β-‐blockers and Cocaine: Fatal Attraction? Cristina Gonzales, PharmD PGY1 Pharmacy Resident Central Texas Veterans Health Care System March 2, 2012 Learning Objectives By the end of this presentation, the participant should be able to: 1. Discuss the historic use of β-‐blockade in cocaine toxicity 2. List the adverse effects related to cocaine use 3. Discuss the management of cocaine-‐associated chest pain (CACP) and myocardial infarction (MI) 4. Evaluate the evidence available regarding use of β-‐blockers in the patients presenting with acute coronary syndromes (ACS) related to cocaine use BACKGROUND INFORMATION I.
Historic use of β-‐blockade in cocaine toxicity59 a. 1976 and 1977-‐ Rappolt et al. published reports advocating the use of IV propranolol in management of cocaine toxicity because of the “strikingly specific antagonistic effects”1-‐3 i. Observed more than 50 cases of successful treatment of cocaine overdose in San Fransisco ii. At that time, the presumed risks of cocaine overdose included cerebrovascular accident, lethal arrhythmias, and high output congestive heart failure (CHF) b. 1982-‐ The first report of myocardial ischemia and infarction as a result of cocaine use4 c. 1985-‐ Ramoska and Sacchetti proposed that propranolol should be used with caution in cocaine intoxication because of “unopposed α stimulation” causing paradoxic hypertension5 i. Initiated a shift to the current clinical practice of withholding β-‐blockers in patients with cocaine-‐induced ACS d. 1990-‐Lange et al. reported that patients exposed to nasal cocaine during catheterization studies following a challenge with intracoronary propranolol had coronary vasoconstriction6 i. Powerful image from study demonstrated abrupt occlusion of the left circumflex artery in one subject, reversal of vasoconstriction was managed with nitroglycerin II.
Two premises for β-‐blocker contraindication59 a. Cocaine chest pain = spasm i. Schachne et al. report that finding normal coronary arteries in young patients with cocaine-‐ triggered MI suggest that “cocaine could cause coronary vasospasm and MI”7 ii. Myocardial perfusion imaging studies rarely demonstrate reversible perfusion defects consistent with vasospams8-‐9 iii. Vasospasms may play a role in CACP, the pathophysiology of cocaine toxicity is complex59 b. Cocaine + β-‐blocker →unopposed α effect i. Ramoska and Sacchetti observed that blood pressure (BP) increased from 170/118 to 180/140 mm Hg after administration of propranolol in a single subject5 ii. Cocaine induced vasoconstriction was exacerbated by propanolol in cardiac catheterization study by Lange et al6 iii. Series of 7 patients with cocaine intoxication treated with esmolol, both hypotension and hypertension were noted10 iv. Other evidence for deleterious effects of β-‐blockade in cocaine toxicity relies on rodent or porcine models11-‐1 14
Figure 4: Proposed Unopposed α Effect Mechanism Gonzales Page 2 III. Epidemiology15,16,17,31,40 a. Cocaine is the second most commonly used illicit drug in the US15 b. Cocaine is the illicit drug that leads to the most emergency department (ED) visits16 c. In 2002 and 2003, more than 1.5 million (0.6%) Americans ≥ 12 years of age had abused cocaine in the past year d. Cocaine use is concentrated among select demographics17: i. Individuals 18 to 25 years of age (1.2%) have highest rate of cocaine use ii. Males (0.9%) had more than twice the use rate of females (0.4%) iii. Rates according to race are 1.1% for blacks, 0.9% for Hispanics, 0.5% for whites, and 0.1% for Asians e. Cocaine is associated with both acute and chronic cardiovascular diseases f. Since the late 1970s the literature has been abundant with cases of cocaine-‐induced myocardial infarction (CIMI) g. MI falls under the umbrella of ACS Figure 1: Acute Coronary Syndrome http://pmj.bmj.com/content/81/954/217/F1.large.jpg h. Chest discomfort has been reported in 40% of patients who present to the ED after cocaine use31 i. The incidence of cocaine associated MI varies between studies from 0.7% to 6%40 IV. Pathophysiologic Effects of Cocaine19,20,22,23,24,26,27,28,30,40,46-‐49 a. Cocaine has multiple cardiovascular and hematologic effects that likely contribute to the development of myocardial ischemia and or MI40 b. Cocaine blocks the reuptake of norepinephrine (NE) and dopamine (DA) at the presynaptic adrenergic terminals causing catecholamine accumulation at the postsynaptic receptor, therefore it acts as a powerful sympathomimetic agent19,20 c. Increases heart rate (HR) and BP in a dose-‐dependent fashion21 d. By increasing HR, BP, and contractility, cocaine leads to increased myocardial demand40 e. Stimulation of the α-‐adrenergic receptors in smooth muscle cells in the coronary arteries likely leads to vasoconstriction 22 f. Cocaine has been shown to increase levels of endothelin-‐1, a powerful vasoconstrictor and decrease levels of nitric oxide, a vasodilator24 g. Combining cocaine use with cigarette smoking has additive effects on coronary vasoconstriction22 h. Cocaine use is associated with premature coronary atherosclerosis and thrombosis Gonzales Page 3 i.
