Unopposed alpha-1 constriction: a critical review of beta blocker use in cocaine-associated cardiovascular events

Unopposed alpha-1 constriction

In this section, we summarize previous studies that support the phenomenon of beta blocker imposed unopposed alpha-1 constriction in patients actively utilizing cocaine (Table 1).

The first clinical instance of unopposed alpha-1 activation was documented in 1985 by Ramoska and Sacchetti [11], in a patient with a history of cocaine abuse who presented for acute cocaine toxicity. The patient was treated for cocaine-induced hypertension and tachycardia with two doses of 1 mg IV propranolol, which 10 min later caused his BP to increase from 170/118 mm Hg to 180/130 mm Hg and his HR to decrease from 112 to 104. The spike in BP was subsequently treated with nitroprusside; notably, no adverse events were reported, and the patient left against medical advice 2 h later. Although propranolol had previously been the mainstay treatment for acute cocaine toxicity in the 1970s, this report of unopposed alpha-1 constriction led to a paradigm shift away from utilizing beta blockers in cocaine-users.

In subsequent years, Lange et al. [12] conducted a randomized double-blind study on 30 clinically stable patients to test for the phenomena of unopposed alpha-1 constriction. The participants were divided into groups and administered intranasal saline or cocaine (2 mg/kg), followed with intracoronary propranolol (2 mg in 5 min). They found that administering propranolol in the cocaine group worsened cocaine-induced coronary artery vasoconstriction by decreasing coronary sinus blood flow (120±20 mL/min to 100±14 mL/min) and increasing coronary vascular resistance (1.05±0.10 mm Hg/mL/min to 1.20±0.12 mm Hg/mL/min). Interestingly, arterial pressure did not rise, as had been witnessed previously by Ramoska and Sacchetti [11]. One adverse event was reported among the 10 patients in the cocaine–propranolol group; that patient had complete coronary artery occlusion and ST segment elevation that resolved with nitroglycerin. This study set the stage for future studies on unopposed alpha-1 constriction and in 2001 led the Advanced Cardiovascular Life Support (ACLS) to caution against the use of beta blockers in patients with cocaine-associated acute coronary syndrome (ACS) [36]. However, in recent years, the external validity of this prominent study has been called into question due to the study’s use of intracoronary propranolol, which is no longer clinically relevant or utilized today [9]. Interestingly, the same research group conducted a similar study utilizing IV labetalol (0.25 mg/kg) [13]. In contrast to their previous conclusions with intracoronary propranolol, the authors reported that IV labetalol had actually reversed cocaine-related increase in arterial pressure (117±14 mm Hg to 110±11 mm Hg; p<0.05) but had no significant effect on the coronary arterial area (3.47±1.37 mm² to 3.37±1.32 mm²; p=NS). It should be noted that, although labetalol is a mixed beta/alpha blocker, its beta-blocking effects are significantly stronger, with an approximate 7:1 beta/alpha ratio when given intravenously. In a retrospective cohort study, Mohamad et al. [14] found that among patients presenting to the emergency department with chest pain and a positive urine cocaine screen, those taking beta blockers at presentation had a significantly higher incidence of myocardial necrosis compared to those not on beta blockers (14.0 vs. 4.4 %, p<0.01).

The significant concern of inhibiting the compensatory vasodilatory effects of beta-2 receptors prompted Sand et al. [15] to investigate whether esmolol, an ultra–short-acting beta-1 selective blocker, could be safely utilized in treating acute cocaine toxicity. In a prospective cohort study utilizing esmolol to treat cocaine-associated cardiovascular complications, the authors reported a mean 23 % decline (range from 0 to 35 %) in HR and an 11 % decline (range from −26 % to + 15 %) in systolic BP. Despite these positive results, three out of seven patients reported adverse events requiring intervention after receiving esmolol – one developed hypertension, another had hypotension, and another experienced emesis and lethargy necessitating intubation – leading the authors to advise against its use. The inconsistent effect on BP in response to esmolol was rationalized by a previous study that reported that 44 % of patients treated with esmolol for supraventricular tachycardia developed hypotension [37].

