The use of cocaine has evolved from chewing the leaves of the Erythroxylon coca bush thousands of years ago, to purification of cocaine hydrochloride over 100 years ago and its use in tonics and elixirs (at one time in popular cola drinks), to insufflating and injecting the fine, white, water-soluble, powder form, to a smokable freebase form called “crack,” which became popular in the 1980s.1 In 2007, 2.1 million Americans had recent cocaine use; 1.6 million met criteria for cocaine dependence or abuse.1 Cocaine accounted for 31% of all visits to the emergency department related to drug misuse or abuse.1 From 1971 to 1987, the incidence of deaths caused by cocaine overdose increased 20-fold in Dade County, Florida.2 In a consecutive series of 233 emergency visits by cocaine-using patients, 56% presented with cardiovascular complaints, including 40% with chest pain.3 A minority of these patients have acute myocardial infarction (MI) (≈6%),4–7 and overall mortality is low (<1%).3–5,8–10 However, cocaine is associated with a number of cardiovascular diseases, including MI, heart failure, cardiomyopathies, arrhythmias, aortic dissection, and endocarditis. Identifying patients with acute disease is challenging. This review describes the relationship between cocaine and various cardiovascular diseases, as well as appropriate diagnostic evaluation and therapies.

Pathophysiology

Molecular

Cocaine stimulates the sympathetic nervous system by inhibiting catecholamine reuptake at sympathetic nerve terminals,11,12 stimulating central sympathetic outflow,11 and increasing the sensitivity of adrenergic nerve endings to norepinephrine (Figure 1).12 Cocaine also acts like a class I antiarrhythmic agent (local anesthetic) by blocking sodium and potassium channels, which depresses cardiovascular parameters.13 Of these 2 primary, opposing actions, enhanced sympathetic activity predominates at low cocaine doses, whereas the local anesthetic actions are more prominent at higher doses.12

Figure 1. Acute effects of cocaine. Cocaine affects the cardiovascular system through 2 major pathways: increased sympathetic output and a local anesthetic effect. Through increased sympathetic tone and catecholamine levels, cocaine increases heart rate, blood pressure, and myocardial contractility, all of which increase myocardial oxygen demand. Myocardial oxygen supply is decreased through coronary vasoconstriction and enhanced thrombosis. Myocardial oxygen demand may exceed myocardial oxygen supply, leading to ischemia or infarction. Cocaine affects cardiac myocytes directly by blocking sodium channels, which decreases left ventricular (LV) contractility and is arrhythmogenic.

In addition, cocaine stimulates the release of endothelin-1, a potent vasoconstrictor, from endothelial cells14 and inhibits nitric oxide production, the principal vasodilator produced by endothelial cells.15 Cocaine promotes thrombosis by activating platelets,16,17 increasing platelet aggregation,16,18 increasing platelet α-granule release,16,19 increasing plasminogen activator inhibitor activity,20 and increasing fibrinogen and von Willebrand factor levels.21 Calcification22 and aneurysms23 occur frequently in the coronary arteries of cocaine users. MI in non–cocaine-using patients with traditional risk factors typically results from plaque fissure or rupture with plaque hemorrhage, which precipitates thrombosis. In contrast, MI in cocaine-using patients involves intracoronary thrombosis superimposed on smooth muscle cell–rich fibrous plaques without plaque rupture or hemorrhage.24 Moreover, plaques in cocaine-using patients feature medial or intimal inflammation (primarily lymphocytes and plasma cells) and adventitial mast cells, whereas non–cocaine-using patients did not have arterial wall inflammation of this morphology.24

Clinical

Cocaine increases myocardial oxygen demand by increasing both heart rate and blood pressure (Table 1).25,26 The influence of cocaine on heart rate and blood pressure is dose dependent and is mediated through α-adrenergic stimulation.25,26 At the same time, cocaine decreases oxygen supply via coronary vasoconstriction.25 Cocaine-induced coronary vasoconstriction occurs in normal (nondiseased) coronary artery segments but is more pronounced in atherosclerotic segments.27 Combining cocaine use with cigarette smoking has additive effects on coronary vasoconstriction while markedly increasing the rate-pressure product.28 Long-term cocaine users demonstrate coronary endothelial dysfunction.29 Because endothelial dysfunction increases the sensitivity of a vessel to the constrictor effects of catecholamines,30 it may be particularly detrimental for cocaine users. Even in the absence of epicardial coronary disease, cocaine causes microvascular disease31,32 and is associated with thrombosis.24,33,34

Table 1. Cardiovascular Effects of Cocaine Causes Myocardial Oxygen Supply-Demand Mismatch Worsens Myocardial Performance Causes Cardiovascular Disease Causes Clinical Cardiovascular End Points Increases heart rate Decreases ejection fraction Arrhythmias Myocardial infarction Increases blood pressure Increases end-systolic volume QT prolongation Arrhythmias Decreases coronary artery diameter Increases end-diastolic pressure Thrombosis Congestive heart failure Decreases coronary blood flow Lengthens deceleration time Atherosclerosis Cardiomyopathy Increases left ventricular hypertrophy Endothelial dysfunction Aortic dissection Microvascular disease Endocarditis Sudden death