Thrombus formation in the setting of cocaine use may be mediated by an increase in plasminogen-‐
activator inhibitor j. Cocaine use has been associated with an increase in platelet count27, increased platelet activation28, and platelet hyperaggregability29 k. Long term cocaine users demonstrate endothelial dysfunction47 i. Endothelial dysfunction increases the sensitivity of a vessel to constrictor effects of catecholamines l. Cocaine users have elevated levels of C-‐reactive protein, von Willebrand factor, and fibrinogen30 m. Cocaine also acts like a class I antiarrhythmic agent (local anesthetic) by blocking sodium (Na+) and potassium channels (K+), which depresses cardiovascular parameters46 i. Cocaine affects cardiac myocytes directly by blocking Na+ which decreases left ventricular contractility and is arrhythmogenic n. Cocaine has opposing actions46 i. Enhanced sympathetic activity predominates at low cocaine dose ii. Local anesthetic actions are more prominent at higher doses 47
Figure 2: Cardiovascular Effects of Cocaine http://circ.ahajournals.org/content/122/24/2558 Table 1: Cardiovascular Effects of Cocaine47 Causes of Myocardial Worsens Myocardial Oxygen Supply-‐
Performance Demand Mismatch Increases HR Decreases ejection fraction Increases BP Increases end-‐systolic volume Decreases coronary Increases end-‐diastolic artery diameter pressure Decreases coronary Lengthens deceleration blood flow time Increases left ventricular hypertrophy Causes Cardiovascular Disease Arrhythmias Causes Clinical Cardiovascular End Points MI QT prolongation Arrhythmias Thrombosis CHF Atherosclerosis Cardiomyopathy Endothelial dysfunction Aortic dissection Microvascular disease Endocarditis Sudden death Gonzales Page 4 V. Clinical Presentation of CACP and MI31,35,47 a. Patients presenting with CACP are typically young, male, cigarette smokers, with few other cardiac risk factors47 b. Cardiopulmonary complaints are most reported (56%)35 i. Chest pain is the single most frequent symptom ii. Other frequent symptoms include: dyspnea, anxiety, palpitations, dizziness, and nausea c. CACP may be caused by aortic dissection47 d. Acute pulmonary syndrome called “crack lung”35 i. Involves hypoxemia, hemoptysis, respiratory failure, and diffuse pulmonary infiltrates ii. Occurs after inhalation of free base cocaine e. In patients with CACP, no historical or presenting features distinguish between patients with and those without MI47 f. Any route of cocaine administration can precipitate MI and no route is more predictive than another47 VI. Timing Between Cocaine Use and MI37,40,47 a. Cocaine-‐associated MI (CAMI) appears to occur soon after cocaine ingestion and individuals are at the highest risk of developing cocaine-‐induced acute coronary syndrome (CIACS) within the first hour of cocaine use40 b. In one study two-‐thirds of MI events occurred within 3 hours of cocaine ingestion37 c. The time between cocaine use and MI has ranged from 1 minute to up to 4 days in various studies37 d. The onset of ischemic symptoms could still occur several hours after cocaine ingestion, at a time when blood concentrations are low or undetectable e. Cocaine metabolites rise in concentrations several hours after cocaine ingestion, can persist in the circulation for up to 24 hours, and may cause delayed or recurrent coronary vasoconstriction40 VII. Complications and Prognosis of CAMI37 a. In the Cocaine-‐Associated Myocardial Infarction study 38% of patients had cardiac complications i. 7% of patients had heart failure ii. 43% of patients had arrhythmias b. 90% of the complications occurred within the first 12 hours of hospital presentation and did not lead to significant adverse events, with an in-‐hospital mortality of 0% DIAGNOSTIC STRATEGIES AND EVALUATION OF ACUTE CORONARY SYNDROMES I.
