Long-Term Beta-Blocker Therapy Outcomes in Acute and Chronic Stimulant Abuse

Abstract

Fear of BBT (beta-blocker therapy) has initiated after a small amount of evidence proposing beta-blockers given during acute stimulant toxicity may create an unopposed alpha-receptor stimulation leading to worse medical outcomes. The objective is to investigate how long-term BBT (both selective and non-selective) affect cardiovascular outcomes compared to no BBT regarding prevention of stimulant-induced-cardiomyopathy. Method is review of most current medical literature. The use of either selective or non-selective beta-blockers to treat the acute effects of cocaine or methamphetamine toxicity demonstrates safety and efficacy. Long-term BBT either selective or non-selective shows success in the prevention of cardiomyopathy in cocaine users by demonstrating a lower rate of death, MI, hospital readmission and improvement of LVEF and NYHA functional class compared to no BBT use. Both selective and non-selective long-term BBT prevent the progression of cardiomyopathy in active cocaine users but not methamphetamine.

1. Introduction

As many medical providers can attest first-hand, the devastation due to the methamphetamine problem does not spare a single person. Methamphetamine abuse is on the rise and recognition of its devastating cardiovascular risks are more important than ever. Similarly, cocaine use does not have benign effects on the heart. In the United States, heart failure (HF) is accountable for more than 1 million hospitalizations and $32 billion in costs annually [1, 2]. Long-term stimulant abuse is a known cause of cardiomyopathy. Beta-blockers have shown improvement of systolic heart failure but use regarding prevention of stimulant-induced-cardiomyopathy is not well investigated. One of the proposed mechanisms of myocardial injury is thought due to catecholamine excess causing increased workload on the heart, which may benefit from BBT. However, BBT has been controversial in this patient population due to reported cases of worsening vasoconstriction due to unopposed alpha-receptor stimulation; and it has been suggested to avoid them altogether in this population with heart failure [1, 2, 3, 4].

If BBT can decrease the extent and progression of stimulant-induced cardiomyopathy then patients might have a greater chance of regaining cardiac function if they one day decide to quite stimulant abuse. Patients may also have improvement in cardiac function and symptoms leading to less heart failure-related hospital admissions; which in turn could decrease the current financial burden placed on healthcare.

There is a lack of quality studies investigating the use of long-term BBT in active cocaine users and almost no data investigating this same issue in regards to methamphetamine. Recent research has suggested that the phenomenon of excessive alpha-stimulation might not be related to beta-blocker use [1, 2, 4]. Therefore, in patients who actively engage in stimulant drug abuse, how does long-term BBT (both selective and non-selective) affect cardiovascular outcomes compared to no BBT regarding prevention of stimulant-induced-cardiomyopathy?

2. Beta-blocker therapy in acute stimulant toxicity

Current literature recommends against the use of beta-blockers in the setting of cocaine-induced-chest-pain. Small catheter-based-human-studies and case reports have suggested they might exacerbate coronary vasospasm and the toxic effects of cocaine by inducing “unopposed” alpha-adrenergic stimulation [1, 2, 3]. Two high quality systematic clinical reviews have demonstrated lack of evidence preventing the use of BBT in both acute methamphetamine and cocaine intoxication. Findings show the superiority of beta-blockers in the management of both stimulant-induced HTN and tachycardia when compared to first-line treatment choices calcium-channel blockers and nitrates; which were shown to only attenuate HTN and not tachycardia [1, 2].

The most recent 2012 ACCF/AHA guidelines endorse the use of labetalol (non-selective with alpha-properties) in acute stimulant toxicity given certain vital sign parameters and only after a vasodilator is given prior. These guidelines also endorse there is a lack of literature investigating these effects in methamphetamine users; and currently recommend that treatment for acute methamphetamine toxicity the same as cocaine toxicity pending future investigation [5].

