February 2011 FAQs
February 2011 FAQs
What drugs are likely to interfere with urine drug screens?
What drugs are likely to interfere with urine drug screens?
Urine drug screens (UDS) are a frequent practice used to detect common drugs of abuse. On-site drug screening is performed for a variety of medical, professional, and legal reasons. A few scenarios in which screening may be done are listed below:1
Reasons for urine drug screening1
- Suspicion of drug abuse (e.g., unexplained negligence/impairment/behavior)
- Random testing outlined in employment contract
- Military service
- Sports participation
- Legal/criminal (e.g., postaccident, parole)
- Drug-therapy compliance monitoring
- Drug abuse rehabilitation monitoring
- Postmortem investigation
Urine drug screens are generally performed using either immunoassays or gas chromatography-mass spectrometry (GC-MS).2 Immunoassay UDS contain specific antibodies against common drugs of abuse and their metabolites. The immunoassay is the most commonly used UDS because it is inexpensive and rapid. Five different immunoassays are available: cloned enzyme donor immunoassay, enzyme-multiplied immunoassay (EMIT), fluorescence polarization immunoassay (FPIA), and immunoturbidimetic assay radioimmunoassay (RIA). The substances most commonly tested by a typical immunoassay include amphetamines, cannabinoid metabolites, cocaine metabolites, opiate metabolites, and phencyclidine (PCP). Expanded immunoassays are available to test for tricyclic antidepressants, barbiturates, methadone, alcohol, and benzodiazepines and may be beneficial when use of these substances is suspected. One major problem with immunoassays is a false-positive result. Therefore, a more specific confirmatory test, such as GC-MS, is needed to confirm a positive finding with an immunoassay. GC-MS is more accurate than an immunoassay, but it is more expensive and time consuming.1 GC-MS breaks down drug molecules into ionized fragments and identifies substances based on mass-to-charge ratio using a mass spectrometer.
Although blood, hair, nails, or saliva can be used, most screening is done using urine samples.2 Ease of collection, higher drug concentrations, and longer durations of detection are primary reasons for using urine samples for drug screening. Table 1 lists common drugs of abuse and their duration of detection in the urine.
Table 1. Length of time drugs of abuse can be detected in the urine.1,2
Drug/drug class Detection time Drug/drug class Detection time Alcohol 7 to 12 hours Marijuana Amphetamine 48 hours Single use 3 days Methamphetamine 48 hours Moderate use (4x/week) 5 to 7 days Barbiturates Daily use 10 to 15 days Short-acting 24 hours Long-term heavy smoker >30 days Long-acting 3 weeks Opiates Benzodiazepine Codeine 48 hours Short-acting 3 days Heroin (morphine) 2 to 4 days Long-acting 30 days Hydromorphone 2 to 4 days Cocaine metabolites 2 to 4 days Methadone 3 days Morphine 48 to 72 hours Oxycodone 2 to 4 days Propoxyphene 6 to 48 hours Phencyclidine 8 days
Collection Methods and Criteria
Proper urine collection methods must be used to avoid false-negative results. Urine should be collected in a tamper-evident container under supervision if necessary.1 Criteria for legitimate urine samples include:
- A volume of 30 mL or more
- Temperature between 32▫C and 38▫C
- pH of 4.5 to 8.5
- Nitrates <500 mcg/mL
- Specific gravity >1.002 and <1.020
- Creatinine >20 mg/dL
Urine samples with characteristics outside of these ranges, or with a cloudy or dark appearance, may be adulterated in some manner, either diluted or substituted.
Urine Drug Test Results
The United States Department of Health and Human Services (DHHS) sets the threshold for drug concentrations for detection by UDS.2 Drug concentrations in the urine below this level are reported as negative. Table 2 contains a list of these values. However, despite standardization, inaccurate results can occur.
Table 2. Standard threshold levels for screening and confirmatory tests 1,3
Drug/drug class Immunoassay screena (ng/mL) GC/MS confirmationa (ng/mL) Amphetamine and methamphetamine 1000 500 Barbiturates 300 200 Benzodiazepines 300 200 Cocaine metabolite (benzoylecgonine) 300 150 Marijuana metabolites (delta-9-tetrahydrocannabinol-9-carboxylic acid) 50 15 Methadone 300 200 Opiates (codeine and morphine) 2,000 2,000 Phencyclidine 25 25 Propoxyphene 300 200
a Standard cutoff levels; alternate cutoff levels may be available.
Abbreviation: GC-MS, Gas chromatography-mass spectrometry.
False negatives are uncommon but can occur as a result of low drug concentrations in the urine, tampering, and in other situations. Possible reasons for false-negative results include: 1,2
- Dilute urine (excess fluid intake, diuretic use, pediatric sample)
- Infrequent drug use
- Prolonged time since last use
- Recent ingestion
- Insufficient quantity ingested
- Metabolic factors
- Inappropriate test used
- Elevated urine lactate
- Tetrahydrozoline (eye drops)
- Lemon juice
- Drain cleaner
- Table salt
- Various chemicals (glutaraldehyde, sodium or potassium nitrate, pyridinium chlorochromate, and peroxide/peroxidase)
Understanding the UDS and ordering the appropriate test can prevent false-negative results. Results from an immunoassay or a GC-MS can be deceiving, as these tests may not be able to detect every drug in a particular drug class.2 This particularly pertains to the opiate and amphetamine/methamphetamine immunoassays. For example, a test for opiates will detect morphine and drugs that are metabolized to morphine, such as codeine and heroin. Heroin itself can only be detected for up to 8 hours after use. After 8 hours, only the morphine metabolite of heroin will be detected in the urine by immunoassay or by GC-MS. Other opiates such as fentanyl, oxycodone, methadone, hydrocodone, buprenorphine, and tramadol will not be detected and require an expanded immunoassay panel for detection.1 The amphetamine/ methamphetamine immunoassay can detect racemic compounds (dextroamphetamine, methamphetamine) and illicit analogues (methylenedioxyethylamphetamine, methylenedioxyamphetamine, and methylenedioxymethylamphetamine [MDMA]). This assay, however, has a low sensitivity for MDMA and a more specific test should be performed if MDMA is suspected.