Detecting Cocaine33 a. The use of cocaine can be ascertained by self-‐reports or by urine analysis b. Qualitative immuno-‐assay detection of the cocaine metabolite benzoylecgonine in the urine is the most commonly used laboratory method i. Cocaine can also be detected in the blood or hair c. Cocaine use is reported as positive when the level of benzoylecgonine is above the standard cut-‐off value (usually 300 ng/ml) i. Benzoylecgonine has a urinary half-‐life of 6-‐8 hours ii. It can be detected in the urine for about 24 to 48 hours after cocaine use iii. Among individuals with long-‐term cocaine use (who may ingest up to 10g/day) benzoylecgonine has been detected for 22 days after last ingestion II. Electrocardiogram (ECG)35,36,50 a. Interpreting the ECG in patients with CACP is challenging because the initial ECG is abnormal in 56%-‐84% of patients36 b. In a cohort of 101 patients with CACP, 42% of patients manifested with electrocardiographic ST-‐segment elevations, although all of them had MI excluded by cardiac marker testing36 c. In 246 patients with CACP, the ECG predicted acute MI with a sensitivity of 36%, a specificity of 90%, a positive predictive value of 18%, and a negative predictive value of 96%50 d. ECG is poorly associated with acute MI in patients with CACP Gonzales Page 5 Cardiac Biomarkers36-‐37 a. Cocaine ingestion may cause rhabdomyolysis with consequent elevation in myoglobin and total creatinine kinase (CK) levels36 b. The specificities of cardiac biomarkers for diagnosing MI varied depending on cocaine use37 i. Specificities in patients without cocaine use were 94% for cardiac troponin I, 88% for creatinine kinase muscle and brain (CK-‐MB), and 82% for CK ii. In patients with cocaine use the specificities were 94% for cardiac troponin I, 75% for CK-‐MB, and 50% for CK c. Cardiac troponins are the most sensitive and specific markers for the diagnosis of CACP IV. Myocardial Perfusion Imaging40 a. Rest myocardial perfusion imaging has been evaluated in low to moderate risk patients after cocaine use b. Of 216 patients, only 5 had positive results; 2 of the 5 patients with an abnormal scan had an MI documented by cardiac marker criteria V. Echocardiography40,51 a. Echocardiography yields information concerning systolic and diastolic function and valvular structure51 b. Dobutamine stress echocardiography has been safely performed in subjects admitted with chest pain after cocaine use, provided they exhibited no signs of ongoing cocaine toxicity40 VI. Coronary Angiography52 a. In a study of 734 patients evaluated for ischemia after cocaine use, 90 underwent coronary angiography i. Of patients with proven MI, 77% had significant coronary artery disease (CAD) ii. Of patients without MI, 35% had significant CAD VII. Evaluation of chest pain38,47,53 a. Diagnosing MI in cocaine-‐using patients is challenging38 b. Clinicians should have a high index of suspicion for cocaine use in young patients presenting with chest pain and should pursue a history of cocaine use with direct questioning in all patients and with urine toxicology in select patients47 c. Diagnostic uncertainty has prompted unnecessary hospitalization in many cocaine using patients d. Given that complications rarely occur >12 hours after initial presentation to the ED, Weber et al. proposed a 12-‐hour observation period for patients with CACP53 GENERAL MANAGEMENT OF COCAINE-‐ASSOCIATED CHEST PAIN I.
Therapeutic Strategies47 a. Treatment for chest pain and ACS in cocaine-‐using patients is similar to that in patients with traditional risk factors but differs in the use of benzodiazepines and phentolamine and avoidance of β-‐blockers III.
