Objectives. Outline. Media Worthy Trials? Making Sense out of the Sensationalism 8/30/2012

Transcription

1 Media Worthy Trials? Making Sense out of the Sensationalism Lara K. Ellinger, PharmD, BCPS Clinical Assistant Professor, Drug Information Group University of Illinois at Chicago I have no actual or potential conflicts of interest in relation to this program. Objectives Describe the methods and key findings of the papers presented. Explain how the WARFASA trial may affect venous thromboembolism (VTE) prevention strategies. Summarize the findings and implications for practice of the trial that found an increase in cardiovascular death with azithromycin use. Discuss the clinical significance of risk of stroke and myocardial infarction with use of hormonal contraception. Compare and contrast 3 months of rifapentine and isoniazid with 9 months of isoniazid as treatment options for latent tuberculosis. Outline Pertinent background Study objective Methods Results Critique/clinical implications 1

2 Media Worthy Trial Assessment #1: ASPIRIN FOR PREVENTING THE RECURRENCE OF VENOUS THROMBOEMBOLISM (WARFASA TRIAL) N Engl J Med. 2012;366(21): Aspirin Most commonly studied antiplatelet drug Treatment and prevention of MI and stroke vascular death by ~15% nonfatal vascular events by ~30% Well known prevention What about of arterial events venous events? CHEST. 2012;141(2_suppl):e89S-e119S. 2

3 Prevention of Recurrent VTE Unprovoked at higher risk for recurrence than provoked Unprovoked VTE Anticoagulation for 3 months Evaluate risk/benefit ratio after 3 months for extended anticoagulation CHEST. 2012;141(2_suppl):e419S-e494S. WARFASA Study objective To assess the benefit of aspirin for prevention of recurrent VTE after completion of a course of vitamin K antagonists (VKA) for unprovoked VTE Methods Multicenter, randomized, placebo controlled, double blinded, event driven, approximate length 2 years N Engl J Med. 2012;366(21): WARFASA Interventions Aspirin 100 mg once daily (n=205), placebo once daily (n=197) Follow up every 3 months for 1 year then every 6 months Inclusion Exclusion N Engl J Med. 2012;366(21): >18 years of age Known cancer First time diagnosis of unprovoked DVT, PE, or both Treated for 6 18 months with vitamin K antagonist Known thrombophilia Indication for long term anticoagulation other than VTE Previous requirement for aspirin or antiplatelets Active bleeding, high risk, or bleed in past 6 18 months 3

4 WARFASA Primary endpoint Symptomatic, objectively confirmed recurrence of VTE (composite of DVT or nonfatal or fatal PE) Secondary endpoints Nonfatal MI, unstable angina, stroke, TIA, acute ischemia of lower limbs, death from any cause Safety Major bleeding N Engl J Med. 2012;366(21): WARFASA Demographics No significant differences between groups Median age: 62 years Approximately 2/3 male 99% white First event: approximately 60% DVT, 40% PE Duration of VKA treatment >50% took for 12 months N Engl J Med. 2012;366(21): WARFASA Statistical analysis Assumption of 40% RRR with aspirin 8.0% expected event rate per year 400 patients total to observe expected number of events Estimated that 70 events would provide power of 80% to show superiority of aspirin over placebo N Engl J Med. 2012;366(21):

5 WARFASA Primary Outcome: Recurrence of VTE within 2 years Aspirin (n=205) Placebo (n=197) HR with 95% CI P value NNT VTE recurrence during study period (6.6% per year) (11.2% per year) HR, 0.58; 95% CI, P= to 0.93 VTE recurrence during study treatment 23 (5.9% per year) 39 (11.0% per year) HR, 0.55; 95% CI, 0.33 to 0.92 P= N Engl J Med. 2012;366(21): WARFASA Results Post hoc Patients with prior PE who had recurrence: Aspirin: 6.7% per year Placebo: 13.5% per year HR, 0.38; 95% CI, 0.17 to 0.88; P=0.02 Patients with prior DVT who had recurrence: Aspirin: 6.5% per year Placebo: 10.2% per year HR, 0.65; 95% CI, 0.65 to 1.20; P=0.17 N Engl J Med. 2012;366(21): WARFASA Results Secondary Death (any cause) Aspirin: 6 patients (1.4% per year) Placebo: 5 patients (1.3% per year) Arterial events Aspirin: 8 patients (including 2 MIs, 2 strokes) Placebo: 5 patients (including 2 MIs, 1 stroke) Major bleeding 1 event in each group N Engl J Med. 2012;366(21):