Although immunoassays are very sensitive to the presence of drugs and drug metabolites, specificity and accuracy varies depending on the assay used and the substance for detection.2 This limitation may result in false-positives from substances cross-reacting with the immunoassay. Positive results seen on immunoassay need to be confirmed using the more accurate GC-MS, the forensic standard. The DHHS detection limits reduce false-positive results, but do not eliminate them. In 1998, the cut-off for opiates was raised from 300 ng/mL to 2000 ng/mL to avoid false positives from poppy seed ingestion. However, these more stringent requirements can lead to false-negatives and many laboratories continue to use the lower value for detection. For example, detectable levels of cannabinoids after ingestion of hemp-containing foods with immunoassay have been reported. Levels of cannabinoids in these samples, however, were not detectable with GC-MS. Passive marijuana or cocaine smoke inhalation has never been documented to achieve detectable urine concentrations in adults, however, passive cocaine smoke inhalation has achieved detectable levels in pediatric cases.
GC-MS is very accurate; however, it is not without problems in drug detection.2 As mentioned earlier, heroin and hydrocodone are metabolized into morphine and hydromorphone respectively, and GC-MS may identify the metabolites rather than the parent compound. Selegiline is metabolized to l-amphetamine and l-methamphetamine, isomers without central nervous system stimulation. Neither immunoassay nor GC-MS can differentiate between the l and d isomers and a positive result for amphetamines will be found; an alternative test, chiral chromatography, may be needed.
Many prescription and nonprescription substances have been reported to cross-react with immunoassays and cause false-positives.2 Most have only been documented in case reports. Table 3 lists substances reported to cause false-positive results using immunoassay. This list may not include all potential substances. The frequency of false-positives varies, depending on the specificity of immunoassay used and the substance under detection. Immunoassay results for cannabinoid and cocaine metabolites are associated with very few false-positives while immunoassay results for amphetamines and opiates are associated with a higher number of false-positives.1
Table 3. Substances that may cause false-positives on immunoassay urine drug screens.1-7
Drug/drug class Interfering drug Drug/drug class Interfering drug Amphetamine and Amantadine Cocaine Amoxicillin methamphetamine Brompheniramine Coca leaf teas Bupropion Tonic water Chlorpromazine Methadone Chlorpromazine Desipramine Clomipramine Desoxyephedrine Diphenhydramine Ephedrine Doxylamine Fluoxetine Ibuprofen Isometheptene Quetiapine Isoxsuprine Thioridazine Labetalol Verapamil Phentermine Opiates Dextromethorphan Phenylephrine Diphenhydramine Phenylpropanolamine Fluoroquinolonesa Promethazine Poppy seeds and oil Pseudoephedrine Rifampin Ranitidine Quinine Selegiline Phencyclidine Dextroamphetamine Thioridazine Dextromethorphan Trazodone Diphenhydramine Trimethobenzamide Doxylamine Trimipramine Ibuprofen Vicks inhalerb Imipramine Barbiturates Ibuprofen Ketamine Naproxen Meperidine Benzodiazepines Oxaprozin Thioridazine Sertraline Tramadol Cannabinoids Dronabinol Venlafaxine Efavirenz Tricyclic Carbamazepine Hemp-containing foods antidepressants Cyclobenzaprine Ibuprofen Cyproheptadine Ketoprofen Diphenhydramine Naproxen Hydroxyzine Piroxicam Quetiapine Promethazine Lyseric acid Amitriptyline Proton pump inhibitorsc diethylamine (LSD) Dicyclomine Sulindac Ergotamine Tolmetin Promethazine Sumatriptan
a Ciprofloxacin, levofloxacin, and ofloxacin.
b Vicks inhaler due to l-methamphetamine content interfered with older immunoassays; interference has not been seen with new enzyme multiplied immunoassay tests (EMIT).
The strengths and limitations of UDS need to be fully understood in order to perform the correct screen and also to correctly interpret the results. All positive results on immunoassay are presumptive until confirmed using GC-MS. An extensive medication history including prescription, nonprescription, and herbal medications should be obtained from the patient. Medication histories are important in order to anticipate false-positives as well as differentiate between drugs used for legitimate medical purposes and drugs of abuse.
1. Standridge JB, Adams SM, Zotos AP. Urine drug screen: a valuable office procedure. Am Fam Physician. 2010;81(5):635-640.
2. Moeller KE, Lee KC, Kissack JC. Urine drug screening: practical guide for clinicians. Mayo Clin Proc. 2008;83(1):66-76.
3. Quest Diagnostics. Standard urine testing for drug and alcohol abuse. www.questdiagnostics.com/employersolutions/standard_urine_testing_es.html
Accessed Nov 11, 2010.
4. Vincent EC, Zebelman A, Goodwin C. What common substances can cause false positives on urine drug screens for drugs of abuse? J Fam Pract. 2006;55(10):893-894, 897.
