Do selective beta blockers need to be avoided in the setting of recent cocaine use?

Comment by InpharmD Researcher

Existing evidence from meta-analyses and retrospective studies suggests beta-blockers may be safe and effective for recent cocaine users with cardiovascular events. However, most data involve non-selective or mixed alpha- and beta-blockers, providing limited insight on selective beta-blockers, Clinical studies are largely characterized by retrospective designs which limits the strength of findings due to potential biases and confounding.

Background

The American College of Cardiology (ACC) and American Heart Association (AHA) guidelines recommend against the use of beta-blockers in patients with ST-elevation myocardial infarction (STEMI) precipitated by cocaine use due to increased risk of coronary spasm exacerbation. Death from cocaine-induced myocardial infarction is stated to be exceedingly low. Propranolol is also contraindicated in cocaine overdose and cocaine-induced acute coronary syndrome (ACS). It is further recommended that beta-blockers should be avoided in the treatment of cocaine toxicity in acute care settings. Use of esmolol, a short-acting selective beta-1 agonist, was associated with a significant increase in blood pressure in up to 25% of patients. Therefore, these findings do not support the use of selective beta-blockers. [1]

The 2012 American College of Cardiology Foundation and the American Heart Association (ACCF/AHA) guidelines on the management of unstable angina/non-ST-elevation myocardial infarction (non-STEMI) stated that the use of labetalol (a combined alpha and beta-blocker, unclear dosing) after cocaine exposure may be reasonable for patients who have systolic blood pressure greater than 150 mmHg or sinus tachycardia with a pulse greater than 100 beats per minutes, given that the patients have received a vasodilator (e.g., nitroglycerine, or calcium channel blocker) within close temporal proximity (e.g. within the previous hour) (Class IIb, level of evidence C). The guidelines recommend combination alpha and beta-blockade in addition to a vasodilator given that the use of beta-blockers in close proximity (i.e., within 4 to 6 hours) of cocaine exposure may cause some harm (e.g., myocardial ischemia). There is no mention regarding the use of selective beta-blockers. [2]

The 2014 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the management of non-ST-elevation acute coronary syndrome (ACS) and the 2015 European Society of Cardiology (ESC) guidelines for the management of ACS without persistent STEMI state that beta-blockers should not be administered in patients with symptoms possibly related to coronary vasospasm or history of cocaine use who demonstrate signs of acute intoxication due to the risk of potentiating coronary spasm. The use of beta-blockers in recent cocaine exposure may precipitate harm due to the proposed risk of unopposed alpha-adrenergic stimulation and worsening coronary vasospasm. Cocaine actively affects both alpha and beta receptors; thus, administering a beta-blocker may leave alpha-mediated vasoconstriction unopposed causing a decrease in myocardial blood flow and coronary vasoconstriction. [3], [4]

A 2020 systematic review investigated the use of beta-blockers for treating heart failure patients with concurrent cocaine use. The review included studies of patients admitted for heart failure exacerbation who were actively using cocaine and received either selective or non-selective beta-blockers. Most of the included studies were retrospective in design. The review found that beta-blocker treatment was associated with either beneficial or non-inferior outcomes relative to readmission rates, myocardial infarction occurrence, and other cardiovascular outcomes, compared to controls. No additional adverse events attributable to beta-blocker use were observed among cocaine-using patients. However, the majority of patients across the included studies received carvedilol or labetalol, whereas only approximately 10% received more cardioselective beta-blockers. This limits conclusions regarding the relative safety and efficacy of selective versus non-selective beta-blockers in cocaine-using heart failure patients. [5]

A 2019 meta-analysis investigated in-hospital and long-term outcomes associated with beta-blocker treatment in recent or active cocaine users presenting with cocaine-associated chest pain. To be included, patients must have received beta-blockers either during hospitalization or in the emergency department setting. Across eight included studies involving 2,048 patients, the majority of beta-blocker use involved selective agents like metoprolol, propranolol, or atenolol. With a mean follow-up of 2.6 years, no significant differences were found in all-cause mortality (risk ratio [RR] 0.79; 95% confidence interval [CI] 0.44-1.41, I2= 26.6%) or myocardial infarction (RR 0.96; 95% CI 0.40-2.33, I2=0.0%) between patients receiving beta-blockers compared to non-receivers. However, the analysis did not specifically evaluate outcomes according to selective versus non-selective beta-blocker therapy, limiting conclusions regarding their relative safety and efficacy in the context of recent cocaine use. [6]

A 2019 meta-analysis examined the use of beta-blockers for acute cocaine-related chest pain. A total of 5 studies were included (N= 1,447) that assessed in-hospital rates of all-cause mortality and myocardial infarction. No significant differences were found between patients treated with beta-blockers versus those without in terms of myocardial infarction (RR 1.08; 95% CI 0.61 to 1.91) or all-cause mortality (RR 0.75; 95% CI 0.46 to 1.24). Metoprolol, a commonly used selective beta-blocker, appeared to be well tolerated across the included studies. Based on these findings, the authors concluded beta-blockers were not associated with adverse clinical outcomes in patients presenting with acute chest pain related to cocaine use, although the studies were largely retrospective in design. [7]

