Longterm betablocker therapy safe and effective in reducing

Long-term beta-blocker therapy safe and effective in reducing cardiomyopathy in patients who actively abuse stimulant drugs Capstone Project, MPAS 218 Spring 2019 Jessica Lynne Bugbee April 11, 2019

CAPSTONE PRESENTATION INFORMATION Review of evidence examining treatment outcomes of acute stimulant intoxication and related ACS and chest pain with beta-blockers compared to without Review of evidence examining treatment outcomes of discharge on beta-blockers after cocaine related ACS and chest pain compared to without Review of evidence examining beta-blocker treatment outcomes in long-term methamphetamine abuse Review of evidence examining beta-blocker treatment outcomes in long-term cocaine abuse

Disclaimer I, Jessica Lynne Bugbee: • Was assisted by University of the Pacific physician assistant program faculty in writing this paper • There were no conflicts of interest

PICOT Question About Prevention of Stimulant-Induced Cardiomyopathy • In patients who actively engage in stimulant drug abuse, how does long-term BBT, both selective and nonselective, affect cardiovascular outcomes compared to no BBT regarding prevention of stimulant-induced-cardiomyopathy?

Key Issues What the Answer to this PICOT Means • Could reduce incidence of stimulant induced cardiomyopathy in this population, improve morbidity/mortality, decrease unnecessary admissions to hospital and ICU, decrease financial burden placed on healthcare • Findings challenge current recommendations • Current recommendations based on low quality evidence • Large gaps in knowledge discovered. Minimal literature investigating this issue in cocaine users. Almost no literature regarding methamphetamine use • Question was answered regarding cocaine users but difficult to say if question was answered regarding methamphetamine use. There is lack of quality research investigating methamphetamine use and more literature is needed

Background Information The Problem—Cardiomyopathy Secondary to Chronic Stimulant Abuse • Statistics in U. S: -1. 5 million regular cocaine users, 40. 3% of drug related ER visits -Approximately 353, 000 regular methamphetamine users -Heart failure (HF) related hospital admissions cost over 32 billion annually, stimulant abusers make up 5% • Areas of concern: -HF related complications common -Significantly elevated rates of medical morbidity -Great cost to society and healthcare resources • How can the instance of this be decreased if stimulant abuse continues?

Background Information The Problem—Cardiomyopathy Secondary to Chronic Stimulant Abuse • Currently used prevention tactics in chronic abuse: -None -Beta-blocker therapy not recommended in heart failure (HF) unless abstinence achieved • Currently used tactics in acute cocaine/methamphetamine toxicity: -1 st line: Benzodiazepines -2 nd line: Calcium channel blockers and nitrates -ACCF/AHA 2012 guidelines for stimulant chest pain: -Labetalol (combined alpha/beta) can be used one hour after vasodilator given if systolic>150 or HR>100 (Class IIb-C recommendation) • Tactics to consider: -Beta blocker therapy -Most effective agent in systolic HF -Prevents cardiac remodeling -Antagonize catecholamine excess

Introductory information Finding Answers—Prevention of Stimulant-Induced Cardiomyopathy • Why is beta-blocker therapy (BBT) avoided in this population? -Fear of unopposed alpha phenomenon -Unopposed alpha-receptor stimulation causing HTN and coronary vasoconstriction following administration of beta-blockade during acute stimulant toxicity -Lack of quality evidence to support this -Literature outdated, questionable research methods -Beta-selective used propranolol and esmolol • What could help prevent stimulant-induced cardiomyopathy? -Prescribing long-term beta-blockade to patients who regularly abuse cocaine/methamphetamine to decrease harmful effects of hyperadrenergic state

Finding answers How can this be achieved? Investigate: -Safety and efficacy of beta-blockers in treatment of acute stimulant toxicity -Outcomes of BBT following hospital discharge -Outcomes of long-term BBT in active cocaine/methamphetamine use -Outcomes comparing beta-selective against nonselective beta-blockers with alpha properties What if safety can be demonstrated with use of long-term BBT, especially newer generation with additional alpha blocking properties? Could it: -Decrease rate of progression of cardiomyopathy? -Improve chances of regaining cardiac function after patient quits stimulant use? -Improve cardiac symptoms? -Decrease incidence of unnecessary HF and cardiovascular related admissions to hospital and ICU?