5. Brahm NC, Yeager LL, Fox MD, Farmer KC, Palmer TA. Commonly prescribed medications and potential false-positive urine drug screens. Am J Health-Syst Pharm. 2010;67(16):1344-1350.
6. Holtorf K. Ur-ine Trouble. Scottsdale, AZ: Vandalay Press; 1998.
7. Woelfel JA. Drug abuse urine tests: false-positive results. Pharmacist's Letter/Prescriber's Letter. 2005;21(3):210314.
Prepared by: Krista Williams, PharmD
Are calcium and magnesium infusions effective for prevention of oxaliplatin-related neurotoxicity?
Are calcium and magnesium infusions effective for prevention of oxaliplatin-related neurotoxicity?
Oxaliplatin (Eloxatin) is an antineoplastic agent indicated for use, in combination with infusional 5-fluorouracil and leucovorin, as adjuvant therapy of stage III colon cancer in patients who have undergone complete resection of a primary tumor and as a primary treatment of advanced colorectal cancer.1 One of the major adverse events associated with oxaliplatin administration is neurotoxicity.2 This adverse effect may be either acute and transient or chronic and cumulative. Acute, transient neurotoxicity occurs rapidly (i.e., during or within hours of infusion) in almost every patient receiving oxaliplatin. Signs and symptoms of acute neurotoxicity include paresthesias and/or dysesthesias in the extremities and/or perioral region, tetanic spasms, fasiculations, and prolonged muscular contraction. These symptoms are often induced or aggravated by exposure to cold. Chronic oxaliplatin-related neurotoxicity may be dose-limiting; 10% to 15% of patients experience chronic neurotoxicity after cumulative doses of 780 to 850 mg/m2. Symptoms of chronic toxicity include dysesthesias and paresthesias of the extremities with impaired sensation, sensory ataxia, and/or deficit in fine sensory-motor coordination potentially occurring with continued therapy. Symptoms generally continue between chemotherapy cycles, increase in intensity with cumulative dose, and may be so severe that patients are limited in their activities of daily living. For the majority of patients, oxaliplatin-induced neurotoxicity is reversible.
In order to reduce the negative consequences of oxaliplatin-induced neurotoxicity, researchers have been investigating a variety of neuromodulatory agents to prevent this adverse event including glutathione, carbamazepine, gabapentin, amifostine, and calcium/magnesium infusions.2
In the early to mid 2000s, the use of calcium/magnesium infusions gained widespread favor as an effective, safe, and cheap option to prevent oxaliplatin-induced neurotoxicity. The theory behind calcium/magnesium administration was that oxalate, a metabolite of oxaliplatin and known chelator of calcium and magnesium, is somehow involved in neurotoxicity development.3 Calcium and magnesium "replacement" would theoretically then aid to prevent or ameliorate neurotoxicity caused by oxaliplatin.
In 2004, Gamelin and colleagues evaluated the potential effects of calcium and magnesium infusions in a retrospective cohort of 161 patients given oxaliplatin, 5-fluorouracil, and leucovorin for advanced colorectal cancer.3 Of the evaluated patients, 96 received 1 g each of calcium gluconate and magnesium sulfate before and after oxaliplatin administration while 65 patients did not receive either therapy. Results of this retrospective cohort revealed that withdrawals due to neurotoxicity were significantly reduced among patients receiving calcium and magnesium therapy (4% vs. 31%; p=0.000003), while a similar tumor response was seen among the groups. In addition, at the end of therapy, neurotoxicity occurred less frequently in the calcium/magnesium group (20% vs. 45%; p=0.003).
The positive results by Gamelin and colleagues emboldened the widespread acceptance of calcium and magnesium infusions as preventive therapy for oxaliplatin-induced neurotoxicity until stoppage of the Combined Oxaliplatin Neuropathy Prevention Trial (CONCEPT) in 2007 after an unplanned interim analysis. The CONCEPT study was designed to evaluate 2 approaches to reduce the potential for cumulative neurotoxicity with oxaliplatin administration: intermittent "stop and go" administration and the use of calcium and magnesium infusions.4,5 At the interim analysis, involving 180 enrolled patients, a significantly reduced response rate was observed among those patients receiving calcium and magnesium infusions as compared to no treatment (17% vs. 33%; p=0.028). This unexpected result caused an immediate shutdown in the CONCEPT study and led to many institutions discontinuing the practice of calcium/magnesium administration to oxaliplatin-treated patients.
These results also led to a new independent, blinded radiologic review of the CONCEPT data.5 Per study researchers, the interim analysis was fraught with problems including incomplete tumor response data and termination of the study at a time point when the final 40 enrolled patients (all of whom were given calcium and magnesium) had just begun therapy. In essence, termination of the CONCEPT study was done "too early to see a response rate in these patients", which biased the results against calcium and magnesium infusion. The new independent analysis involved data from 118 of the 140 original randomized patients. The investigators used 3 different criteria to measure response rates: sequentially confirmed responses (i.e., response was seen on 1 scan and confirmed by another scan 1 month later), subsequently confirmed responses (i.e., response on 1 scan is confirmed by any subsequent scan), and unconfirmed responses (i.e., response was seen on 1 scan but there was no other confirmatory assessment). This review concluded that calcium and magnesium infusions had no significant effect on response rates and may actually provide some response benefit; patients receiving calcium and magnesium were 29% more likely to have a partial or complete response than those receiving no treatment per sequentially confirmed criteria (p=NS).
In addition, since termination of the CONCEPT study, results from other prospective and retrospective studies have been published. These are summarized in table 1. In general, the majority of these studies found calcium and magnesium infusions to reduce oxaliplatin-related neurotoxicity without a negative impact on response rates.