Figure 3: Treatment algorithm for patients with cocaine-‐associated chest pain
47 Gonzales Page 6 b. Benzodiazepines54-‐56 i. In the setting of cocaine use, benzodiazepines relieve chest pain and have beneficial cardiac hemodynamic effects ii. In animal models, benzodiazepines decrease the central stimulatory effects of cocaine, thereby indirectly reducing cardiovascular toxicity iii. Intravenous diazepam54 and lorazepam56 have been studied c. Phentolamine47,57 i. An α-‐antagonist used predominantly in the treatment of hypertensive emergencies, appears to benefit cocaine-‐using patients with ischemia ii. In 45 patients undergoing cardiac catheterization for the evaluation of chest pain, phentolamine abolished the effects of cocaine on HR, BP, coronary artery diameter, and coronary sinus blood flow57 iii. Short half-‐life and significant side effects limit the clinical utility of phentolamine in the general population, but the mechanism of action is ideal for treatment of cocaine-‐induced vasoconstriction47 d. Calcium channel blockers (CCBs)40,47 i. Because CCBs have not demonstrated important clinical endpoints in trials including patients with ACS unrelated to cocaine use, their role in cocaine-‐using patients with chest pain may be limited to second-‐line therapy ii. Short acting nifedipine should not be used iii. Diltiazem and verapamil should be avoided in patients with heart failure, systolic dysfunction, bradycardia, or heart block e. Nitroglycerin47,54 i. Nitroglycerin can be used to control hypertension when a patient does not respond to benzodiazepines ii. Nitroglycerin is similar to benzodiazepines with respect to relief of CACP54 f. Other therapeutic agents40,47 i. Cocaine promotes thrombus formation, so antiplatelet and antithrombin agents may be beneficial, but they have not been well studied in patients with CACP ii. Aspirin should be routinely administered for patients with CACP and continued indefinitely for patients with MI or CAD iii. Other agents including clopidogrel, heparin, and glycoprotein IIb/IIIa inhibitors, should be administered as indicated by published guidelines g. Discharge management and secondary prevention40 i. Cessation of cocaine use should be the primary goal for secondary prevention ii. No established drug treatment exist for cocaine dependency iii. Aggressive modification of traditional risk factors indicated for patients with MI or evidence of atherosclerosis 1. Smoking cessation 2. Hypertension control 3. Diabetes control 4. Aggressive lipid lowering therapy 5. Long term antiplatelet therapy with aspirin for patients with evidence of MI or atherosclerosis 6. Nitrates and CCBs to treat antianginal symptoms 7. Angiotensin-‐converting enzyme (ACEIs) inhibitors Gonzales Page 7 Scientific strength for treatment recommendations 40,63 a. Classification of recommendations and levels of evidence are expressed in the American College of Cardiology/American Heart Association (ACC/AHA) format as follows: Class I: Conditions for which there is evidence for and/or general agreement that the procedure or treatment is beneficial, useful, and effective. Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatment. Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy. Class IIb: Usefulness/efficacy is less well established by evidence/opinion. Class III: Conditions for which there is evidence and/or general agreement that the procedure/treatment is not useful/effective and in some cases may be harmful. Level of Evidence A: Data derived from multiple randomized clinical trials. Level of Evidence B: Data derived from a single randomized trial or nonrandomized studies. Level of Evidence C: Only consensus opinion of experts, case studies, or standard of care. Table 2: Scientific Strength for Treatment Recommendations for Initial Management of Cocaine-‐Associated Myocardial Ischemia or Infarction40 Therapy Classification of Controlled Cardiac Case Series or Case Controlled In Recommendation/Level Clinical Catheterization Observational Reports Vivo Animal of Evidence Trials Laboratory Studies Experiments Studies II.
Benzodiazepines I/B X X X Aspirin I/C X Nitroglycerin I/B X X X CCBs IIb/C X X Phentolamine IIb/C X X X III/C X X X β-‐blockers Labetalol III/C X X X No. of patients in studies/reports: benzodiazepines, 67; phentolamine, 45; CCBs, 15; β-‐blockers without α-‐blocking properties, 30; labetalol, 15; fibrinolytics, 66. Table 3: Scientific Strength for Treatment Recommendations for Management of Patients with Unstable Angina/Non STEMI63 Therapy Classification of Recommendation/Level of Evidence Nitroglycerin I/C CCBs I/C Labetalol IIb/C β-‐BLOCKERS I.
