor and delivery and possibly the emergency room.
- Do not substitute other magnesium salts in preeclampsia. As this time, there are no data on the use of other salts of magnesium for preeclampsia.
1. American Society of Heath System Pharmacists. Current drug shortages: Magnesium sulfate shortage. http://www.ashp.org/DrugShortages/Current/Bulletin.aspx?id=757. Accessed July 23, 2011.
2. Lindheimer MD, Taler SJ, Cunningham FG. ASH Position Paper: Hypertension in pregnancy. J Clin Hypertens. 2009;11(4):214-225.
3. American College of Obstetricians and Gynecologists. Diagnosis and management of preeclampsia and eclampsia. ACOG Practice Bulletin no 33. Obstet Gynecol. 2002;99(1):159-167.
4. Sibai BM, Ramadan MK, Usta I, Salama M, Mercer BM, Freidman SA. Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). Am J Obstet Gynecol. 1993;169(4):1000-1006.
5. Haram K, Svendsen E, Abildgaard. The HELLP syndrome: clinical issues and management. BMC Pregnancy Childbirth. 2009;9(8):1-15.
6. Duley L, Gülmezoglu AM, Henderson-Smart DJ, Chou D. Magnesium sulphate and other anticonvulsants for women with pre-eclampsia. Cochrane Database of Syst Rev. 2010;11:CD000025.
7. Society of Obstetricians and Gynecologists of Canada. Diagnosis, evaluation and management of hypertensive disorders of pregnancy. J Obstet Gynaecol Can. 2008;30(3 suppl 1):S1-S48.
What are alternatives to N-acetylcysteine as a mucolytic?
What are alternatives to N-acetylcysteine as a mucolytic?
N-acetylcysteine (NAC) is a mucolytic agent approved as adjuvant therapy for patients with abnormal or viscid mucous secretions associated with chronic bronchopulmonary diseases, cystic fibrosis, or other conditions associated with mucous obstruction.1 It is also the treatment of choice for acetaminophen overdose. At the time of this writing, NAC is one of the many therapeutic agents affected by drug shortages.2 Since NAC is first-line therapy for acetaminophen overdose, it use should be restricted to that indication. This paper will review other pharmacologic agents used as a mucolytic in various populations.
Conditions associated with mucus dysfunction
Mucus is essential to normal lung function, providing hydration to lung tissues and also moving bacteria and other potential pathogens out of the lung tissue.3,4 Mucus is cleared from the respiratory tract by ciliary action; clearance can be affected by mucus quality and quantity, as well as ciliary function. Increased production of mucin (a glycoprotein and the major constituent of mucus), ciliary damage, or alterations in periciliary liquid volume induced by various inflammatory respiratory diseases can change the characteristics of mucus and impair its clearance. Accumulation of mucus can worsen inflammation of the respiratory tract and increase the risk for infection. A number of inflammatory respiratory diseases can result in mucus dysfunction, including cystic fibrosis, chronic obstructive pulmonary disease (COPD), noncystic fibrosis bronchiectasis, and bronchiolitis. 4,5
Treatment of mucus dysfunction
Various pharmacologic agents are used in the treatment of inflammatory respiratory diseases, including corticosteroids and antibiotics, to decrease mucin production/secretion or to treat respiratory tract infections.4 Nonpharmacologic and pharmacologic therapies are also used to promote clearance of mucus. Chest percussion, postural drainage, or other methods that promote cough (such as exercise) have been used in patients with cystic fibrosis. Medical devices are also used to aid in mucus clearance including handheld flutter valves and high frequency chest compression systems (vests). Bronchodilators may have a short-term effect on mucus clearance by increasing luminal diameter. Mucolytic agents (dornase alfa and hypertonic saline) can promote mucus clearance through several mechanisms with an end result of reducing mucus viscosity.4,6
Dornase alfa is a recombinant form of human deoxyribonuclease I, an enzyme that cleaves DNA and is indicated to improve lung function in patients with cystic fibrosis.7 Extracellular DNA is released by degenerating leukocytes that accumulate in pulmonary secretions in patients with cystic fibrosis, increasing mucus viscosity. Dornase alfa hydrolyzes this extracellular DNA to reduce concentrations and reduce mucus viscosity. Use and efficacy of dornase alfa appear to be limited to cystic fibrosis, in which higher pulmonary concentrations of extracellular DNA are seen compared to other inflammatory respiratory diseases.4,6 However, several studies have evaluated the use of dornase alfa for treatment of mucus dysfunction from noncystic fibrosis conditions in pediatric and adults patients.