6 Aspirin Dose? 81 mg aspirin may achieve same effects as 100 mg aspirin mg no different than mg for prevention of stroke, MI, cardiovascular death (CURRENT OASIS 7) Antiplatelet effect similar dose dependent inhibition of prostacyclin N Engl J Med. 2010;363(10): WARFASA Strengths Well designed trial Appropriate diagnostic criteria Appropriate length Limitations Smaller study Location/ethnicity Compliance? Other medications taken concomitantly? Vague descriptions for VTE risk factors Majority treated with warfarin for 12 months N Engl J Med. 2012;366(21): WARFASA Use of aspirin for unprovoked VTE may be in next CHEST guidelines Related trials to keep a watchful eye for: ASPIRE Similar design to WARFASA Inclusion: VKA for 3 months to < 12 months Study length: median of 3 years Analysis planned to combine results of WARFASA and ASPIRE N Engl J Med. 2012;366(21):

7 Which patient might be a candidate for aspirin for prevention of recurrent VTE? A. Unprovoked VTE, 6 month of VKA therapy, low bleed risk B. Unprovoked VTE, 3 months of VKA therapy, low bleed risk C. Provoked VTE, 6 months of VKA therapy, low bleed risk D. Unprovoked VTE, 6 months of VKA therapy, GI bleed 15 months ago Media Worthy Trial Assessment #2: AZITHROMYCIN AND THE RISK OF CARDIOVASCULAR DEATH N Engl J Med. 2012;366(20): Azithromycin Background Macrolide antibiotics have proarrhythmic potential QT prolongation Torsades de pointes Sudden cardiac death Up until recently, findings did not apply to azithromycin Clin Infect Dis. 2006;43(12):

8 Azithromycin and CV Death Study objective To determine the risk of cardiovascular death in patients taking azithromycin. Methods Retrospective, matched control, observational cohort study N Engl J Med. 2012;366(20): Azithromycin and CV Death Study cohort Tennessee Medicaid population between 1992 and 2006 Inclusion Prescribed azithromycin No other abx filled same day as azithromycin Not in hospital on day of azithromycin Rx Ages years at Rx fill date Ongoing medical surveillance N Engl J Med. 2012;366(20): Serious illness Exclusion Rx benefits through Medicare Prolonged nursing home stays Azithromycin and CV Death Controls Matched nonusers antibiotic free periods Indication controlled for by patients who took other abx Amoxicillin (primary control antibiotic) Ciprofloxacin Levofloxacin N Engl J Med. 2012;366(20):

9 Azithromycin and CV Death Endpoint CV death and death from any cause Time frame of 5 and 10 days from date of Rx fill N Engl J Med. 2012;366(20): Azithromycin and CV Death Study Group Baseline Characteristics Number of Prescriptions Primary Indication (%) Mean Summary CV Risk Score Azithromycin 347,795 Ear nose throat (42) 9.3 Mthd Matched control no antibiotic 1,391,180 n/a 9.2 Amoxicillin 1,348,672 Ear nose throat (51) 9.5 Ciprofloxacin 264,626 Genitourinary (45) 10.3 Levofloxacin 193,906 Ear nose throat (24) 10.6 N Engl J Med. 2012;366(20): Azithromycin and CV Death Demographics Mostly female (77.5%) and white (~80%) Mean age 49 years Frequent use of CV or respiratory meds In past 30 days from Rx fill ~15% had ED visits >1/4 had used abx Most baseline characteristics in non azithro groups were P<0.01 when compared to nonuser group N Engl J Med. 2012;366(20):