Table 1. Trial Results.6-9
Citation Design Population Interventions Outcomes and conclusions Grothey 2010
Prospective, randomized, placebo-controlled, double-blind, 2-arm, phase III study N=102 patients with stage II or stage III adenocarcinoma of the colon given either FOLFOX4 or modified FOLFOX6 Calcium gluconate and magnesium sulfate: 1 g each in 100 mL 5% dextrose infused over 30 minutes before and just after oxaliplatin
- Study closed early due to results from CONSULT interim analysis
- Incidence of chronic, cumulative, grade 2 or greater sensory neurotoxicity as measured by NCI-CTC was significantly reduced with calcium/magnesium: 22% vs 41%; p=0.038
- Similar significant reductions in grade 2 or greater sensory neurotoxicity were seen with use of the oxaliplatin-specific scale as well: 28% vs 51%; p=0.018
Ishibashi 2010 Prospective, randomized, double-blind, placebo-controlled N=33 patients with histologically confirmed colorectal cancer given modified FOLFOX6 Calcium gluconate 850 mg and magnesium sulfate 720 mg before and just after oxaliplatin
- Incidences of ≥ grade 1, 2, and 3 neurotoxicity were not significantly different between groups after 6 cycles using both the DEB-NTS and NCI-CTC criteria
- DEB-NTS criteria results (calcium/magnesium vs placebo):
- Grade 1: 100% vs 94%; p=0.48
- Grade 2: 71% vs 56%; p=0.48
- Grade 3: 6% vs 0%; p>0.99
- NCI-CTC criteria results:
- Grade 1: 100% vs 94%; p=0.48
- Grade 2: 6% vs 6%; p>0.99
- Grade 3: 6% vs 0%; p>0.99
- Response rates did not differ significantly between groups; 36% calcium/magnesium vs 40% placebo; p>0.99
- Disease control rates were also similar; 73% calcium/magnesium vs 70% placebo; p 0.99
- Median progression-free survival time: 9.2 months calcium/magnesium vs 8.1 months placebo; p=0.56
Knijn 2010 Retrospective N=755 previously untreated advanced colorectal cancer patients who were treated in the phase III CAIRO2 study Calcium and magnesium dosage regimens not clearly defined
- 732 patients evaluable for analysis
- 551 patients in calcium/magnesium group; 181 patients received no therapy
- Incidence of all grade neurotoxicity (calcium/magnesium vs no treatment): 85% vs 92%; p=0.02
- Incidence of grade ≥ 2 neurotoxicity: 40% vs 45%; p=0.22
- Median progression-free survival: 10.1 months vs 10.7 months; p 0.92
- Median overall survival: 19.8 months vs 20.7 months; p=0.1
- Response rate: 43.1% vs 50%; p=0.11
Prospective, randomized, double-blind, placebo-controlled N=154 patients given FOLFOX4 regimen Calcium gluconate 1 g and magnesium sulfate 1.5 g in 250 mL of fluid before and just after oxaliplatin
- Preliminary data involved first 52 patients with metastatic colorectal cancer; 50% received calcium/magnesium and 50% no treatment
- Blinding still maintained since all data were not collected at time of interim analysis
- Objective response rate: 50% vs 53%; p=0.45
- Progression-free survival: 12 ± 0.6 months vs 12 ± 0.5 months; p=0.79
- Overall survival: 25.1 ± 4 months vs 25.5 ± 4.1 months; p=0.45
- Grade 3 neurotoxicity: 5% vs 24%; p<0.001
NCI-CTC = National Cancer Institute-Common Toxicity Criteria; DEB-NTS = Debiopharm Neurotoxicity Scale.
The administration of calcium and magnesium infusions for the prevention of oxaliplatin-induced neurotoxicity was widely accepted in clinical practice until the interim results of the CONCEPT trial were made available. The CONCEPT results suggested that calcium/magnesium may adversely impact response rates. These surprising results quickly led to discontinuation of calcium and magnesium infusions as a standard therapy for oxaliplatin-related neurotoxicity. More recently, an independent review of the CONCEPT data, as well as newer trial data, have found no negative impact on response rates with calcium/magnesium. These data may usher in the return of this needed therapeutic intervention for patients given oxaliplatin.
1. Eloxatin [package insert]. Lake Forest, IL: Hospira; 2009.
2. Saif MW, Reardon J. Management of oxaliplatin-induced peripheral neuropathy. Ther Clin Risk Manag. 2005;1(4):249-258.
3. Gamelin L, Boisdron-Celle M, Delva R, et al. Prevention of oxaliplatin-related neurotoxicity by calcium and magnesium infusions: a retrospective study of 161 patients receiving oxaliplatin combined with 5-fluorouracil and leucovorin for advanced colorectal cancer. Clin Cancer Res. 2004;10(12 Pt 1):4055-4061.
4. Hochster HS, Grothey A, Childs BH. Use of calcium and magnesium salts to reduce oxaliplatin-related neurotoxicity. J Clin Oncol. 2007;25(25):4028-4029.
5. Laino C. Warning about calcium and magnesium's effect on response to oxaliplatin called premature. Oncology Times. 2008;30(13):32-33.
6. Grothey A, Nikcevich DA, Sloan JA, et al. Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7. J Clin Oncol. 2010; Dec 28. [Epub ahead of print].
7. Ishibashi K, Okada N, Miyazaki T, Sano M, Ishida H. Effect of calcium and magnesium on neurotoxicity and blood platinum concentrations in patients receiving mFOLFOX6 therapy: a prospective randomized study. Int J Clin Oncol. 2010;15(1):82-87.