Current evidence shows that providers have been using BBT during acute stimulant toxicity without causing any adverse cardiac events [1, 2, 6]. For instance, a retrospective study examined 376 patients presenting to the emergency department (ED) with acute coronary syndrome (ACS) and self-reported cocaine use within 24-hours in the presence of positive urine drug screen (UDS) for cocaine. Beta-blockers given were metoprolol (45%), carvedilol (26%), labetalol (27%), or atenolol (2%). No differences were found between selective, non-selective beta-blockers, rate of death, stroke or arrhythmia compared to those not receiving BBT [6]. These findings demonstrate that it is safe to implement BBT during the management of patients presenting with ACS secondary to acute cocaine intoxication.

A systematic review and meta-analysis of five studies were performed involving 1794 patients presenting with cocaine-associated-chest-pain (CACP). The authors found no increased risk of non-fatal MI or all-cause mortality in patients given BBT versus no BBT [7]. This evidence supports the idea that BBT is safe in patients experiencing concomitant stimulant toxicity. This same idea can be applied to the use of long-term BBT. If BBT is safe in acute toxicity then it should demonstrate safety in patients who are prescribed beta-blockers daily who also abuse cocaine or methamphetamine.

3. Beta-blocker therapy after hospital discharge

BBT has shown safety in patients experiencing acute stimulant intoxication. Safety has also been demonstrated in patients discharged on BBT immediately after hospitalization for cocaine-related-chest-pain. It has been demonstrated that taking either selective or nonselective BBT following hospital discharge has a 70% reduction in the rate of death over a median follow-up of 972 days compared to no BBT. The authors of this same study admit that patients with CACP have been shown to exhibit a high mortality rate, and outpatient BBT may help protect against cardiovascular death [8].

A prospective single-center study examined outcomes in 57 patients ≤50 years of age admitted with ACS and urine drug screen (UDS) positive for cocaine. Patients discharged on BBT showed a 12.5% increase in 90-day survival. Discharge on BBT also had 14.7% less chance of death and 2.6% less chance of hospital admission secondary to MI compared to discharge without BBT [4]. Overall, the authors of this study support the use of long term BBT in this patient population.

A retrospective cohort study examined 60 patients with positive UDS for cocaine. Of these patients, 40 (66%) received selective beta-blockers (propranolol, metoprolol, atenolol), 13 patients (21%) received nonselective beta-blockers (carvedilol, labetalol), and 8 patients (13%) received both. Results showed proportionately fewer cases of death and myocardial infarction (MI) during hospital admission and during 5-year follow-up in patients that received BBT (6.1%) compared to none (25.9%) [9].

BBT has been shown to improve outcomes after MI in non-stimulant users [8]. Evidence from the previously mentioned studies suggests the safety of discharge on BBT after cocaine-related ACS by demonstrating a decreased rate of death and cardiac-related complications during the time period following hospital discharge.

4. Long-term beta-blocker therapy in active methamphetamine use

Beta-blockers use regarding prevention of methamphetamine-induced cardiomyopathy has been minimally investigated [1]. Investigators performed a study based out of 2 medical centers in Germany in order to describe clinical characteristics and histological changes in the myocardium of 24 subjects with methamphetamine-associated-cardiomyopathy (MACM). Of patients receiving BBT, 20 patients stopped using methamphetamine while 4 patients continued methamphetamine abuse. Mean age was 30-years and echocardiograms showed severe systolic dysfunction and left ventricular chamber dilatation. The majority had regurgitant valve lesions, ventricular thrombi, and pleural or pericardial effusions. All patients were treated with standard heart failure therapy including the use of BBT. Follow-up averaged 12 months later and improvement in symptoms and ventricular function were only identified in the patients who discontinued methamphetamine abuse [10].