10 Cumulative Incidence of Death (no./1 million courses) Among Patients Taking a 5 Day Course of Azithromycin, Amoxicillin, or No Antibiotic No Antibiotic Amoxicillin Azithromycin HR, % CI, P< HR, % CI, P< HR, % CI, P< NS HR, % CI, P< Total CV Death Cumulative Incidence Sudden Cardiac Death Other CV Death Other Cause of Death Total CV Death Cumulative Incidence N Engl J Med. 2012;366(20): Azithromycin and CV Death Azithromycin Vs. No Antibiotic SUMMARY 5 day course of azithromycin increased risk of CV death and death from any cause compared to no antibiotic CV risk still greater with azithromycin in 10 day period following Rx fill, but not death from any cause N Engl J Med. 2012;366(20): Azithromycin and CV Death Azithromycin Vs. Amoxicillin Azithromycin increased risk for CV death compared to amoxicillin HR, 2.49; 95% CI, , P=0.002 Azithromycin increased risk for death from any cause compared to amoxicillin HR, 2.02; 95% CI, , P=0.005 Risk of CV death also higher for a 10 day period N Engl J Med. 2012;366(20):

11 Azithromycin and CV Death Azithromycin Vs. Fluoroquinolones Azithromycin increased risk for CV death compared to ciprofloxacin HR, 3.49; % CI, 132t 1.32 to ; P001 P=0.01 Azithromycin did not increase risk for CV death compared to levofloxacin HR, 1.27; 95% CI, 0.66 to 2.47; P=0.48 N Engl J Med. 2012;366(20): Azithromycin and CV Death Overall Conclusion Patients should not stop taking Azithromycin until resulted discussing in with small healthcare but significant professional. Prescribers should increase in risk for CV death be aware of the potential for QT Increase greatest prolongation for those and found arrhythmias to be at highest CV risk with azithromycin. 47 additional CV deaths per 1 million courses of azithromycin therapy when compared to amoxicillin Also increased risk for overall death, but not non CV death N Engl J Med. 2012;366(20): Azithromycin and CV Death Strengths Large cohort observed over several years 2 controls for confounders Validity of study assumptions tested, with similar results Limitations Observational, cannot observe cause and effect Data from only 1 geographic location Difficult to extrapolate to men, race other than white Accuracy of database/coding N Engl J Med. 2012;366(20):

12 Which of the following is true regarding azithromycin based on the recent trial in N Engl J Med? A. It can cause sudden CV death. B. It increases the risk for CV death compared to levofloxacin. C. It increases the risk for non CV death. D. It increases the risk for death from any cause compared to amoxicillin. Media Worthy Trial Assessment #3: THROMBOTIC STROKE AND MYOCARDIAL INFARCTION WITH HORMONAL CONTRACEPTION N Engl J Med. 2012;366(24):

13 Hormonal Contraception and VTE Attributed to Estrogens ethinyl estradiol Induction of hepatic procoagulant proteins Sex hormone binding globulins Newer generation progestins desogestrel, norgestimate, drospirenone Effect on coagulation and fibrinolytic pathways Resistance to activated protein C Pharmacists Letter/Prescriber s Letter. August 2012: # Hormonal Contraception and Thrombosis FDA study (n=835,826) Compared thrombosis rates between newer and older combined contraceptives VTErisk increased with ring, patch, anddrospirenone drospirenone compared to older combined contraceptives Denmark study VTE (n=1,626,158) Compared VTE rates between nonoral users to nonusers Risk increased with vaginal ring and transdermal patch BMJ. 2012;344:e Stroke, MI, and Hormonal Contraception Study objective To assess the risks of thrombotic stroke and MI associated with various types of hormonal contraception, according to estrogen dose, progestin type, and route of administration. Methods Historical cohort study N Engl J Med. 2012;366(24):

14 Stroke, MI, and Hormonal Contraception Study cohort Danish population from 1995 to 2009 Inclusion (and Endpoint Inclusion) Exclusion (and Endpoint Exclusion) Women 15 to 49 years of age Diagnostic codes for cerebral infarction and cerebral apoplexy Acute myocardial infarction N Engl J Med. 2012;366(24): Diagnostic code of transient ischemic i attack Prior diagnosis of venous or arterial thrombotic event Cancer (prior to study period) Gynecologic surgeries (some censored) Censored pregnancy and coagulation disorders Stroke, MI, and Hormonal Contraception Prescription/Lifestyle Data Obtained from The Register of Medicinal Product Statistics Categorized by: estrogen dose, progestin type, route of administration Duration of use: Rx fill date to last fill date/event Rxs for DM, arrhythmia, HTN, hyperlipidemia Smoking habits (from National Registry) N Engl J Med. 2012;366(24): Stroke, MI, and Hormonal Contraception Endpoints First ever thrombotic stroke and myocardial infarction N Engl J Med. 2012;366(24):