Cocaine causes systolic and diastolic dysfunction, arrhythmias, and atherosclerosis. Cocaine decreases myocardial contractility and ejection fraction by blocking sodium and potassium channels within the myocardium.35 Intracoronary infusion of cocaine decreases left ventricular ejection fraction and increases left ventricular end-diastolic pressure and end-systolic volume (Table 1).36 Long-term cocaine use is associated with left ventricular hypertrophy37 and prolonged deceleration time.38 Cocaine prolongs the PR, QRS, and QT intervals.39,40 Cocaine is associated with coronary atherosclerosis even in young users with relatively few cardiac risk factors.41,42

Chest Pain

Compared with nonusers of cocaine, cocaine users have a higher overall incidence of MI (odds ratio [OR], 3.8 to 6.9),43,44 and the risk of MI increases by 24-fold in the first hour after cocaine use.45 Cocaine contributes to ≈1 of every 4 MIs in persons between 18 and 45 years of age.44 MI occurs in ≈6% of all patients presenting to the emergency department with cocaine-associated chest pain (CACP).4–7

Clinical Presentation and Patient Characteristics

Patients presenting with CACP are typically young, male cigarette smokers with few other cardiac risk factors (Table 2). CACP is often substernal and pressure-like and may be associated with dyspnea and diaphoresis (Table 3). Atypical presentations, pleuritic pain, nausea, palpitations, syncope, and vomiting also occur. In patients with CACP, no historical or presenting features distinguish between patients with and those without MI.4,6,10,47 In a prospective cohort of 261 patients with CACP, the Thrombolysis in Myocardial Infarction risk score did not stratify patients into risk categories, and almost half of all adverse events occurred in patients with a Thrombolysis in Myocardial Infarction risk score of ≤1.51 Of patients with CACP, compared with patients without MI, patients with MI were slightly older,4,6 less often had a history of previous chest pain (21% versus 53%),4 and more often had known coronary artery disease.52 Any route of cocaine administration can precipitate MI, and no route is more predictive than another (Table 2).4,10,47

Table 2. Demographics, Medical History, and Route of Cocaine Administration in Patients With Cocaine-Associated Chest Pain Cohort; No. of Cocaine-Using Patients and Clinical Setting MI, %* Age, Average, y Male, % Cigarette Smoker, % Hypertension, % Hyperlipidemia, % Diabetes Mellitus, % Family History, % History of CP, % History of MI, % Cocaine Route, % Nasal Insufflation Smoked (Crack) Intravenous 246 Presented to ED with CP4 6 33 72 84 19 5 4 15 51 4 27 73 11 250 Presented to ED with CP5 6 34 77 77 26 8 6 34 40 6 6 85 2 364 Presented to ED with CP6 7 47 73 90 54 15 22 10 78 12 302 Presented to ED with CP8† 0 38 66 84 17 4 3 31 45 2 19 77 4 101 Hospitalized with CP9 0 32 77 3 10 60 30 49 Hospitalized with CP7 6 29 69 8 0 0 47 0 0 65 38 70 Hospitalized with CP10 31 34 80 69 14 0 3 1 42 44 14 90 Angiography for CP46 30 42 69 78 54 36 54 39 32 33 Angiography to rule out MI47 36 37 79 73 15 3 27 20 30 50 91 With MI48 100 33 88 87 15 10 3 17 36 49 30 21 136 With MI49 100 38 80 91 33 15 7 38 35 13 30 55 15 97 With MI50 100 47 73 86 61 19 24

Table 3. Presenting Symptoms and ECG Findings in Patients With Cocaine-Associated Chest Pain Cohort; No. of Cocaine-Using Patients and Clinical Setting MI, %* Substernal Pain, % Pressure/ Tightness, % Pleuritic Pain, % Shortness of Breath, % Diaphoresis, % Nausea, % Palpitations, % ECG, % Abnormal Early Repolarization Ischemia/ Infarction 246 Presented to ED with CP4 6 71 47 36 59 39 27 33 72 31 12 250 With CP5 6 76 55 11 62 48 28 13 73 34 10 364 Presented to ED with CP6 7 44 32 49 16 22 12 77 7 2 302 Presented to ED with CP8† 0 75 58 23 63 34 30 14 60 101 Hospitalized with CP9 0 46 18 56 32 28 14 68 32 8 49 Hospitalized with CP7 6 100 100 33 84 33 136 With MI49 100 91 68 11 59 56 48 18 85 62

MI usually occurs within several hours of cocaine use but can be delayed. In a case-crossover study, the risk of MI increased by 24-fold in the first hour after cocaine use and decreased sharply thereafter to only a 4-fold increase in the second and third hours.45 Time elapsed from cocaine use to onset of chest pain has been as short as a median of 60 minutes4 and within 1 hour in 58% of patients9 or as long as a median of 18 hours.10