Two other case studies have reported adverse cardiovascular events after administering beta blockers in patients with cocaine-associated chest pain. Fareed et al. [16] reported a case of cocaine-induced ACS in which the patient, treated with nitroglycerin, experienced persistent tachycardia (115 beats per minute [bpm]) that did not resolve upon administering 15 mg of IV diazepam. Two hours later, 5 mg of IV metoprolol was given, and 10 min later, the patient developed crushing substernal chest pain, systolic BP of 50 mm Hg, and an HR of 120/min before expiring. Although this case provides some evidence of beta blocker induced unopposed alpha-1 constriction, the authors admit that the complex clinical presentation and lack of postmortem examination may make it difficult to assign causality.

Treating cocaine toxicity with beta blockers

In recent years, a growing body of evidence from several case reports, large retrospective studies, and prospective studies have demonstrated that beta blockers can be safely utilized in people who utilize cocaine (Table 1). Moreover, several of these studies have demonstrated a beneficial effect.

Several case studies have corroborated the use of beta blockers in successfully treating acute cocaine toxicity. In the first study, Rappolt et al. [38] reported a 28-year-old male who presented tremulous, nauseous, and faint after snorting approximately 200 mg of cocaine. His initial BP was 140/90 mm Hg and he had an HR of 130/min. He was subsequently treated with 2 mg of IV propranolol, and he was discharged 30 min later after his vitals stabilized with a BP of 110/70 mm Hg and an HR of 84/min. Gay and Loper [17] describe a case in which a 31-year old male presented with worsening agitation after ingesting 20 g of cocaine. On arrival, he had a BP of 230/110 mm Hg and an HR of 185/min. His vitals were managed with 20 mg IV labetalol over 10 min, which lowered his BP to 160/85 mm Hg with a pulse of 96/min. At the intensive care unit (ICU), his BP and HR were subsequently controlled with a labetalol drip, and no major adverse cardiovascular events (MACEs) were reported before discharge the next day. More recently, Richards et al. [18], 39] has published several case reports demonstrating the successful use of beta blockers in managing the hemodynamic effects of acute cocaine toxicity. In another case study, Richards et al. [19] describes a 56-year-old male presenting with profuse epistaxis who became hypertensive, tachypneic, and tachycardic after 4 % cocaine-soaked cotton pledget tamponades were inserted intranasally as part of his treatment. He was subsequently treated with 10 mg IV labetalol, with normalization of his vital signs within 5 min [19]. In a case report, Öcal et al. [29] described a 34-year-old woman who developed acute heart failure after first-time cocaine use and was successfully treated with 6.25 mg carvedilol, resulting in full recovery of left ventricular function within 1 week without adverse effects. In another report, Pollan and Tadjziechy [30] reported a case of severe perioperative cardiovascular toxicity that developed after topical cocaine was applied for nasal polyp surgery. The patient, who had chronic atrial fibrillation treated with digoxin, was successfully managed with transdermal nitroglycerin and 20 mg IV esmolol, resulting in stabilization of BP and HR.

The safety of beta blockers in patients utilizing cocaine has been demonstrated by several retrospective studies. Ibrahim et al. [20] reported that neither beta-1 selective nor mixed alpha/beta blockers were associated with troponin elevation when utilized to treat cocaine-associated chest pain. Fanari et al. [21] reported no significant changes in electrocardiogram (ECG), troponin levels, or echocardiography in cocaine-associated chest pain patients treated with metoprolol, carvedilol, labetalol, and atenolol.

In a prospective observational cohort study, Cediel et al. [22] examined whether beta blockers improved the long-term outcomes in people who utilize cocaine (n=57) who had previously been admitted for ACS associated with cocaine consumption [22]. The study found that patients who had been treated and discharged on a beta blocker (n=33) had a significantly better 90-day survival than patients who had not been prescribed a beta blocker (n=24) (87.5 vs. 100 %; log rank test p=0.035) [22]. Over a median follow-up of 4.0 years (interquartile range [IQR]: 2.4–6.5), 2 patients (6.1 %) who received beta blocker therapy died, and 6 (18.2 %) were readmitted for MI. In contrast, among patients who did not receive beta blocker therapy, 5 (20.8 %) died, and 5 (20.8 %) were readmitted for MI. In a prospective cohort study of patients with ACS and a positive urine cocaine screen, labetalol was associated with significant reductions in inflammatory markers, including CD40 ligand and interleukin 6 (IL-6), as well as significant and equivalent changes in BP and HR compared with diltiazem, without adverse events [28].