Examining the evidence • • • Most studies were retrospective cohort studies Several meta-analysis A case series Most studies investigated cocaine use Few studies have investigated methamphetamine use

Examining the Evidence Articles Discussed • Studies investigating BBT in acute stimulant toxicity: • Two high quality systematic clinical reviews of 1744 cocaine users and 329 methamphetamine users: -Evidence supports use of selective/nonselective BBT for treatment of hyperadrenergic state in acute cocaine/methamphetamine toxicity -Superiority of BBT compared to calcium channel blockers, nitrates, alpha blockers -First line attenuated HTN, not tachycardia -BBT does both • Strengths • Limitations

Examining the Evidence More Articles Discussed • Studies investigating BBT in acute stimulant toxicity: • Retrospective cohort study of 376 patients: -Effects of BBT given vs none in cocaine positive patients with ACS after recent cocaine use -Metoprolol (45%), carvedilol (26%), labetalol (27%), atenolol (2%). -No differences between selective/nonselective BBT, mortality, stroke, arrhythmia • Systematic review/meta-analysis of five studies, 1, 794 patients with cocaineassociated-chest-pain (CACP). -No increased risk of non-fatal MI or all-cause mortality in patients given BBT

Examining the Evidence More Articles Discussed • Studies investigating BBT following hospital discharge: • Retrospective cohort of 331 patients treated with selective/nonselective BBT vs no BBT in emergency department for CACP -(IV) metoprolol (74%), oral metoprolol (11%), IV labetalol (12%), oral labetalol (2%), oral atenolol (1%), and oral propranolol (1%). A total of 124 patients were discharged on a BBT: 55% on a metoprolol regimen, 25% on an atenolol regimen, 15% labetalol, 3% on a carvedilol regimen, and 2% on a propranolol regimen. -Showed 70% reduction in rate of death over median follow-up 972 days -Secondary analysis: No differences in outcomes between selective and non selective

Examining the Evidence More Articles Discussed • Studies investigating BBT following hospital discharge: • Prospective single center study: -Examined major adverse cardiac events (MACE) in 57 patients discharged on BBT following ACS after recent cocaine use -12. 7% increase 90 -day survival -14. 7% decrease in mortality -Only 2. 6% decrease in hospital readmission rate secondary to myocardial infarction (MI) • Retrospective cohort of 60 admitted patients positive for cocaine: -(66%) selective (propranolol, metoprolol, atenolol), (21%) nonselective (carvedilol, labetalol), (13%) received both at discharge -Fewer death/MI during hospital admission and 5 -year follow-up with BBT (6. 1%) vs none (25. 9%). • Limitations

Examining the Evidence More Articles Discussed • Long-term beta-blocker therapy in active methamphetamine use: • Single study, two medical centers in Germany: -Mean age 30 -Investigated clinical characteristics/histological changes of myocardium of 24 subjects with methamphetamine-associated-cardiomyopathy (MACM). -20 patients stopped methamphetamine, 4 patients continued abuse -Follow-up period 12 months -Improvement in symptoms/ventricular function only if abstinence achieved • Strengths • Limitations

Examining the Evidence More Articles Discussed • Long-term beta-blocker therapy in active cocaine use: • Meta-analysis: outcomes of BBT among 90 -systolic HF patients who actively abuse cocaine vs. 177 non-ischemic systolic HF without cocaine use -No differences in HF readmissions, major adverse cardiovascular events or death over 4, 000 -day interval. -60% prescribed selective (metoprolol tartrate and succinate, bisoprosol, 40% prescribed nonselective (carvedilol, labetalol) -No differences between nonselective versus selective • Single-center retrospective cohort: -268 adult systolic HF patients, positive for cocaine on UDS -86% discharged on long-term BBT, 14% were not. -HF/all-cause 30 -day readmission rates 21% less with BBT vs none -No differences after 1 -year • Limitations

Examining the Evidence More Articles Discussed • Long-term beta-blocker therapy in active cocaine use: • Case series of 4 active cocaine users: -Outcomes of long-term BBT -Found clinical/ECHO recovery with carvedilol in severe systolic HF with ongoing cocaine abuse -NYHA class improved 1. 5 and left ventricular ejection fraction (LVEF) improved 36. 5% at followup -None required hospitalization 1 year after enrollment -Almost full recovery of LVEF during long-term treatment with carvedilol and concurrent cocaine abuse during a two-year follow-up • Strengths • Limitations