Therapeutic Recommendations 40,42,43 a. β-‐adrenergic antagonists should not be administered acutely in patients with CACP and/or MI because of concerns about provoking or exacerbating coronary spasm i. ACC/AHA ST-‐segment elevation MI guidelines state, “Beta-‐blockers should not be administered to patients with STEMI precipitated by cocaine use because of the risk of exacerbating coronary spasm” (pE38)42 ii. The 2005 AHA Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care state “propranolol is contraindicated in cocaine overdose” (p130) and “propranolol is contraindicated for cocaine induced ACS” (p129)43 Gonzales Page 8 b. 2011 ACCF/AHA Focused Update Incorporated Into the American College of Cardiology/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non STEMI states, “Administration of combined alpha-‐ and beta-‐blocking agents (e.g., labetalol) may be reasonable for patients after cocaine use with hypertension (systolic blood pressure greater than 150 mm Hg) or those with sinus tachycardia (pulse greater than 100 beats per min) provided that the patient has received a vasodilator, such as NTG or a calcium channel blocker, within close temporal proximity (Class IIb/C,)”63 i. The 2008 scientific statement from the AHA/ACC regarding management of CACP lists classification of recommendation/level of evidence for benzodiazepines as I/C and phentolamine as IIb/C respectively, neither medication is mentioned in the updated 2011 guidelines ii. Additionally the 2008 AHA/ACC statement lists CCBs as IIb/C, nitroglycerin as I/B, and β-‐blockers as III/C c. Post-‐discharge use of β-‐blockers, although clearly beneficial among patients with previous MI and cardiomyopathy who do not abuse cocaine, merits special consideration in the setting of cocaine abuse40 d. Chronic β-‐blocker use should be reserved for those with the strongest indications including:40 i. Documented MI ii. Left ventricular systolic dysfunction iii. Ventricular arrhythmias iv. In patients whom the benefits may outweigh the risks even among patients at risk for recurrent use of cocaine e. The decision should be individualized on the basis of careful risk-‐benefit assessment and after counseling the patient about the potential negative interactions between recurrent cocaine use and β-‐
blockade II. Mechanism of action a. Several mechanisms of action have been proposed b. β-‐blockers have negative chronotropic and ionotropric cardiac effects that reduce cardiac output c. β-‐Adrenoceptors are located on the surface of juxtaglomerular cells, and β-‐blockers inhibit these receptors and thus the release of rennin Table 3: Major effects mediated by α and β adrenoceptors α 1 α 2 β1 β2 Vasoconstriction Tachycardia Vasodilation Increased peripheral resistance Inhibition of norepinephrine release Inhibition of insulin release Increased lipolysis Increased blood pressure Mydriasis Increased myocardial contractility Increased release of renin Slightly decreased peripheral resistance Bronchodilation Increase in closure of internal sphincter of bladder Increased muscle and liver glycogenolysis Increased release of glucagon Relaxed uterine smooth muscle III.
Pharmacokinetics58 a. Pharmacokinetic differences among β-‐blockers relate to first-‐pass metabolism, route of elimination, degree of lipophilicity, and serum half-‐lives b. Propranolol and metoprolol undergo extensive first-‐pass metabolism i. Amount of drug needed to attain β-‐blockade with either drug varies from patient to patient c. Atenolol and nadolol are renally excreted d. β-‐blockers with highly lipophilic properties, penetrate the CNS and can cause other effects i. Propranolol is the most lipophilic drug and atenolol is the least lipophilic Gonzales Page 9 e. Most β-‐blockers are well absorbed after oral administration; peak serum concentrations occur 1-‐3 hours after ingestion f. β-‐blockers are rapidly distributed and have large volumes of distribution g. Selectivity of β-‐blockers differs: Cardioselective Atenolol Betaxolol Bisoprolol Metoprolol tartrate Metoprolol succinate Nonselective Nadolol Propranolol Timolol ISA Acebutolol Carteolol Penbutolol Pindolol Mixed α and β blockers Carvedilol Labetalol Adverse effects41,58 a. Cardiovascular i. Precipitation or worsening of CHF and significant chronotropy ii. β-‐blocker withdrawal b. Noncardiovascular i. Increased airway resistance ii. Exacerbation of peripheral artery disease (PAD) iii. Facilitation of hypoglycemia iv. Hyperkalemia v. Depression, fatigue, weight gain, and sexual dysfunction V. The Controversy a. Should β-‐blockers be used in the treatment of CIACS? i. β-‐blockers have been avoided when cocaine use is suspected due to potential augmentation of coronary artery vasoconstriction ii. The guidelines indicate that CACP should be evaluated differently that other patients with ACS 1. Although some authors may disagree, this advice has been accepted as fact for more than two decades iii. Elevated troponins remain the only reliable indicator in CIMI compared with typical ACS measures such as ECG and elevated CK iv. β-‐blockers have been shown to reduce myocardial oxygen demand, cardiac workload, and morbidity and mortality LITERATURE REVIEW Potentiation of Cocaine-‐Induced Coronary Vasoconstriction by Beta-‐Adrenergic Blockade6 OBJECTIVE To determine whether β-‐adrenergic blockade augments cocaine-‐induced coronary artery vasoconstriction METHODS Subjects: IV.