No benefit of BBT was identified during ongoing methamphetamine use, however, the study only involved 4 patients using BBT yielding results of low statistical value. Further limitations of this study include an inability to confirm outpatient adherence to BBT therapy and that methamphetamines were not the sole drugs of abuse. Most patients profiled used other substances such as alcohol, heroin, and cocaine which are all known to have cardiotoxic effects. Since most methamphetamine users often simultaneously abuse alcohol and other drugs [10]. It is difficult to say whether or not BBT could counteract the cardiotoxic effects of multiple substances used simultaneously.

This study suggests that only cessation of methamphetamine abuse is associated with improvement in cardiac function and symptoms; whereas continued methamphetamine abuse leads to ongoing heart failure and worse outcome despite concurrent long-term BBT. Given the limitations of the study, randomized controlled experimental studies are needed to investigate these findings further.

5. Long-term beta-blocker therapy in active cocaine use

It has been suggested that long-term BBT is ineffective in reducing cardiomyopathy in active methamphetamine users according to a single experimental study. The use of long-term BBT in the prevention of cocaine-induced cardiomyopathy has been investigated on a larger scale. A meta-analysis studied outcomes of BBT among 90-systolic heart failure (HF) patients who actively abuse cocaine compared to 177 patients with non-ischemic systolic HF without cocaine use. The authors found no differences in HF readmissions, major adverse cardiovascular events or death when comparing the two groups over a 4000-day interval. Within HF patients with active cocaine use, mortality rates were not different between nonselective BBT versus selective BBT [11].

Findings of this study suggest that BBT produces the same outcomes in systolic HF patients whether or not they abuse cocaine. Findings demonstrate the safety of long-term BBT with cocaine use and suggest that this population should not be precluded from its’ benefits. Limitations of this study include a sample size of mostly males and significant differences between cocaine positive and cocaine-negative groups involving age, BMI, co-morbidities, and ACE-I use. Another limitation is that this study does not include outcomes of cocaine use without BBT.

Fortunately, a single-center retrospective cohort study decided to investigate outcomes with and without BBT in active cocaine users. The study investigates 268 adult patients with heart failure with reduced ejection fraction (HFrEF) who tested positive for cocaine on UDS. Of the patients involved, 86% were placed on long-term BBT while 14% were not. Results show that 30-day readmission rates related to either all-cause or HF were 21% less with BBT compared to none. No differences were found between these same groups after 1-year [12].

Limitations of this study include the significantly larger number of patients placed on long-term BBT compared to none, thereby lowering the statistical significance of findings. Another limitation involves significant variation in intervals of follow-up echocardiograms. The authors were unable to evaluate the effects of BBT on LVEF in cocaine users and instead could only measure the incidence of all-cause mortality. The authors’ inability to assess LVEF in this study is unfortunate since the use of BBT in this population is meant to reduce the instance of cardiomyopathy.

A case-series of four patients investigated long-term BBT outcomes by measuring changes in the instance of cardiomyopathy. Results found clinical and echocardiographic (ECHO) recovery with carvedilol therapy in severe systolic HF with ongoing cocaine use. None of the patients were prescribed beta-blockers on admission, after 2.5 months each patient was being treated with carvedilol 25 mg twice daily. At mean follow up of 9.25 months, New York Heart Association functional class (NYHA) on average improved by 1.5 and left ventricular ejection fraction (LVEF) improved by 36.5% at follow-up [13].

None of the patients required hospitalization 1-year after enrollment. Furthermore, each had almost full recovery of LVEF during ongoing treatment with carvedilol and concomitant cocaine use during a 2-year follow-up. The authors concluded that patients with severe cocaine-induced-cardiomyopathy are capable of achieving full clinical and echocardiographic recovery with maximum dose of carvedilol [13].

Limitations of this study include case series design and lack of comparison without BBT use. Unfortunately, this limits the significance of the study’s findings. Strengths include actual measurement of LVEF to determine the success of long-term BBT. Findings from the study are promising and prompt need for future large randomized studies.