A 2018 systematic review and meta-analysis compared outcomes of beta-blockers versus no beta-blockers for adult patients with cocaine-associated chest pain. The ACC/AHA and ESC guidelines for the management of ACS in patients presenting without persistent STEMI, beta-blockers should not be administered to patients with non-STEMI precipitated by cocaine use because of the risk of potentiating coronary spasm. However, the authors disclaim that these recommendations may have been derived mostly from animal studies and trials with small sample sizes. Given the ongoing debate and conflicting data, the investigators performed a meta-analysis to assess the safety of beta-blocker therapy in patients with cocaine-associated chest pain; non-fatal myocardial infarction and all-cause mortality were among the outcomes of interest. Five studies with a total of 1,794 subjects were included. Overall, there was no significant difference in myocardial infarction between cocaine-associated chest pain patients on beta-blockers and those not on beta-blockers (odds ratio [OR] 1.36, 95% CI 0.68 to 2.75). Similarly, there was no statistically significant difference in all-cause mortality between patients taking a beta-blocker and those who did not (OR 0.68; 95% CI 0.26 to 1.79). Based on these findings, the authors concluded that beta-blocker use did not appear to be associated with an increased risk of MI or all-cause mortality in patients presenting with acute chest pain and underlying cocaine use. [8]

References:

[1] McCord J, Jneid H, Hollander JE et al. Management of cocaine-associated chest pain and myocardial infarction. Circulation. 2008;117:1897-1907.
[2] Anderson JL, Adams CD, Antman EM, et al. 2012 ACCF/AHA focused update incorporated into the ACCF/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(23):e179-347. doi: 10.1016/j.jacc.2013.01.014
[3] Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2014;64(24):e139-e228. doi: 10.1016/j.jacc.2014.09.017
[4] Roffi M, Patrono C, Collet JP, et al. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: task force for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2016;37(3):267-315. doi:10.1093/eurheartj/ehv320
[5] Mann BK, Bhandohal JS, Saeed M, Pekler G. Beta Blocker Therapy in Heart Failure Patients with Active Cocaine Use: A Systematic Review. Cardiol Res Pract. 2020;2020:1985379. Published 2020 May 8. doi:10.1155/2020/1985379
[6] Shin D, Lee ES, Bohra C, Kongpakpaisarn K. In-Hospital and Long-Term Outcomes of Beta-Blocker Treatment in Cocaine Users: A Systematic Review and Meta-analysis. Cardiol Res. 2019;10(1):40-47. doi:10.14740/cr831
[7] Lo KB, Virk HUH, Lakhter V, et al. Clinical Outcomes After Treatment of Cocaine-Induced Chest Pain with Beta-Blockers: A Systematic Review and Meta-Analysis. Am J Med. 2019;132(4):505-509. doi:10.1016/j.amjmed.2018.11.041
[8] Pham D, Addison D, Kayani W, et al. Outcomes of beta blocker use in cocaine-associated chest pain: a meta-analysis. Emerg Med J. 2018;35(9):559-563. doi:10.1136/emermed-2017-207065

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Do selective beta blockers need to be avoided in the setting of recent cocaine use?

Please see Tables 1-2 for your response.


 

Beta-blockers for chest pain associated with recent cocaine use

Design

Retrospective cohort study

N= 331

Objective

To test safety of beta-blockers when administered to patients with chest pain and recent cocaine use

Study Groups

Received beta-blocker (n= 151)

No beta-blocker (n= 177)

Inclusion Criteria

Admitted to emergency department (ED) with chest pain and urine toxicologist test results positive for cocaine

Exclusion Criteria

Chest pain of pulmonary etiology

Methods

Patient data were obtained via review of medical charts and electronic medical record based on ICD-9 codes. Patients may have received beta-blocker in ED or hospital ward. 

Duration

Patients admitted between January 2001 to December 2006

Outcome Measures

Primary: mortality

Secondary: peak troponin level in first 24 hours of admission, ventricular fibrillation (VF) or ventricular tachycardia (VT) requiring defibrillation, need for intubation, need for vasopressor agents, cardiovascular death

Baseline Characteristics

 

Received beta-blocker (n= 151)

No beta-blocker (n= 177)

 

Age, years

51  48  

Male

74% 71%  

Race

White

Black

Hispanic

South Asian

Native American

 

13%

77%

9%

1%

0

19%

73%

6%

1%

1%

 

Homeless

40%

42%

 

Comorbidities

History of hypertension

History of congestive heart failure

Prior diagnosis of coronary artery disease

Prior coronary percutaneous intervention

Prior coronary artery bypass grafting

Prior myocardial infarction

HIV positive

 

70%

15%

28%

11%

5%

25%

5%

 

58%

16%

24%

7%

3%

21%

10%

 

Type and route of beta-blocker first dose

Intravenous metoprolol

Oral metoprolol

Intravenous labetalol

Oral labetalol

Oral atenolol

Oral propranolol

 

74%

11%

12%

2%

1%

1%

 

-

-

-

-

-

-

 

Cocaine last used, hours before triage

29 22  

 

Results

Endpoint

Received beta-blocker (n= 151)

No beta-blocker (n= 177)

p-Value

Positive troponin level

26 (24%) 37 (21%)  0.52

Required intubation in first 24 hours

4 (3%)  10 (6%)  0.18

Required vasopressor agents in first 24 hours

1 (1%) 12 (7%) 0.005

VF or VT requiring electrical cardioversion or defibrillation

1 (1%) 1 (1%) 0.91

Mortality

2 (2%) 3 (2%) 0.76

No significant differences were observed for other outcomes reported within the study, including electrocardiogram (ECG) findings, incidence of myocardial infarction, and duration of hospital stay. 