8. Knijn N, Tol J, Koopman M, et al. The effect of prophylactic calcium and magnesium infusions on the incidence of neurotoxicity and clinical outcome of oxaliplatin-based systemic treatment in advanced colorectal cancer patients. Eur J Cancer. 2010; Nov 8. [Epub ahead of print].
9. Gamelin L , Boisdron-Celle M, Morel A, et al. Oxaliplatin-related neurotoxicity: interest of calcium-magnesium infusion and no impact on its efficacy. J Clin Oncol. 2008;26(7):1188-1189.
Should Truvada (emtricitabine/tenofovir) be given for preexposure prophylaxis against HIV?
Should Truvada (emtricitabine/tenofovir) be given for preexposure prophylaxis against HIV?
Results of the Preexposure Prophylaxis Initiative (iPrEx) trial were published in the New England Journal of Medicine.1 This randomized, double-blind, placebo-controlled, multinational (South Africa, United States, South America, and Thailand) clinical trial evaluated the safety and efficacy of emtricitabine/tenofovir for prevention of human immunodeficiency virus (HIV) among men and transgender women who have sex with men. Subjects were eligible if they were at least 18 years of age, HIV-negative, and at high-risk for HIV infection. Emtricitabine/tenofovir (n=1224) or placebo (n=1217) was given by mouth once daily, and subjects had HIV testing and received condoms, risk-reduction counseling, and management of sexually transmitted diseases. Subjects were seen every 4 weeks to obtain study drug/placebo, undergo a pill count and adherence counseling, rapid HIV testing, and medical history. Anyone who reported unprotected exposure to an HIV-infected partner was referred for postexposure prophylaxis. The primary outcome measure was development of HIV seroconversion. A subgroup analysis was conducted to determine if serum drug levels correlated with protective effect.
Twenty-nine percent of subjects reported their gender identity as female, and the groups were similar at baseline with the exception of a slightly older population in the treatment group (27.5 vs. 26.8 years, p=0.04).1 Median follow-up time was 1.2 years (3324 person-years). Blinding appeared to be maintained as subjects who guessed their treatment assignment were evenly distributed between groups. Self-reported adherence (mean) was lower for active therapy at weeks 4 (89% vs. 92%, p<0.001) and 8 (93% vs. 94%, p=0.006), but did not differ thereafter. According to dispensing records/dates, adherence decreased from 99% to 91% during the first year, which conflicted with self-reported adherence and pill count data. Subjects in both groups reported a decrease in the number of sexual partners with whom they had receptive anal intercourse and reported an increase in the use of condoms for this practice.
A total of 110 subjects experienced HIV seroconversion, but 10 had HIV subsequently detected at in the sample they provided at the enrollment. 1 Of these 10 subjects, 2 of 2 in the active therapy group and 1 of 8 in the placebo group had emtricitabine-resistant infections. Of the remaining 100 subjects who developed HIV during the course of the trial, 36 were in the emtricitabine/tenofovir group compared to 64 in the placebo group (relative risk reduction 44%, 95% confidence interval [CI] 15 to 63, p=0.005). Among the treatment group, study drug was detected in 22 (51%) of seronegative subjects and 3 (9%) of 34 who became infected (p<0.001). The risk of HIV infection was reduced by a factor of 12.9 (95% CI 1.7 to 99.3, p<0.001) among subjects with emtricitabine/tenofovir detected by assay. In terms of safety, elevated serum creatinine (1.1 times the upper limit of normal or 1.5 times baseline) was found more frequently with active drug (2% vs. 1%, p=0.08), but the difference did not reach statistical significance. Nausea (22 vs. 10 events, p=0.04) and weight loss of at least 5% (34 vs. 19 events, p=0.04) were also more frequent with active therapy.
The authors concluded that emtricitabine/tenofovir provided protection against HIV infection among men and transgender women who have sex with men. 1 Detectable levels of the drug in the blood correlated with the prophylactic effect.
In an accompanying editorial, Dr. Michael suggests some points for consideration regarding the iPrEx study.2 He points out one of the primary challenges of the trial was the discrepancy between self-reported adherence and detection of study drug in the blood. The lack of adherence would likely carry over to clinical practice if this intervention were implemented since patients in clinical practice may not have the benefit of intensive adherence counseling as done in the study.
In addition the trend toward development of renal insufficiency with emtricitabine/tenofovir was concerning and could signal a safety problem if the intervention becomes widespread in clinical practice.2 Monitoring of renal function may be necessary, especially if adherence is superior to that found in iPrEx. Dr. Michael was also concerned about the finding of emtricitabine resistance in the patients found to have had HIV at baseline who subsequently received treatment with combination therapy (2 of 2). If the intervention becomes widespread in practice, increased emtricitabine resistance may be seen in patients with undiagnosed HIV at therapy initiation. Finally, the author raises some questions that need to be evaluated such as the role of preexposure prophylaxis in patients at lower risk for HIV acquisition and long-term safety issues of administering emtricitabine/tenofovir to healthy persons.
Centers for Disease Control and Prevention Response
According to a fact sheet released the same day as the iPrEx trial, the Centers for Disease Control and Prevention (CDC) plans to collaborate with stakeholders to fully review the data and develop public health guidelines on the safe and effective use of preexposure prophylaxis.3 The CDC has urged practitioners to await the guidelines prior to using preexposure prophylaxis in clinical practice. However, since emtricitabine/tenofovir is currently marketed, the agency has released some immediate cautions for patients and practitioners (available at: http://www.cdc.gov/nchhstp/newsroom/PrEPforHIVFactSheet.html). The key points of the cautions include:
- Trial results apply to men and transgender women who have sex with men; no data exist for heterosexuals or injection drug users.