Most recently, a retrospective analysis was performed on 72 beta-blocker-naive active cocaine users affected by HFrEF <40%. After 12-months, 38 patients receiving BBT were more likely to have an improvement in their NYHA class and left ventricular ejection fraction (LVEF). Results also included lower rates of cardiovascular events and HF hospitalizations compared to 34 patients not receiving BBT. When comparing 23 patients receiving carvedilol against 15 patients receiving metoprolol succinate no difference was found in LVEF improvement while NYHA class showed larger improvement with carvedilol [3]. Overall, this study provides evidence supporting the equal success of long-term therapy with both selective and non-selective beta-blockers in regards to reducing cardiomyopathy in active cocaine users compared to no BBT.

The majority of patients in the study were able to achieve full or almost full recovery of their LVEF after one year of long-term BBT. Limitations include failure to fully investigate the pathological substrate of HF since coronary angiography was performed in the majority (72%) but not all patients. Also, a cardiovascular magnetic resonance was not performed in order to investigate the extent of myocardial fibrosis and edema. Therefore, large experimental studies involving coronary imaging are strongly needed to explore the findings of this study further.

6. Discussion

6.1 Strengths

Common strengths of the previously mentioned studies include the fact that patients given BBT were reported to be at higher risk for cardiovascular events compared to those not given BBT [6, 8, 9]. Patients were older, had higher presenting systolic BPs, and more often had a history of hypertension. They were also more likely to be taking outpatient angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), statins, and aspirin. Those who received BBT in the ED showed a statistically larger decrease in systolic blood pressure compared to those receiving BBT in the hospital ward only [8].

Patients had increased risk of systolic dysfunction compared to patients not given BBT [6, 8, 9]. Even though the most common limitation between the studies involves the use of UDS to determine illicit drug toxicity, most emergency departments determine cocaine and other illicit drug ingestion through utilization of UDS [9]. Further strengths include the recency of the studies used [3, 4, 7, 10, 11, 12].

6.2 Limitations

Common limitations of the studies used include retrospective cohort study design [3, 4, 6, 8, 9, 12] and the inclusion of a case series [13]. There was an inability to determine the timing of cocaine ingestion with use of UDS since cocaine can be present in urine 48–72 hours after last ingestion [4, 6, 7, 8, 9]. Lack of data regarding cocaine serum levels and knowledge on time of cocaine ingestion could be problematic. Acute cocaine toxicity may have different effects compared to cocaine toxicity determined by positive UDS [9].

Further limitations include several studies failed to provide data on selectivity, route, and type of BBT used [4, 7, 10, 12]. Authors were unable to assess interim behaviors and treatments after discharge and relied only on data obtained from the index hospitalization and the National Death Index to determine long-term mortality [8]. Also, there was a lack of quantitative data measuring the frequency of cocaine use [3, 8, 10, 11, 12, 13] including compliance with BBT during follow-up [3, 4, 8, 10, 11, 12].

7. Conclusion

The use of either selective or non-selective beta-blockers to treat the acute effects of cocaine or methamphetamine toxicity demonstrates safety and efficacy. Avoidance of using BBT in this population is secondary to the fear of causing adverse cardiac events during acute toxicity. Since safety has been demonstrated in recent literature, then the use of long-term BBT in patients that regularly use these drugs should demonstrate safety as well. Long-term BBT either selective or non-selective shows success in the prevention of cardiomyopathy in cocaine users by demonstrating a lower rate of death, MI, hospital readmission and improvement of LVEF and NYHA functional class compared to no BBT use. Therefore, both selective and non-selective long-term BBT prevents the progression of cardiomyopathy in active cocaine users but not methamphetamine. Since a single study has attempted to investigate this topic in methamphetamine users’ additional experimental studies are strongly needed in order to determine if long-term BBT can decrease cardiomyopathy in this population.

Funding

The author received no financial support for the research, author-ship, and/or publication of this chapter.

Disclosures

The author reports no relationships that could be construed as a conflict of interest.