Inclusion Criteria • Clinically stable patient volunteers referred for catheterization for evaluation of chest pain STATISTICAL ANALYSIS RESULTS Exclusion Criteria • Hypertension • Recent MI • History of pseudocholinesterase deficiency Study design: Randomized, double-‐blind, placebo-‐controlled trial Setting: A cardiac catheterization laboratory in an urban teaching hospital Interventions: • HR, arterial pressure, coronary sinus blood flow, and epicardial left coronary arterial dimensions were measured before and 15 minutes after intranasal saline or cocaine administration (2mg/kg body weight) and again after intracoronary propranolol administration (2mg in 5 minutes) Statistical tests: Paired t-‐ tests • For all analyses, a P value of less than 0.05 was considered significant Baseline characteristics: • 30 patients agreed to participate in the study Gonzales Page 10 25 men and 5 women ranging from 38 to 68 years of age All subjects were studied in the fasting state after premedication with between 5 and 10mg of oral diazepam • Anti-‐anginal medications were discontinued more than 12 hours before the study Hemodynamic and Arteriographic Response to Intranasal Saline or Cocaine Administration: •
•
Hemodynamic and Arteriographic Response to Intranasal Cocaine Administration Followed by Propranolol: • Intracoronary propranolol administration caused no change in arterial pressure or rate pressure product, but decreased coronary sinus blood flow and increased coronary vascular resistance • Arteriogram of the left coronary artery after propranolol administration shows occlusion of the circumflex artery o Flow to the artery was quickly resorted by administration of sublingual nitroglycerin Top panel: Arteriogram of the left coronary artery in the right anterior oblique projection after intranasal cocaine administration. Gonzales Page 11 Bottom panel: Arteriogram of the left coronary artery shows occlusion (arrow). AUTHOR’S “Cocaine-‐induced coronary vasoconstriction is potentiated by β-‐adrenergic blockade. Beta-‐adrenergic CONCLUSION blocking agents probably should be avoided in patients with cocaine associated myocardial ischemia or infarction.” CRITIQUE Strengths Weaknesses • Randomized, double-‐blind placebo • Small sample size controlled trial • Effects of cocaine are limited to intranasal route • Equal distribution of patients into • Patients in study did not have a history of cocaine use two groups IMPLICATIONS This study was one of few randomized-‐placebo controlled trials to evaluate β-‐blockers in a catheterization lab. Further studies are needed since the deleterious effects of β-‐blockers may be more pronounced immediately after cocaine use. β-‐blockers Are Associated With Reduced Risk of Myocardial Infarction After Cocaine Use44 OBJECTIVE To analyze the safety of β-‐blockers in patients with positive urine toxicology results for cocaine METHODS Subjects: Inclusion Criteria • Patients admitted to telemetry, medical, and coronary ICUs with UDS positive for cocaine between July 1, 2000 and June 30,2005 STATISTICAL ANALYSIS Exclusion Criteria • Patients who had been prescribed β-‐blockers as an outpatient but not during their course of admission • Admissions during which cardiac markers were not checked were excluded from analysis Study design: Retrospective cohort study Primary endpoint: • Myocardial infarction o Defined by troponin I level greater than 0.10 or significant ST elevations in 2 contiguous leads by ECG associated with chest pain or anginal equivalents Secondary endpoints: • In-‐hospital mortality o Defined as death from any cause and at any time in the course of hospitalization after β-‐blocker administration Statistical tests: Multivariate logistic regression model, propensity scores, Hosmer and Lemeshow goodness-‐of-‐fit test Gonzales Page 12 RESULTS Baseline demographics: • Patients who received β-‐blockers were older, and had a more frequent history of hypertension and heart failure and a less frequent history of asthma • Patients given β-‐blockers had higher systolic BP on admission, higher glucose, and lower serum albumin levels • Among patients who had echocardiograms, EF was lower for patients who received β-‐blockers • Patients who received β-‐blockers were at greater risk for CAD and systolic dysfunction Primary Endpoint: Myocardial Infarction • The incidence of myocardial infarction was significantly lower for patients who received β-‐
blockers (6.1% vs. 26%; difference in proportion 19%; CI 10.3% to 30%;OR 0.17, 95% CI 0.04, 0.08) • Multivariate analysis showed that the use of β-‐blockers significantly reduced the risk of MI (odds ratio 0.06; 95% CI 0.01 to 0.61) Secondary endpoint: In-‐hospital Mortality Gonzales Page 13 14 patients died during hospitalization o 1 patient who received a β-‐blocker compared to 13 patients who did not • Were significantly more likely to be women and have a history of HIV disease, history of heart failure, lower systolic BP, lower serum albumin, and higher BUN, potassium, and Scr on admission • β-‐blocker use was associated with a nonsignificant reduction in risk of death “In our cohort, administration of β-‐blockers was associated with reduction in incidence of myocardial infarction after cocaine use. The benefit of β-‐blockers on myocardial infarction may offset the risk of coronary artery spasm.” Strengths Weaknesses • Propensity scores used to assess non-‐