- Preexposure prophylaxis is only for HIV negative patients; initial and regular testing during use is required.
- Preexposure prophylaxis is not the first line of defense against HIV infection; it was partially effective when used with regular testing, condoms, and other methods.
- Men who have sex with men should continue to use condoms, know their HIV status as well as that of their partner(s), get tested and treated for sexually transmitted diseases that can facilitate HIV transmission, reduce drug use and sexual risk behavior, and reduce number of sexual partners.
- If preexposure prophylaxis is used, daily use is crucial; protection was garnered for those who took the drug regularly. Poor adherence negatively affected efficacy.
Healthcare providers are encouraged to visit the CDC's website for additional information on preexposure prophylaxis and the iPrEx trial: http://www.cdc.gov/hiv/prep/.4
Prevention of HIV is a global priority, and it appears that preexposure prophylaxis with emtricitabine/tenofovir in men and transgender women who have sex with men reduces the rate of transmission. However, it is prudent to await further guidance from CDC on the role of this drug combination in clinical practice and to review follow-up data from iPrEx when available (data regarding subjects with concurrent hepatitis B virus infection are expected). Practitioners should continue to emphasize the role of condoms and safe sexual practices as the cornerstone of HIV prevention.
1. Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27):2587-2599.
2. Michael NL. Oral preexposure prophylaxis for HIV – another arrow in the quiver? N Engl J Med. 2010;363(27):2663-2665.
3. Centers for Disease Control and Prevention. Fact sheet. Pre-exposure prophylaxis (PrEP) for HIV prevention: promoting safe and effective use in the United States. www.cdc.gov/nchhstp/newsroom/PrEPforHIVFactSheet.html. Accessed January 28, 2011.
4. Centers for Disease Control and Prevention. Pre-exposure prophylaxis (PrEP). www.cdc.gov/hiv/prep/. Accessed January 28, 2011.
What are the new recommendations in the 2011 Focused Update to the ACCF/AHA atrial fibrillation guidelines?
What are the new recommendations in the 2011 Focused Update to the ACCF/AHA atrial fibrillation guidelines?
Recently, the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) published a focused update to their 2006 guidelines for the management of atrial fibrillation (AF).1 The 2011 focused update provides clinicians with the most recent data from the 2009 annual scientific meetings of the ACC, AHA, and European Society of Cardiology (ESC), as well as more recent data available through April 2010. The updated guidelines include recommendations for strict versus lenient heart rate control, combined use of antiplatelet and anticoagulant therapy, and dronedarone use. It is important to note that the newly approved direct thrombin inhibitor, dabigitran, is not included in the recommendations because it had not yet received Food and Drug Administration (FDA) approval at the time the focused update document was approved. Clinicians are encouraged to read the full document available at http://content.onlinejacc.org/cgi/content/full/j.jacc.2010.10.001.
Strict versus lenient rate control
The 2006 guidelines were the first to address rhythm versus rate control strategies when treating patients with AF. The landmark AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) trial found no difference in stroke rates and a trend towards reduced mortality in patients who were managed with rate control versus rhythm control.2 Additionally, the RACE (Rate Control versus Electrical cardioversion for persistent atrial fibrillation) study found rate control noninferior to rhythm control for the prevention of death and morbidity.3 "Adequate" rate control was defined differently in these 2 studies and there are currently no recommendations for the parameters of optimal rate control when this treatment modality is used rather than rhythm control. The 2011 focused update provides clinicians with some guidance on this issue.
The Race II (Rate Control Efficacy in Permanent Atrial Fibrillation) trial studied the effects of strict (resting heart rate <80 bpm, heart rate <110 bpm during moderate exercise) versus lenient (resting heart rate <110 bpm) rate control in 614 patients.4 Sixty-six percent of the study subjects were male with a mean age of 68, had a median duration of any AF of 18 months, and a majority had CHADS2 scores of 0 or 1. Beta-blockers, nondihydropyridine calcium-channel blockers, and digoxin were used alone or in combination to achieve the target heart rate in each group. The primary outcome was a composite of death from cardiovascular causes, hospitalization for heart failure, and stroke, systemic embolism, bleeding, and life-threatening arrhythmic events. There were 38 composite events reported in the lenient-control group and 43 in the strict-control group [hazard ratio (HR): 0.84, 0.58 to 1.21]. Had the study met power, there may have been a difference noticed between the 2 treatment groups. Regardless, there seems to be no difference in outcomes when treating this patient population with strict versus lenient rate control.
Combining clopidogrel with aspirin for thromboembolism prophylaxis
Historically, warfarin has been the drug of choice for preventing thromboembolism in patients with AF and has proven to be superior to aspirin in clinical trials.1 Two recent trials studied the effectiveness of clopidogrel plus aspirin for stroke prevention.
The ACTIVE-W (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention Of Vascular Events) trial was a non-inferiority study that compared clopidogrel plus aspirin versus warfarin for prevention of vascular events in patients with AF and an average of 2 stroke risk factors.5 The primary outcome was the first occurrence of stroke, non-central nervous system systemic embolism, myocardial infarction, or vascular death. The relative risk (RR) of achieving the primary endpoint with clopidogrel plus aspirin was 1.44 [95% confidence interval (CI): 1.18 to 1.76; p=0.0003; number needed to treat (NNT): 47]. Rates of major hemorrhage were similar between groups; however, significantly more minor and total bleeds occurred in the clopidogrel plus aspirin group. The trial was stopped early due to overwhelming evidence showing the superiority of warfarin over clopidogrel plus aspirin.