15 Variables Age Calendar year Educational level Type of contraception Duration of use Predisposing risk factors DM HTN Hyperlipidemia Arrhythmia Smoking N Engl J Med. 2012;366(24): Results: Overall Rates of Events 1,626,158 women with 14,251,063 person years of observation Hormonal Contraception Status Thrombotic Stroke Myocardial Infarction Rates higher in nonusers due to older Number/ age and more risk person years factors compared to nonusers Users Nonusers 1051/4.9 million 2260/9.3 million Crude incidence rates per 100,000 personyears Number/ Person years 497/4.9 million 1228/9.3 million Crude incidence rates per 100,000 personyears N Engl J Med. 2012;366(24): Does type of hormonal contraception affect rates of MI and stroke (according to this study)? 15

16 Results All other things being equal Progestin only products did not significantly increase risk of stroke or MI These include IUD and subcutaneous implants Risk of stroke was increased with vaginal ring (Adjusted RR=2.49; 95% CI, 1.41 to 4.41) but not patch N Engl J Med. 2012;366(24): Does type of progestin affect rates of MI and stroke (according to this study)? Results Progestins with lowest risk in combo with µg estrogen are of the 3 rd All other things being equal No difference in rates among COCs generation containing 30 to 40 µg ethinyl estradiol based on progestin type Combined Oral Contraceptives with µg Estrogen Event Risk Stroke, Adjusted RR (95% CI) MI, Adjusted RR (95% CI) Highest Lowest Desogestrel 2.20 ( ) Norethindrone 2.17 ( ) Norgestimate 1.52 ( ) Drospirenone 1.64 ( ) Norethindrone 2.28 ( ) Desogestrel 2.09 ( ) Norgestimate 1.33 ( ) Drospirenone 1.65 ( ) N Engl J Med. 2012;366(24):

17 ARR=2.20, 2.28 for stroke, MI when in combo with µg estrogen Results Combined Oral Contraceptives with 20 µg Estrogen Progestin Type Stroke ARR (95% CI) ARR=1.64, 1.65 for MI stroke, MI when in combo with µg estrogen Desogestrel 1.53 ( ) 1.55 ( ) Drospirenone 0.88 ( ) No MIs N Engl J Med. 2012;366(24): Results No difference in risk between previous users and those who had never used hormonal contraception Smoking was a risk factor, not a confounder N Engl J Med. 2012;366(24): Does estrogen dose affect rates of MI and stroke (according to this study)? 17

18 Results Adjusted RRs for Events with COCs Based on Estrogen Dose 50 µg: S, 1.97 and MI, µg: S, 1.75 and MI, µg: S, 1.60 and MI, 1.40 N Engl J Med. 2012;366(24): Stroke, MI, and Hormonal Contraception Strengths Limitations Large amount of data Study design Valid Rx detail Accuracy of Sensitivity analysis database/coding performed Some subgroups smaller Danish population Stroke, MI, and Hormonal Contraception Overall Conclusion Estrogen dose of µg combined with progestin correlated to a risk of arterial event 1.3to 2.3 timeshigher than nonusers Estrogen dose of 20 µg had risk of 0.9 to 1.7 times higher than nonusers Only small differences among progestins Arterial events not as frequent as VTE with hormonal contraception 18

19 Which of the following combinations had the highest rates of arterial events? A. Drospirenone + estrogen 20 µg B. Desogestrel + estrogen 20 µg C. Norethindrone + estrogen µg D. Norgestimate + estrogen µg Media Worthy Trial Assessment #4: THREE MONTHS OF RIFAPENTINE AND ISONIAZID FOR LATENT TUBERCULOSIS INFECTION N Engl J Med. 2011;365(23):