Significant predictors of incident mortality were found to include history of congestive heart failure, end-stage renal disease, positive troponin level, and abnormal systolic function. 

Adverse Events

N/A

Study Author Conclusions

Administration of beta-blockers to patients with cocaine-associated chest pain appears to be safe and may even be beneficial. Patients with cocaine-associated chest pain exhibited a high mortality rate, and outpatient beta-blockers may help protect against cardiovascular death. 

InpharmD Researcher Critique

While this study does not provide a direct comparison of selective and non-selective beta-blockers, the vast majority of included patients (81%) were administered selective beta-blockers. 



References:

Rangel C, Shu RG, Lazar LD, Vittinghoff E, Hsue PY, Marcus GM. Beta-blockers for chest pain associated with recent cocaine use. Arch Intern Med. 2010;170(10):874-879. doi:10.1001/archinternmed.2010.115

 

Safety of β-blockers in the acute management of cocaine-associated chest pain

Design

Retrospective cohort study

N= 378

Objective

To evaluate the safety of beta-blockers (BBs), α1/β-BBs, and no BBs during treatment of patients presenting with cocaine-associated chest pain

Study Groups

BB group (n= 162)

β1-selective (n= 88)

α1/β-BBs (n= 74)

No BB group (n= 216)

Inclusion Criteria

Age ≥ 18 years presenting to the emergency department (ED) with chest pain, positive urine drug screen for cocaine metabolites in the preceding 24 hours

Exclusion Criteria

N/A

Methods

Patient data were collected from 2 large inner-city hospitals. Patients were divided into either those who were not treated with any type of BB, or were treated with any type of BB. The BB group was further divided into those who received either β1-selective or α1/β-BBs. The quantification of troponin T and troponin I were assessed based on previous research that suggests that infarct severity and cardiac enzymes are closely related.

Duration

Patients admitted between 1998 to 2011

Outcome Measures

Primary: incidence of troponin elevation (defined as troponin I > 0.6 ng/mL and troponin T > 0.1 ng/mL; if creatinine < 2 mg/dL)

Secondary: mean peak troponin levels

Baseline Characteristics

 

BB group (n= 162)

No BB (n= 216)

p-Value

Age, years

46.2 42.3 < 0.001

Male

67.3% 75.0% 0.107

Race

Black

White

Other

 

82.1%

9.3%

8.6%

 

75.5%

13.4%

11.1%

 

Typical pain

16% 9.7%  

Creatinine, mg/dL

1.50 1.34  

Comorbidities

HLP

HTN

CAD

Diabetes

HIV

Asthma

COPD

 

24.1%

79.0%

33.3%

27.8%

9.3%

8.0%

4.9%

 

11.6%

39.4%

13.9%

15.7%

12.0%

6.0%

3.7%

 

0.002

< 0.001

< 0.001

0.005

0.409

0.539

0.611

Echocardiogram

LVH

Diastolic dysfunction

Wall motion abnormality

EF< 50%

 

22.8%

13.0%

20.4%

37.7%

 

11.6%

6.0%

8.8%

11.6%

 

0.005

0.028

0.002

< 0.001

Beta-blocker use

Metoprolol

Labetalol

Carvedilol

Atenolol

 

53%

27.2%

26.6%

2%

--

--

Results

Endpoint

BB group (n= 162)

No BB (n= 216)

p-Value

Rise in troponin

22

20

0.2

Mean peak troponin levels, ng/mL

6.7

5.7

0.6

 

β1-selective (n= 88)

α1/β-BBs (n= 74)

 
Rise in troponin

5

16

--

Mean peak troponin levels, ng/mL

7.5

4.1

0.4

Adverse Events

No cases of hypertensive urgency were reported. Other safety parameters were not specified

Study Author Conclusions

Troponin rise is not uncommon in patients with cocaine-associated chest pain and occurred in 11% of the patients. In patients with cocaine-associated chest pain, BBs did not appear to change the incidence of troponin rise. β1-Selective BBs did not appear to worsen troponin levels compared with mixed α1/β-BB.

InpharmD Researcher Critique

The study was limited by its retrospective design, potential confounding, small number with troponin elevation, and inability to assess medication adherence/timing. The surrogate marker of troponin levels was the primary focus rather than clinical outcomes.



References:

Ibrahim M, Maselli DJ, Hasan R, Hamilton A. Safety of β-blockers in the acute management of cocaine-associated chest pain. Am J Emerg Med. 2013;31(3):613-616. doi:10.1016/j.ajem.2012.09.027