The ACTIVE-A (Effect of Clopidogrel Added to Aspirin in Patients with Atrial Fibrillation) trial studied the potential benefit of adding clopidogrel to aspirin in patients considered not suitable for warfarin therapy.6 Reasons patients were deemed not suitable for warfarin include a specific risk of bleeding (22.9%), patient preference (26%), or physician preference (49.7%). The primary outcome was a composite of stroke, myocardial infarction, noncentral nervous system systemic embolism, or death from vascular causes. Patients in this study were 70 years of age, had a mean CHADS 2 score of 2, and a majority had permanent AF with a duration >2 years. Major vascular events occurred at a rate of 6.8% per year in the clopidogrel group and 7.6% per year in the placebo group after a median follow-up period of 3.6 years (RR with clopidogrel 0.89; 95% CI: 0.81 to 0.98; p=0.01). The benefit seen with clopidogrel was largely due to its reduction in strokes. Major hemorrhage occurred in 251 patients (2% per year) in the clopidogrel group and 162 patients (1.3% per year) in the aspirin group. Treating 143 patients with clopidogrel for 1 year will result in 1 major hemorrhage (severe or fatal) and treating 200 patients will prevent 1 disabling or fatal stroke.
Dronedarone for the prevention of recurrent AF
Dronedarone is a new antiarrhythmic agent that received FDA approval in July 2009. Dronedarone was developed in hopes of having a similar efficacy profile and but an improved safety profile compared to amiodarone. Structural modifications made to the dronedarone molecule include the removal of the iodine moiety and the addition of a methyl sufonamyl group.7 These modifications result in a decreased lipophilicity and thus shorter half life (13 to 19 hours versus 58 days with amiodarone) and lower tissue accumulation than amiodarone. Its metabolism via cytochrome (CYP) 3A4 leaves potential for drug-drug interactions. The pharmacologic action of dronedarone is due to its inhibition of L-type calcium current, the inward sodium current, multiple potassium currents, and its antiadrenergic properties. In clinical trials, dronedarone has been shown to decrease ventricular rate in AF by 11 to 13 beats per minute.8-9 Spontaneous conversion to sinus rhythm with dronedarone was demonstrated to be a dose dependent effect.
The DIONYSOS (Efficacy and Safety of Dronedarone Versus Amiodarone for the Maintenance of Sinus Rhythm in Patients With Persistent Atrial Fibrillation) study found dronedarone to be less effective than amiodarone.10 The composite primary endpoint was recurrence of AF (including unsuccessful electrical cardioversion, no spontaneous conversion, and no electrical cardioversion) or premature study discontinuation was achieved in 75.1% of study subjects in the dronedarone group versus 58.8% in the amiodarone at 12 months (HR: 1.59; 95% CI: 1.28 to 1.98; p<0.0001). The study found no significant differences in the main safety endpoints; however, there were fewer thyroid, neurologic, dermatologic, and ocular events in the dronedarone group.
The ATHENA (A placebo-controlled , double-blind, parallel arm trial to assess the efficacy of dronedarone 400 mg twice daily for the prevention of cardiovascular hospitalization or death from any cause in patients with atrial fibrillation/atrial flutter) found dronedarone to be superior in reducing the primary composite endpoint of death and cardiovascular hospitalizations.11 It should be noted that the effectiveness of dronedarone in this trial was mainly due to its reduction of hospitalizations due to AF and cardiovascular death, not all-cause death or maintenance of sinus rhythm.
The ANDROMEDA (Antiarrhythmic Trial With Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease) found that dronedarone increased mortality in patients with recently decompensated heart failure and depressed LV function.12 Dronedarone now has a black box warning restricting its use in patients with New York Heart Association (NYHA) class IV heart failure or class II-III with a recent decompensation.
Other safety issues with dronedarone include the major cardiac adverse effects of bradycardia and QT prolongation.11 Torsades de pointes has been reported as well. Like amiodarone, dronedarone is associated with a increases in serum creatinine due to inhibition of renal tubular secretion of creatinine, although glomerular filtration rate is unaffected.13 Its concurrent administration with warfarin does not alter the international normalization ratio; however, concurrent administration with digoxin results in 1.7 to 2.5 fold increased digoxin levels. Although not mentioned in the 2011 focused update, the FDA Medwatch program recently issued a drug safety communication on January 14, 2011 concerning dronedarone and 2 case reports of liver failure leading to transplantation.14
Catheter-based ablation therapy for atrial fibrillation
Catheter ablation is most commonly used in patients with symptomatic paroxysmal AF who have failed treatment with 1 or more antiarrhythmic drugs, with normal or mildly dilated atria, normal or mildly reduced ventricular function, and absence of severe pulmonary disease. The ThermoCool trial compared radiofrequency ablation versus additional antiarrhythmic drugs in patients with paroxysmal AF who did not show improvement with at least 1 antiarrhythmic drug.15 Patients included in the study had an average age of 55.7 years and a 5.7 year duration of paroxysmal, symptomatic AF. Catheter ablation resulted in significantly few episodes of recurrent AF than did additional antiarrhythmic drugs. Thirty-four percent of ablation patients had recurrent AF during the 9-month follow-up period compared with 84% of the drug-treated group. Despite the success of catheter ablation in this trial, it requires further study, especially in heart failure and other advanced structural heart disease patient populations.