20 Treatment of Latent Tuberculosis (TB) MMWR Recomm Rep. 2003;52(RR-11):1-80. Treatment of Latent TB INH treatment completion rates usually 30% to 64% Efficacy important from public health standpoint Concern for hepatotoxicity 2002 RCT showed efficacy of weekly rifapentine and INH in continuation phase in patients with low bacterial burden Lancet. 2002;360(9332): Months of Treatment for Latent TB Study Objective To determine if a 3 month course of weekly rifapentine and INH could be effective in treating latent M tuberculosis (TB) Methods Prospective, open label, randomized, multi center, noninferiority trial N Engl J Med. 2011;365(23):

21 3 Months of Treatment for Latent TB Interventions Combination therapy group (N=3986): Rifapentine 900 mg + INH mg/kg (rounded to nearest 50 mg, max 900 mg) by mouth once weekly given under direct observation Isoniazid only group (N=3745): INH 5 15 mg/kg (rounded to nearest 50 mg, max 300 mg) by mouth daily self administered Followed for 33 months N Engl J Med. 2011;365(23): Months of Treatment for Latent TB Inclusion High risk for progression from latent to active TB Close contact of person with confirmed TB Positive result on tuberculin skin test HIV and positive tuberculin test, or negative if close contact CXR consistent with previously untreated TB N Engl J Med. 2011;365(23): Exclusion Confirmed TB Resistance to INH or rifampin (in source case) Tx with rifamycin or INH in past 2 years Previous TB Tx AST 5x ULN HIV Tx within 90 days after enrollment 3 Months of Treatment for Latent TB Primary endpoint Culture confirmed TB in patients >18 years Culture confirmed or clinical TB in patients <18 years Secondary endpoint Culture confirmed or clinical TB among all subjects Completion/discontinuation of study therapy Grade 3 or 4 drug related toxicities Death Resistance to a study drug N Engl J Med. 2011;365(23):

22 3 Months of Treatment for Latent TB Statistics Expected event rate of 1.5% in INH group Noninferiority margin set at 0.75% (upper limit) 3200 subjects/group provide power of 80% to show noninferiority of combination group to isoniazid only group N Engl J Med. 2011;365(23): Months of Treatment for Latent TB Demographics Median age 35 54% male 57% white, 25% black 89% from U.S. or Canada 57% completed HS 2% were HIV infection and very few had HBV, HCV 50% had a history of EtOH use >25% were current smokers N Engl J Med. 2011;365(23): Months of Treatment for Latent TB Overall, patients considered high risk 322 ineligible: drug resistant or Cx negative source cases Mean number of months in study ~30 Completion of 33 months Combination group: 88% Isoniazid group: 86% N Engl J Med. 2011;365(23):

23 3 Months of Treatment for Latent TB Upper bound of CI is <0.75% for both study populations = combo noninferior to INH N Engl J Med. 2011;365(23): Months of Treatment for Latent TB Results Adverse Events Subjects were more likely to complete therapy in combination group (82.1%) vs. isoniazid group (69.0%), P<0.001 But more in combo group discontinued due to adverse event (4.9% vs. 3.7%), P=0.009 More serious AEs in isoniazid group (2.9% vs. 1.6%, P<0.001) Hepatotoxicity higher with isoniazid (2.7% vs. 0.4%, P<0.001) N Engl J Med. 2011;365(23):

24 3 Months of Treatment for Latent TB Overall conclusions Rate of TB in combo group half of that in isoniazid alone group Combo therapy x 3 months may be treatment option for HIV negative patients with latent TB Formal cost analysis N Engl J Med. 2011;365(23): Months of Treatment for Latent TB Strengths Similar findings when risk factors adjusted for Large sample size Limitations Open label study Large noninferiority margin compared to incidence rate Only applicable to countries with low and medium rates of TB incidence Difficulty in capturing rare but serious AEs N Engl J Med. 2011;365(23): Latent TB Treatment Pros/Cons 3 Months of Rifapentine + Isoniazid 9 Months of Isoniazid Pros Cons Pros Cons Shorter duration/greater compliance Possibly more cost effective than isoniazid alone May be more effective in TB prevention than isoniazid alone Direct observation Current standard of care Lower compliance rates Not an option for Used in patients May be more costly patients withhiv with HIV than combination therapy May not be able to use in areas with high prevalence of TB Unknown resistance issues with rifapentine Used in areas with high prevalence of TB May be less effective than combination regimen N Engl J Med. 2011;365(23):