Examining the Evidence More Articles Discussed • Long-term beta-blocker therapy in active cocaine use: • Retrospective analysis on 72 beta-blocker-naive active cocaine users with EF<40% After 12 months: -38 patients given BBT vs none more likely to improve NYHA class/LVEF -Lower rates of cardiovascular events and HF hospitalizations vs 34 not receiving BBT -Majority of patients achieved full/almost full recovery of their LVEF after one year of long-term BBT -Carvedilol group = 23 patients, Metoprolol succinate = 15 patients -No difference in LVEF -NYHA class larger improvement with carvedilol • Strengths • Limitations

Examining the evidence • Common strengths • Common limitations

Summary of the Evidence • Lack of evidence that selective/nonselective beta-blockers increase coronary vasoconstriction and worsen outcomes during treatment of cocaine and methamphetamine related ACS/chestpain • Selective/nonselective beta-blockers successful in treating hypertension and tachycardia of hyperadrenergic state • Safety is shown after discharge on selective/nonselective immediately following admission for cocaine-related ACS/chestpain. Significant decrease in the rate of death, MI and hospital readmission vs no beta-blockers during time period following hospital discharge.

Summary of the Evidence • Cessation of methamphetamine use shown to reverse heart failure while continued abuse shows no improvement despite standard heart failure therapy treatment (including use of beta-blockers) • Evidence based on single study • 4 patients continued abuse compared to 20 patients who stopped • Future studies needed with larger sample comparison

Summary of the Evidence • Cocaine users have same systolic HF outcomes as non users with use of selective/nonselective treatment • Systolic HF patients who use cocaine and long-term BBT have decrease in all-cause/HF readmissions within 30 days but no differences in mortality after one year. This study initially aimed to measure LVEF instead of mortality after one year but was not able secondary to poor patient follow-up

Summary of the Evidence • 4 patients with severe cocaine-induced-cardiomyopathy were capable of achieving full clinical and echocardiographic recovery with the maximum dose of carvedilol • Metoprolol and carvedilol use over a 12 -month interval has shown improvement in NYHA class, LVEF and decrease in cardiovascular events and HF hospitalizations in cocaine users with ejection fractions <40%

General Conclusions • Selective/nonselective beta-blockers show safety and efficacy in treatment of acute effects of cocaine and methamphetamine toxicity • Use of long-term BBT in patients that regularly use stimulant drugs should demonstrate safety as well • Long-term selective/nonselective therapy shows success in preventing cardiomyopathy in cocaine users but not methamphetamine • Long-term therapy with both selective and nonselective beta-blockers shown to decrease extent and progression of cocaine-induced cardiomyopathy • Nonselective beta-blocker carvedilol with alpha properties shows greatest effectiveness in treatment of symptoms and improvement of ejection fraction in cocaine users

Implications for Practice • Practice changes? • Use of selective and nonselective beta-blockers appears safe and effective for use of preventing stimulant-induced cardiomyopathy in active cocaine users based on current found evidence • Current ACCF/AHA 2012 guidelines recommend treatment of methamphetamine the same as cocaine until further investigation

Knowledge Gaps • Long-term therapy may offer patients greater chance of regaining cardiac function if they one day decide to quit stimulant abuse • Improvement in cardiac function and lessening of symptoms is shown to decrease heart failure-related hospital admissions which could decrease healthcare costs

Next Steps • Future high quality studies needed investigating methamphetamine users cardiac function by comparing ejection fractions before and after long-term treatment with beta-blockers • Stronger evidence currently supports use of nonselective betablockers with additional alpha blocking properties compared to beta-1 and beta-1, 2 blockers • Additional studies needed to compare outcomes between different classes of beta-blockers in order to make future recommendations

Take-Home Points • What do the answers tell us? Stronger evidence is in support of nonselective beta-blockers with additional alpha blocking properties compared to beta-1 and beta-1, 2 blockers. Therefore, treatment with mixed beta-blockers such as labetalol and newer generation carvedilol should be prescribed to patients who regularly use stimulant drugs for long-term prevention of heart failure

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QUESTIONS Contact Information: J_bugbee@u. pacific. edu