Riethmueller and colleagues conducted a retrospective observational study on the use of intratracheally instilled dornase alfa in 63 mechanically-ventilated pediatric patients with atelectasis or pulmonary infiltrates.8 Dornase alfa 0.1 mg/kg was instilled via an endotracheal tube twice daily in 46 of the patients until extubation. Outcomes were compared to historical controls with atelectasis who were treated with 0.9% saline. Among 35 patients with atelectasis, 74% showed improvement 24 hours after treatment with dornase alfa (p=0.003 from baseline). In contrast, only 6% of the historical control group showed improvement (p=0.41).
A similar study was conducted by Hendriks and colleagues.9 Use of dornase alfa for pediatric patients with atelectasis was evaluated retrospectively. Dornase alfa was given via nebulization (2.5 mg) or endotracheally (0.25 mg) twice daily until atelectasis improved. Following dornase alfa, median chest x-ray scores improved within 24 hours, from 4 to 2 (p<0.001), in 22 of 30 patients with evaluable data. Atelectasis resolved completely in 3 patients; 17 patients improved, no change was seen in 2, and 3 patients worsened. Clinical variables (respiratory rate, carbon dioxide partial pressure, and fraction of inspired oxygen) were also significantly improved from baseline following dornase alfa. No change was seen in heart rate. The authors noted that 3 patients deteriorated immediately following dornase alfa administration, likely due to rapid mobilization of mucus.
Boogaard and colleagues evaluated the use of dornase alfa in infants with respiratory syncytial virus (RSV)-bronchiolitis.10 A total of 225 oxygen-dependent infants with RSV-bronchiolitis were randomly assigned to treatment with either dornase alfa 2.5 mg or placebo nebulized twice daily until supplemental oxygen was no longer needed or the patient transferred to an intensive care unit (ICU). The primary outcome was the duration of hospital stay. Secondary outcomes included supplemental oxygen use, ICU admission, and symptom resolution. No significant difference was seen in the primary outcome, with mean hospital stays of 4.4 and 3.8 days for dornase alfa and placebo, respectively, regardless of baseline symptom scores. Use of supplemental oxygen was also similar-2.6 and 2.0 days for dornase alfa and placebo, respectively. Only age and baseline symptoms scores were found to be significant variables for length of hospital stay.
Nasr and colleagues conducted a smaller, double-blind, randomized trial, enrolling 75 pediatric patients with RSV bronchiolitis.11 Dornase alfa (2.5 mg) or placebo were given once daily via nebulization. Of the variables measured-respiratory rate, wheezing, retraction, and chest x-ray scores-improvement with dornase alfa over placebo was only seen for chest x-ray. Patients given dornase alfa had a 0.46 improvement compared with a -0.60 worsening in chest x-rays (p<0.001).