25 T/F: Rifapentine in combination with isoniazid had a greater rate of hepatotoxicity than did isoniazid alone. A. True B. False Questions? References Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease. CHEST. 2012;141(2_suppl):e419S e494s. Eikelboom JW, Hirsh J, Spencer FA, Baglin TP, Weitz, JI. Antiplatelet drugs. CHEST. 2012;141(2_suppl):e89S e119s. Becattini C, Agnelli G, Schenone A, et al. Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012;366(21): Mehta SR, Bassand JP, Chrolavicius S et al; CURRENTOASIS 7 Investigators. Dose comparisons of clopidogreland aspirin inacute coronary syndromes. N Engl J Med.2010 ;363(10): Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366(20): Owens RC Jr, Nolin TD. Antimicrobial associated QT interval prolongation: pointes of interest. Clin Infect Dis. 2006;43(12): PL Detail Document. Hormonal contraceptives and the risk of thrombosis. Pharmacists Letter/Prescriber s Letter. August 2012: #

26 References Ouellet Hellstrom R, Graham DJ, Staffa JA, et al. Combined hormonal contraceptives (CHCs) and the risk of cardiovascular disease endpoints. October 22, Accessed August 7, Lidegaard OM, Nielsen LH, Skovlund CW, Lokkegaard E. Venous thrombosis in users of nonoral hormonal contraception: follow up study, Denmark BMJ. 2012;344:e2990. Lidegaard O, Lokkegaard E, Jensen A, Skovlund CW, Keiding N. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med. 2012;366(24): Sundhedsstyrelsen: Danish Health and Medicines Authority. About the register of medicinal product statistics. Updated April 12, prices and reimbursement/statisticsand analyses/about the register of medicinal product tatistics. Accessed August 7, Sterling TR, Villarino E, Borisov AS, et al. Three months of rifapentine and isoniazid for latent tuberculosis infection. N Engl J Med. 2011;365(23): American Thoracic Society, CDC. Targeted tuberculin testing and treatment of latent tuberculosis infection. Am J Respir Crit Care Med. 2000;161:S221 S247. Available at References Centers for Disease Control and Prevention. Treatment of tuberculosis: American Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR Recomm Rep. 2003;52(RR 11):1 80. Benator D, Bhattacharya M, Bozeman L, et al. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug susceptible pulmonary tuberculosis in HIV negative patients: a randomized clinical trial. Lancet. 2002;360(9332): Supplementary appendix to Three months of rifapentine and isoniazid for latent tuberculosis infection. ndix.pdf. Accessed August 10, The World Health Organization. WHO policy on collaborative TB/HIV activities. Accessed August 13, Which of the following is TRUE regarding noninferiority trials? a. The standard of care is used as the active control. b. Superiority cannot be assessed. c. Placebo is used as the control. d. Achieving noninferiority means the comparison is the same as the active control 26

27 2. Which of the following statements is a reasonable conclusion from the WARFASA trial? a. Aspirin 325 mg daily is an effective regimen for further prevention of unprovoked venous thromboembolism after warfarin treatment is completed. b. The risk of bleeding outweighs the benefits of prevention of venous thromboembolism with aspirin. c. A low dose of aspirin for further prevention may be considered in patients with unprovoked venous thromboembolism who have completed warfarin treatment. d. The WARFASA trial showed a decrease in venous thromboembolism, myocardial infarction, and stroke in patients with unprovoked venous thromboembolism who were treated with aspirin, as compared to placebo, after warfarin therapy was completed. 3. True/false. Combination therapy of rifapentine with isoniazid was effective treatment of latent TB in patients who were co infected with HIV. a. True b. False 4. True/false. In combination oral contraceptives, the type of progestin correlated to a difference in arterial event risk when used in combination with 20 µg estrogen, but not when used in combination with µg estrogen. a. True b. False 27

28 5. Which of the following is true regarding azithromycin and the risk of sudden cardiac death? a. The results of the study warrant routine cardiac monitoring for patients taking azithromycin. b. The risk of death from any cause is increased with azithromycin as compared to amoxicillin. c. The risk of cardiovascular death is increased with azithromycin as compared to levofloxacin. d. The Food and Drug Administration recommends prescribers to avoid prescribing azithromycin in patients with risk factors for sudden cardiac death. 28