• Retrospective design randomly assigned data • β-‐blocker group had higher risk of CAD, higher glucose levels,↑BP, and poor left ventricular function • Comorbidities contributed to results observed • Small sample size • Lacked sufficient statistical power to explore the effect on in-‐hospital mortality • Large number of sepsis patients where β-‐
blockers are generally avoided • Long term mortality was not assessed • Only a small portion of patients were admitted with chest pain • No data on the actual time of cocaine ingestion Determining whether patients were acutely intoxicated with cocaine was difficult to access since that data was not provided. Study results are preliminary and warrant a randomized, prospective trial with a larger group of patients. •
AUTHOR’S CONCLUSION CRITIQUE IMPLICATIONS OBJECTIVE METHODS β-‐blockers for Chest Pain Associated With Recent Cocaine Use45 To test the hypothesis that β-‐blockers are safe in the setting of cocaine use Subjects: Inclusion Criteria • Consecutive patients admitted to San Francisco General Hospital with chest pain and urine toxicological test results positive for cocaine from January 20011 to December 2006 STATISTICAL ANALYSIS Exclusion Criteria • Patients with chest pain diagnosed as pulmonary in etiology while in the ED (such as pneumonia or pulmonary embolus) Study design: Retrospective cohort study Follow-‐up: Median of 972 days Primary endpoint: Death Secondary endpoints: Peak troponin level in the first 24 hours of admission, ventricular fibrillation or ventricular tachycardia requiring defibrillation, need for intubation, need for vasopressor agent, and cardiovascular death as determined by death certificates from the National Death Index Statistical tests: • Wilcoxon signed ranked, t-‐tests, X2 tests, linear regression analysis, Cox proportional hazards, Kaplan-‐Meier • Two-‐tailed P value <.05 were considered statistically significant Power analysis: • 80% to detect a difference in proportions of 5% vs 11%, with a 2-‐tailed α level of 0.05 Gonzales Page 14 RESULTS Baseline characteristics: • Patients who received β-‐blockers in the ED were older, had higher presenting systolic BPs, more often had a history of hypertension, more likely to be taking outpatient ACEIs or ARBs, statins, and aspirin Primary endpoint: Mortality • Neither receipt of β-‐blocker nor being discharged on a β-‐blocker regimen was associated with incident mortality • Over a median follow-‐up of 972 days (interquartile range, 555-‐1490 days), after adjusting for potential confounders, patients discharged on a β-‐blocker regimen exhibited a significant reduction in cardiovascular death (hazard ratio, 0.29; 95% confidence interval, 0.09-‐ 0.98) (P=.047). Gonzales Page 15 Secondary endpoints: Outcomes during hospitalization • No significant differences in catastrophic events (such as requiring intubation, vasopressor agents, developing malignant ventricular arrhythmias, or death) nor was there a difference in the length of hospital stay between those who did and did not receive β-‐blocker in the ED • After adjusting for other antihypertensive medications received at the time of first β-‐blocker administration, patients that received a β-‐blocker in the ED had a mean 8.6 mmHg greater decrease in systolic BP (95% CI, 14.7– to 2.5– mmHg greater decrease) than those who received a β-‐blocker in the hospital ward (P = .006) “β-‐blockers do not appear to be associated with adverse events in patients with chest pain and recent cocaine use.” Strengths Weaknesses • Sample size • Retrospective observational study, no standardization of care between the two groups • Other antihypertensive medications listed studied • Equal distribution of patients in two groups • Other antihypertensive medications listed • Unable to confirm last time of cocaine ingestion • Average age of patients was 50 IMPLICATIONS This was the first study to demonstrate that β-‐blockers administered in the setting of cocaine use and chest pain did not cause any adverse effects. Prospective clinical trials are warranted to better understand the true risk and benefit of β-‐blocker administration in the acute setting of cocaine use. There is not sufficient data to support the immediate administration of β-‐blockers in a ED setting. AUTHOR’S CONCLUSION CRITIQUE Gonzales Page 16 SUMMARY OF ADDITIONAL LITERATURE Source Boehrer JD, et al.60 1993 Design Prospective, non-‐