Within this literature search, no study reported instances in which mixed alpha/beta blocker use was associated with unopposed alpha vasoconstriction requiring an elevated level of care or resource intensive hospitalization [9]. On the contrary, several prospective studies have indicated that mixed alpha/beta blockers can provide better hemodynamic control. In two randomized double-blind crossover studies, Sofuoglu et al. [23], 24] reported that pretreatment with labetalol and carvedilol attenuated cocaine-induced increase in HR (p<0.05) and systolic BP (p<0.05). Carvedilol also significantly reduced diastolic BP, suggesting that it is more effective than labetalol at controlling the negative cardiovascular effects of cocaine. Of note, labetalol has an approximate 3:1 beta/alpha ratio when administered orally, in contrast to the 7:1 ratio when utilized intravenously, as cited by the Boehrer et al. study [13] and the MacCarthy and Bloomfield study [40]. A prospective cohort study by Hoskins et al. [28] compared the hemodynamic changes between labetalol and diltiazem in treating patients with cocaine-induced ACS. The patients administered labetalol (n=90) had a significant decrease in HR and systolic/diastolic BP when measured 48 h later (p<0.005). The authors also reported that labetalol and diltiazem provided statistically similar hemodynamic control. Of note, no adverse events in the labetalol group were reported during hospitalization.

A few studies have demonstrated that beta-selective blockers can also have a beneficial effect. In a prospective study, Vongpatanasin et al. [25], 41] reported that propranolol could attenuate the chronotropic effects of cocaine, from an increase in the HR of 12±1 beats/minute to 2±1 beats/minute (p<0.01). In a retrospective cohort study with 348 ICU patients with a positive urine drug screen for cocaine, Dattilo et al. [26] found that patients who were administered a beta blocker had significantly decreased incidence of MI (6.1 vs. 26.0 %; 95 % confidence interval [CI] 10.3–30.0 %). A subsequent retrospective cohort study in patients who utilize cocaine presenting with chest pain reported no significant differences in ECG, troponin levels, length of stay, use of vasopressor agents, intubation, or arrhythmias in patients who received a beta blocker [27]. With a mean follow-up of 972 days, Rangel et al. [27] found that patients who had been discharged with a beta blocker (n=124) exhibited a statistically significant 70 % reduction in the risk of cardiovascular death (hazard ratio, 0.29; 95 % CI, 0.09–0.98 [p=0.047]).

Treating heart failure in patients who utilize cocaine

Several studies have investigated whether beta blockers can safely be utilized to treat heart failure in patients with a history of active cocaine use (Table 1). Contemporary guidelines for heart failure with reduced ejection fraction (HFrEF) recommend full guideline-directed medical therapy (GDMT) and do not explicitly list ongoing cocaine use as a contraindication to beta-blockage, except in cases of acute intoxication [42]. However, they acknowledge the limited availability of subgroup data in this regard.

Beta blockers utilized in those with active cocaine use and HFrEF

A retrospective cohort study by Lopez et al. [31] found that utilizing beta blockers to treat HFrEF patients with active cocaine use was beneficial, with no MACEs reported in any of the 38 patients. The authors demonstrated that in a 12-month period, beta blockers were associated with a statistically significant improvement in left ventricular ejection fraction (LVEF) (p<0.0001) and New York Heart Association functional class (p<0.0001).

A subsequent retrospective study by the same authors compared HFrEF treatment outcomes from this population group (n=38) to a control group of people who utilize cocaine treated with GDMT (n=34). The study found that beta blockers, when utilized in combination with GDMT, improved LVEF (p=0.0031; relative risk [RR] 2.46; CI, 1.27–4.78) and New York Heart Association functional class (p=0.0106; RR 2.24; CI, 1.14–4.41) [32]. Furthermore, their group demonstrated that there was no difference in outcomes or reports of adverse events between mixed alpha/beta blockers vs. beta-1 selective blockers.