O'Donnell and colleagues evaluated the effects of dornase alfa in 349 adult outpatients with stable idiopathic bronchiectasis.12 Patients were randomized to treatment with either dornase alfa 2.5 mg or placebo twice daily for 24 weeks in a double-blind fashion. The primary outcome was the rate of protocol-defined exacerbations, with change in pulmonary function tests as secondary outcomes. Protocol-defined exacerbations included abnormalities in 4 of 9 pulmonary symptoms. Nonprotocol-defined exacerbations were also assessed, which included events with less than 4 symptoms. The rate of protocol-defined exacerbations was higher with dornase alfa treatment compared with placebo-0.66 versus 0.56-for a relative risk (RR) of 1.17 (95% confidence interval [CI], 0.85 to 1.65). Nonprotocol-defined exacerbations were also increased with treatment, RR 2.01 (95% CI, 1.15 to 3.50) and reached statistical significance. The risk of combined exacerbations was 1.35 (95% CI, 1.01 to 1.79). Secondary outcomes favored placebo, with greater improvement in forced vital capacity (FVC; 0.3% vs. -3.4%), less antibiotic use (44.1 vs. 56.9 d), and rates of hospitalization (0.21 vs. 0.39/patient/168 d). The authors concluded that not only was dornase alfa ineffective for these patients, it could potentially cause harm. Literature searches have revealed no additional relevant information on the use of dornase alfa in adult patients without cystic fibrosis.
Hypertonic (3% to 7%) saline has also been used to promote mucus clearance in various inflammatory respiratory diseases by drawing water from the airway epithelium to rehydrate the periciliary layer. It has been investigated in both pediatric and adult patients for various inflammatory respiratory disorders, including cystic fibrosis, bronchiolitis, and COPD. There are no comparative studies of hypertonic saline and NAC for mucus clearance in these chronic respiratory disorders.
Efficacy of hypertonic saline in the treatment of patients with cystic fibrosis has recently been reviewed by Pettit and Johnson.13 Use of hypertonic saline resulted in 14% to 23.8% improvement in mucociliary clearance from baseline. The largest study included in the review was by Elkins. In this study, 164 patients (mean 18 y) with stable cystic fibrosis were randomized to treatment with either 7% hypertonic saline or 0.9% saline via nebulizer twice daily for 48 weeks.14 All patients received a bronchodilator prior to nebulization of the study drug. The primary outcome measured for efficacy was the linear rate of change in lung function from baseline. The absolute difference in lung function between the 2 groups was a secondary outcome. The percent change in mucociliary clearance was not reported. At 48 weeks no significant difference was seen in the linear slope for lung function, based on forced expiratory volume in 1 second (FEV1), FVC, and forced expiratory flow at 25% to 75% of FVC (FEF 25-75), with p=0.79. When the absolute change in lung function was examined, both FVC and FEV1 showed greater improvements from baseline with hypertonic saline compared with 0.9% saline. The absolute differences in FEV1 and FVC were 68 mL (95% CI, 3 to 132) and 82 mL (95% CI, 12 to 153), respectively. The difference for FEF25-75 did not reach statistical significance (39 mL, 95% CI, -67 to 146).
A Cochrane review on the use of 3% to 7% hypertonic saline in cystic fibrosis found the treatment to improve lung function in comparison to placebo.15 Twelve trials (enrolling 442 patients age 6 to 46 y) were included in the analysis. Compared to placebo, the difference in FEV 1 at 4 weeks was 4.15 (95% CI, 1.14 to 7.16) in favor of hypertonic saline. This difference was not maintained at week 48. Similarly, mean percent change in FVC was greater with hypertonic saline at 4 weeks, with no difference seen at 48 weeks. Hypertonic saline was compared to dornase alfa in 2 trials, with one showing no difference between treatments in regards to FEV1 and the other favoring dornase alfa.
Al-Ansari compared 5%, 3%, and 0.9% saline for the treatment of acute bronchiolitis in infants.16 Treatment consisted of 5 mL of study drug with 1.5 mL of epinephrine every 4 hours until discharge. A total of 187 patients with viral bronchiolitis were randomized to treatment. Efficacy outcomes were the change in acute bronchiolitis Wang severity scores at 24, 48 (primary), and 72 hours after treatment The Wang system is based on scores for respiratory rate, wheezing, retraction, and general condition, with higher scores indicating more severe disease. At 48 hours, mean severity scores were 3.69, 4,00, and 4.12 for 5%, 3% and 0.9% saline, respectively. Only the 5% saline was significantly different from 0.9% (p=0.04). No difference was seen between treatments at 24 hours (3.75, 4.00, and 3.97 for 5%, 3%, and 0.9%, respectively). A trend was seen throughout 72 hours favoring 5% saline. Length of hospital stay was also similar between the treatment groups (p=0.53). The rates of return to the emergency department after discharge did not differ between groups, ranging from 59% to 63% (p=0.91).