Overall summary of the 2011 focused update recommendations
- Treatment to achieve strict rate control of heart rate (<80 bpm at rest of < 110 bpm during a 6-minute walk) is not beneficial compared to achieving a resting heart rate <110 bpm in patients with persistent AF who have stable ventricular function (left ventricular ejection fraction >0.40) and no or acceptable symptoms related to the arrhythmia, though uncontrolled tachycardia may over time be associated with a reversible decline in ventricular performance. (Class III-no benefit)
- The addition of clopidogrel to aspirin to reduce the risk of major vascular events, including stroke, might be considered in patients with AF in whom oral anticoagulation with warfarin is considered unsuitable due to patient preference or the physician's assessment of the patient's ability to safely sustain anticoagulation. (Class IIb)
- Dronedarone is reasonable to decrease the need for hospitalization for cardiovascular events in patients with paroxysmal AF or after conversion of persistent AF. Dronedarone can be initiated during outpatient therapy. (Class IIa)
- Dronedarone should not be administered to patients with class IV heart failure or patients who have had an episode of decompensated heart failure in the past 4 weeks, especially if they have depressed left ventricular function (left ventricular ejection fraction ≤35%). (Class III-harm)
- Catheter ablation performed in experienced centers is useful in maintaining sinus rhythm in selected patients with significantly symptomatic, paroxysmal AF who have failed treatment with an antiarrhythmic drug and have normal or mildly dilated left atria, normal or mildly reduced left ventricular function, and no severe pulmonary disease. (class Ic)
- Catheter ablation is reasonable to treat symptomatic persistent AF. (Class IIa)
- Catheter ablation may be reasonable to treat symptomatic paroxysmal AF in patients with significant left atrial dilation or with significant LV dysfunction. (Class IIb)
On February 15, an update to the ACCF/AHA/HRS guidelines for management of patients with AF with a focus on dabigatran was published.16 The guidelines now recommend that dabigatran is a useful alternative to warfarin for prevention of stroke and systemic thromboembolism in patients with paroxysmal to permanent AF and risk factors for stroke or systemic embolization who do not have a prosthetic heart value or hemodynamically significant valve disease, severe renal failure (defined as a creatinine clearance of <15 mL/min), or advanced liver disease (characterized as impaired baseline clotting function).
The guidelines go on to say that because of the twice-daily dosing and greater risk of nonhemorrhagic adverse events with dabigatran, patients receiving warfarin who have “excellent” international normalized ratio (INR) control may have little to gain by switching to this agent.
Overall, the guidelines recommend that numerous factors need to be considered when considering switching such as individual clinical features, adherence to twice-daily dosing with dabigatran versus or routine INR monitoring visits for warfarin, patient preference, and cost.
Therefore, although the new AF update now addresses dabigatran, our original recommendations are still valid.
1. Wann LS,Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;123(1):104-123.
2. Olshansky B, Rosenfeld LE, Warner AL, et al. The atrial fibrillation follow-up investigation of rhythm management (AFFIRM) study: approaches to control rate in atrial fibrillation. J Am Coll Cardiol. 2004;43(7):1201-1208
3. Hagens VE, Ranchor AV, Van SE, et al. Effect of rate or rhythm control on quality of life in persistent atrial fibrillation. Results from the rate control versus electrical cardioversion (RACE) study. J Am Coll Cardiol. 2004;43(2):241-247.
4. Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med. 2010;362(15):1363-1373
5. Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the atrial fibrillation clopidogrel trial with Irbesartan for prevention of vascular events (ACTIVE W): a randomised controlled trial. Lancet. 2006;367(9526):1903-1912.
6. Connolly SJ, Pogue J, Hart RG, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360(20):2066-2078.
7. Gold Standard, ed. Clinical Pharmacology. Tampa, FL: Gold Standard; 2011. http://clinicalpharmacology-ip.com.proxy.cc.uic.edu/Default.aspx. Accessed January 27, 2011.
8. Touboul P, Brugada J, Capucci A, et al. Dronedarone for prevention of atrial fibrillation: a dose- ranging study. Eur Heart J. 2003;24(16):1481-1487.
9. Davy JM, Herold M, Hoglund C, et al. Dronedarone for the control of ventricular rate in permanent atrial fibrillation: the efficacy and safety of dronedarone for the control of ventricular rate during atrial fibrillation (ERATO) study. Am Heart J. 2008; 156(3):527-529.
10. Piccini JP, Hasselblad V, Peterson ED, et al. Comparative efficacy of dronedarone and amiodarone for the maintenance of sinus rhythm in patients with atrial fibrillation. J Am Coll Cardiol. 2009;54(12):1089-1095.
11. Hohnloser SH, Crijns HJ, van Eickels M: for the ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360(7):668-678.
12. Kober L, Torp-Pederson C, McMurray JJ, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med. 2008;358(25):2678-2687.
13. Patel C, Yan GX, Kowey PR. Dronedarone. Circulation. 2009;120(7):636-644.
14. Food and Drug Administration. FDA drug safety communication: severe liver injury associated with the use of dronedarone (marketed as Multaq). http://www.fda.gov/Drugs/DrugSafety/ucm240011.htm. Accessed January 25, 2011.
15. Wilber DJ, Pappone C, Neuzil P, et al. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA. 2010;303(4):333-340.
16. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (update on dabigatran). Wann SL, Curtis AB, Ellenbogen KA, et al. J Am Coll Cardiol. 2011; doi:10.1016/j.jacc.2011.01.010.
Prepared by: Brennan Ertmer, PharmD Candidate