In the context of treating patients with HFrEF, Egbuche et al. [33] reported that beta blockers reduced 30-day all-cause readmission rates by 25 vs. 46 % (odds ratio [OR]: 0.19, 95 % CI, 0.06–0.64, p=0.007) and heart failure related readmission rates by 20 vs. 41 % (OR: 0.17, 95 % CI, 0.05–0.56, p=0.004. However, improvements in 1-year mortality were not significant. In a retrospective cohort study, Garry et al. [35] found that both mixed alpha/beta (carvedilol) and selective beta blockers (metoprolol) could safely be utilized in managing HFrEF in patients with a history of active cocaine use. Among the 133 heart failure patients with active cocaine use who had available medication prescription data (n=104 on beta blockers, n=29 not on beta blockers), the authors found no significant differences in 30-day readmission (hazard ratio 0.89; 95 % CI, 0.40–1.98) or 1-year mortality (hazard ratio 0.39; 95 % CI, 0.13–1.16) after adjusting for age and gender [35].

Banerji et al. [34] conducted a retrospective cohort study on the safety and benefits of carvedilol among heart failure patients with cocaine-use disorder. Self-reported data on cocaine use was stratified among patients, finding no significant differences between the carvedilol (n=404) and noncarvedilol (n=99) groups in frequency of cocaine usage, mode of administration, or cocaine type. Despite patients in the carvedilol group starting treatment with lower LVEF, HR, and N-terminal pro–B-type natriuretic peptide concentrations, a mean follow-up of 19 months revealed that adverse cardiovascular events were statistically insignificant between the carvedilol and noncarvedilol groups (32 vs. 38 %, respectively; p=0.16). Furthermore, analysis between different types of heart failure found no significant difference in adverse cardiovascular events between HFpEF (32 vs. 38 %; p=0.16) and HFrEF (34 vs. 58 %; p=0.02) patients in the carvedilol vs. noncarvedilol groups, respectively. Moreover, analysis of a multivariate model found that carvedilol therapy reduced the incidence of adverse cardiovascular events among heart failure patients with cocaine-use disorder (hazard ratio: 0.67; 95 % CI, 0.481–0.863).

Registry/large-cohort data on GDMT uptake and outcomes

In a comprehensive single-center heart failure registry comprising 503 participants with cocaine-use disorder, 80 % were prescribed carvedilol upon discharge. Among the participants with HFrEF, carvedilol use was associated with a reduced incidence of MACEs compared to the absence of beta blocker therapy (34 vs. 58 %; p=0.02) [34]. In an academic safety-net cohort comparing 738 heart failure participants with cocaine use to 738 matched nonusers, investigators analyzed discharge records for hospitalizations with HFrEF [35]. Among cocaine users with HFrEF, the use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) was significantly higher with a beta blocker (95.2 %) compared to without (44.8 %) (p<0.0001). Similarly, the use of spironolactone was significantly higher with a beta blocker (42.3 %) compared to without (3.4 %) (p<0.0001). These findings suggest a substantial variation in GDMT uptake based on beta blocker status at discharge among cocaine users with HFrEF. Within the same cohort, 1-year mortality and 30-day readmissions were comparable among participants discharged on metoprolol, carvedilol, or no beta blockers. Adjusted estimates favored beta-blockade, but wide CIs suggested safety, with no clear distinction between selective and nonselective agents.

Why beta blockers may be particularly important in cocaine cardiomyopathy

Cocaine induces sympathetic activity through catecholamine overload, resulting in calcium-handling abnormalities, oxidative stress, myocyte necrosis, and arrhythmias – mechanisms that beta blockers directly address [3], 34]. A comprehensive systematic review and meta-analysis elucidates an association between chronic cocaine usage and structural alterations indicative of diastolic dysfunction [3], 34]. Furthermore, the study suggests that beta blockers do not pose significant safety concerns and may prove efficacious in managing cocaine-induced heart failure [3], 34]. Clinically, two cohort studies demonstrate improvement in symptoms and LVEF over approximately 12 months of beta blocker therapy in individuals with active cocaine use [31], 32]. This suggests that reverse remodeling can occur even when abstinence remains incomplete.