Grewal also compared 3% saline to normal saline, both with epinephrine, for treatment of acute bronchiolitis. 17 Forty-six infants with acute respiratory distress were randomly assigned to nebulized 3% or 0.9% saline given up to 2 times during a 120-minute evaluation period. All patients received racemic epinephrine in addition to the study drug. The primary outcomes were the change in Respiratory Assessment Change Score (RACS) and in oxygen saturation from baseline to 120 minutes. Hospital admission and return emergency department visits were assessed as secondary outcomes. No difference was seen between the 2 groups for the primary outcomes. Change in RACS was 4.39 for 3% saline and 5.13 for 0.9% saline (95% CI for difference, -1.45 to 2.93). Change in oxygen saturation was similar between groups (95% CI for difference, -0.50 to 4.06). No difference was seen in hospital admissions or return emergency department visits.
In contrast to the finding by Grewal, a Cochrane review found 3% saline to be effective for treatment of bronchiolitis in infants.18 Four trials (254 infants) were included in the analysis. Compared with 0.9% saline, 3% saline resulted in significantly shorter hospital stays (-1.16 d for difference, p<0.00001) and lower clinical severity scores on day 1 posttreatment (-0.95 for difference, p=0.04). However, other outcomes, including rate of hospitalization, rate of readmission, and posttreatment day 2 severity scores did not differ significantly between the groups.
Valderramas compared 3% saline to 0.9% saline in adult patients with COPD in a randomized, double-blind trial.19 Patients received 5 mL of either treatment nebulized, along with an 8-week exercise training program and patients' regular medications. The primary outcome was the 6-minute walk test. General health status, measured using the Medical Outcomes Study 36-item short-form survey, was a secondary outcome. A total of 68 patients with moderate to severe COPD were enrolled. Following the 8-week program, both groups' functional activity (by the 6-minute walk test) improved from baseline (p<0.001). However, the normal saline group had a greater improvement than the 3% saline group (p<0.001). Dyspnea was improved in both groups with no significant difference between treatments (p=0.08). Quality of life was also improved for both groups with normal saline having significant improvement from baseline in all 8 domains compared with 6 for 3% saline.
The current shortage of NAC has required the use of other mucolytic agents for mucus clearance in the treatment of inflammatory respiratory diseases. Only two other mucolytic agents are available for use-dornase alfa and hypertonic saline. The primary use of dornase alfa is in the treatment of cystic fibrosis-because of its mechanism of action, its efficacy in other inflammatory respiratory diseases appears to be limited. Current guidelines on the treatment of cystic fibrosis recommend either dornase alfa or 7% hypertonic saline for treatment of symptomatic infants (<2 years of age) as well as to improve lung function and reduce the risk of exacerbations in children >6 years.20,21
Hypertonic saline (3% to 7%) has been used in cystic fibrosis as well as other inflammatory respiratory diseases. Although data are available for children, less literature is available in the adult population. Some efficacy has been seen in adult patients with COPD and guidelines from the British Thoracic Society recommend the use of hypertonic saline as adjuvant therapy for clearing the lung pathway in patients with bronchiectasis.22
Although data are limited, hypertonic saline, 3% to 7%, would appear to be a viable alternative to NAC when a mucolytic is needed. In select patients with cystic fibrosis, dornase alfa may also be suitable.
1. Acetylcysteine inhalant [package insert]. Shirley, NY: American Regent, Inc.; 2005.
2. American Society of Health-systems Pharmacists. Drug shortages: current drugs. http://www.ashp.org/DrugShortages/Current/. Accessed July 28, 2011.