randomized, non-‐controlled study. N=15. Sand IC, et al.10 1991 Case series. N=7 Ramoska E, Sacchetti AD. 5 1985 Case Study. N=1 Gay GR, Loper KA.61 1988 Case report. N=1 Dusenberry SJ, Hicks MJ.62 1987 Case report. N=1 Vargas R, et al.11 1990 Animal study Results Hemodynamics were measured during PCI, before and after administering intranasal cocaine, and again after labetalol administration. Author’s conclusion: Labetalol reverses the cocaine-‐induced rise in mean arterial pressure (MAP), but does not alleviate cocaine-‐induced coronary vasoconstriction. No consistent hemodynamic benefit was found with the use esmolol. Although there was a decline in mean HR of 23% they were unable to show a consistent antihypertensive response. Adverse effects occurred in three patients. One patient had marked exacerbation of hypertension and one became hypotensive. Another patient developed emesis and lethargy during esmolol therapy and required endotracheal intubation. Author’s conclusion: We cannot recommend the routine use of esmolol in cocaine cardiotoxicity. Patient presented to the ED with BP 180/120, and HR 120. After giving propranolol, the HR decreased, but BP increased. The patient was then treated with nitroprusside. Author’s conclusion: The effect of propranolol was expected due to propranolol blocking β1 and β2 receptors, resulting in unopposed α1 stimulation. Labetalol was used successfully to treat BP 230/110 and HR 185 after ingesting a large dose of cocaine (20g). A labetalol drip was started to keep HR less than 100, and DBP less than 90. Author’s conclusion: Labetalol offers the advantage of α and β blockade in attenuating the hyperdynamic cardiovascular state. Labetalol was used successfully to treat BP 220/110 and HR 180 in the setting of cocaine use. There were no adverse effects noted from labetalol in this patient. Author’s conclusion: Combined α and β blockade may have a promising role in the management of adrenergic storm, such as from cocaine use. Porcine coronary arteries were used this study. Cocaine itself did not promote contraction, but a concentration-‐response curve was obtained in the presence of propranolol. In the presence of propranolol, the vasoconstrictive effect of cocaine was subject to rapid tachyphylaxis. Author’s conclusion: Coronary vasoconstriction elicited in the presence of propranolol can be mediated through local adrenergic mechanisms involving β -‐ receptor antagonism and activation of both α1 and α2 adrenoceptors. CONCLUSIONS I.
General Recommendations a. All patients discharged from hospitals for CACP should have a primary goal of cocaine cessation b. Discharge management and secondary prevention of CACP and MI should be followed according to AHA/ACC guidelines40 II.
Cocaine abuse remains prevalent with large numbers of patients presenting to the ED each year with CACP a. Despite the pathophysiologic effects of cocaine, the incidence of MI remains low b. Standard monitoring with ECG and serial troponins in an observation unit appears to be safe c. Although limited data exists, treatment with aspirin, benzodiazepines, nitroglycerin, phentolamine, and CCBs are recommended III.
The current data concerning the use of β-‐blockers during the acute management of CACP or MI have significant limitations IV.
Clinicians must weigh the risk versus benefits for patients for ACS and positive UDS results for cocaine who are not acutely intoxicated V.
Future research a. Additional well-‐designed studies evaluating the risk of using β -‐blockers in the acute management of cocaine toxicity are needed in order to make more concrete recommendations i. Due to the low overall assumed risk of cocaine-‐induced cardiovascular complications and lack of financial incentives large prospective, randomized trials may never be performed ABBREVIATIONS ABBREVIATION ED CIMI CAMI MI ACS STEMI NSTEMI UA DEFINITION Emergency Department Cocaine-‐Induced Myocardial Infarction Cocaine-‐Associate Myocardial Infarction Myocardial Infarction Acute Coronary Syndromes ST-‐Segment Elevation Myocardial Infarction Non-‐ST-‐Elevation Myocardial Infarction Unstable Angina ABBREVIATION O2 CACP ER CIACS CHF CK-‐MB OR ACC/AHA HR BP +
K +
Na CV Α Β SOB UDS NE DA Heart Rate Blood Pressure Potassium Sodium Cardiovascular α β Shortness of Breath Urine Drug Screen Norepinephrine Dopamine CCB ACEIs ARB ISA PAD ECG, EKG CK ARF MAP CAD Scr DEFINITION Oxygen Cocaine-‐Associated Chest Pain Emergency Room Cocaine-‐Induced Acute Coronary Syndrome Congestive Heart Failure Creatinine Kinase Muscle and Brain Odds Ratio American College of Cardiology/American Heart Association Calcium Channel Blockers Angiotensin-‐Converting Enzyme Inhibitors Angiotensin Receptor Blocker Intrinsic Sympathomimetic Activity Peripheral Arterial Disease Electrocardiogram Creatinine Kinase Acute Respiratory Failure Mean Arterial Pressure Coronary Artery Disease Serum Creatinine REFERENCES 1. Rappolt RT, Gray GR, Inaba DS. Propranolol in the treatment of cardiopressor effect of cocaine [letter]. N Engl J Med. 1976;295:448. 2. Rappolt RT, Gay G, Inaba DS, et al. Propranolol in cocaine toxicity. Lancet. 1976;2:640-‐641. 3. Rappolt RT, Gay GR, Inaba DS. 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