3. Voynow JA, Rubin BK. Mucins, mucus, and sputum. Chest. 2009;135(2):505-512.
4. Fahy JV, Dickey BF. Airway mucus function and dysfunction. N Engl J Med. 2010;363(23):2233-2247.
5. Braman SS, Abu-Hijleh M. The spectrum of nonasthmatic inflammatory airway diseases in adults. Otolaryngol Clin North Am. 2010;43(1):131-146.
6. Rogers DF. Mucoactive agents for airway mucus hypersecretory diseases. Respir Care. 2007;52(9):1176-1193.
7. Pulmozyme [package insert]. San Francisco, CA: Genentech, Inc; 2005.
8. Riethmueller J, Kumpf M, Borth-Bruhns T, et al. Clinical and in vitro effect of dornase alfa in mechanically ventilated pediatric non-cystic fibrosis patients with atelectases. Cell Physiol Biochem. 2009;23(1-3):205-210.
9. Hendriks T, de Hoog M, Lequin MH, Devos AS, Merkus PJ. DNase and atelectasis in non-cystic fibrosis pediatric patients. Crit Care. 2005;9(4):R351-356.
10. Boogaard R, de Jongste JC, Merkus PJ. Pharmacotherapy of impaired mucociliary clearance in non-CF pediatric lung disease: a review of the literature. Pediatr Pulmonol. 2007;42(11):989-1001.
11. Nasr SZ, Strouse PJ, Soskolne E, et al. Efficacy of recombinant human deoxyribonuclease I in the hospital management of respiratory syncytial virus bronchiolitis. Chest. 2001;120(1):203-208.
12. O'Donnell AE, Barker AF, Ilowite JS, Fick RB. Treatment of idiopathic bronchiectasis with aerosolized recombinant human DNase I. rhDNase Study Group. Chest. 1998;113(5):1329-1334.
13. Pettit RS, Johnson CE. Airway-rehydrating agents for the treatment of cystic fibrosis: past, present, and future. Ann Pharmacother. 2011;45(1):49-59.
14. Elkins MR, Robinson M, Rose BR, et al. A controlled trial of long-term inhaled hypertonic saline in patients with cystic fibrosis. N Engl J Med. 2006;354(3):229-240.
15. Wark P, McDonald VM. Nebulised hypertonic saline for cystic fibrosis. Cochrane Database Syst Rev. 2009;(2):CD001506.
16. Al-Ansari K, Sakran M, Davidson BL, El Sayyed R, Mahjoub H, Ibrahim K. Nebulized 5% or 3% hypertonic or 0.9% saline for treating acute bronchiolitis in infants. J Pediatr. 2010;157(4):630-634.
17. Grewal S, Ali S, McConnell DW, Vandermeer B, Klassen TP. A randomized trial of nebulized 3% hypertonic saline with epinephrine in the treatment of acute bronchiolitis in the emergency department. Arch Pediatr Adolesc Med. 2009;163(11):1007-1012.
18. Zhang L, Mendoza-Sassi RA, Wainwright C, Klassen TP. Nebulized hypertonic saline solution for acute bronchiolitis in infants. Cochrane Database Syst Rev.2008;(4):CD006458.
19. Valderramas SR, Atallah AN. Effectiveness and safety of hypertonic saline inhalation combined with exercise training in patients with chronic obstructive pulmonary disease: a randomized trial. Respir Care. 2009;54(3):327-333.
20. Flume PA, O'Sullivan BP, Robinson KA, et al. Cystic fibrosis pulmonary guidelines: chronic medications for maintenance of lung health. Am J Respir Crit Care Med. 2007;176(10):957-969.
21. Cystic Fibrosis Foundation, Borowitz D, Robinson KA, et al. Cystic Fibrosis Foundation evidence-based guidelines for management of infants with cystic fibrosis. J Pediatr. 2009;155(6 Suppl):S73-93.
22. Pasteur MC, Bilton D, Hill AT. British Thoracic Society guideline for non-CF bronchiectasis. Thorax. 2010;65:i1-i58. doi:10.1136/thx.2010.136119.