Complications and Prognosis

Of all cocaine-induced MIs, Q waves develop in approximately half, and the location is evenly distributed between the anterior and inferior territories (Table 4).4,5,7,10,47–49 Angiography in patients with cocaine-induced MI reveals 1- or 2-vessel disease in 31% to 66%, 3-vessel disease in 13% to 15%, normal coronary arteries in 18% to 45%, and thrombus without obstructive disease in as many as 24% (Table 5).48–50 In patients with CACP without MI, the spectrum of disease shifts toward more normal and nonobstructive disease.6,10,46,47

Table 4. Acute Complications in Patients With CACP Cohort; No. of Cocaine-Using Patients and Clinical Setting MI, %* Q Wave, % Anterior MI, % Inferior MI, % Death, % CHF, % Supraventricular Tachyarrhythmia,% Sustained VT, % Bradyarrhythmia, %s Total No. of Stress Tests/No. of Stress Tests on Patients With MI/No. of Positive Stress Tests 246 Presented to ED with CP4 6 36 21 50 1 1.6 1.6 1.2 1.6 16/6/0 250 With CP5 6 60 53 40 0 0.4 1.2 0.8 0.4 302 Presented to ED with CP8† 0 0 0 0 0 0 158/0/4 101 Hospitalized with CP9 0 0 0 0 0 0 70 Hospitalized with CP10 31 50 45 32 0 1.4 0 4/3/0 91 With MI48 100 55 41 3 7 10 11/11/0 136 With MI49 100 36 45 44 0 7 4 4 19

Table 5. Angiographic Findings in Cocaine-Using Patients With Chest Pain Cohort; No. of Cocaine-Using Patients and Clinical Setting MI, %* Angiography, n Patients Angiographic Findings, % Normal Nonobstructive 1-Vessel Disease 2-Vessel Disease 3-Vessel Disease Thrombosis 364 Presented to ED with CP6 7 40 62 18 16 4 70 Hospitalized with CP10 31 8 38 38 12 12 90 Angiography for CP46 30 90 50† 32 10 6 33 Angiography to rule out MI47 36 33 40 21 21 12 6 91 With MI48 100 54 45 31‡ 24 136 With MI49 100 52 33† 25 29 13 97 With MI50 100 66 18 46 20 15 6

Death (<1%), congestive heart failure (<2%), and arrhythmias (<3%) are rare in patients with CACP (Table 4).4,5,8–10 Complications rarely occurred >12 hours after arrival in the emergency department, even in patients with MI.5,49 In 136 patients with cocaine-induced MI, congestive heart failure occurred in 7%, sustained ventricular tachycardia occurred in 4%, and 48% of all complications occurred by the time of arrival in the emergency department.49 Complications tended to occur more frequently in patients with ischemia or infarction indicated on the initial ECG (42% versus 26%; P=0.06) and occurred more frequently in patients with Q waves (57% versus 24%; P=0.0006).49

In 261 patients with CACP followed up prospectively for 30 days, only elevated cardiac biomarkers increased the risk of the composite end point of all-cause mortality, MI, or revascularization (OR, 8.8), and almost half of all adverse events occurred in patients with a Thrombolysis in Myocardial Infarction risk score ≤1.51 Of 300 low-risk patients with CACP followed up prospectively for 30 days, 25% had recurrent chest pain, none had ventricular dysrhythmias or cardiovascular death (2 noncardiac deaths), and 4 (1.3%) developed nonfatal MI (all 4 continued to use cocaine and had at least 2 cardiac risk factors).8

Of 203 patients with CACP (MI occurred in 5% during the initial presentation) followed up prospectively for a mean of 408 days, 2 patients (1%) developed a nonfatal MI and 6 patients (3%) died (5 noncardiovascular, 1 cardiac arrest).53 Of 130 patients, 78 (60%) continued to use cocaine (continued cocaine use unknown in 73). Both nonfatal MIs and 4 deaths occurred in patients who admitted continued cocaine use. No cardiovascular events occurred in patients who stopped using cocaine. Recurrent chest pain was more likely in persistent cocaine users (75% versus 31%; OR, 6.5). In contrast, outcomes did not differ in patients with versus without MI during the initial presentation.

Electrocardiogram

Interpreting the ECG in patients with CACP is challenging because the initial ECG is “abnormal” in 56% to 84% of patients (Table 3).4–10 In 101 patients with CACP, 43% met ECG criteria for thrombolytic therapy despite 0% having elevated creatine kinase (CK)-MB.9 In 246 patients with CACP (acute MI in 6%), the ECG predicted acute MI with a sensitivity of only 36%, a specificity of 90%, a positive predictive value of 18%, and a negative predictive value of 96%.4 Eighteen of 97 patients (19%) with elevated cardiac troponin had normal ECGs.50 Many of the “abnormal” ECGs in patients with CACP were due to “normal” variants (ST-segment and J-point elevations) in patients <35 years of age.54 ECGs were not significantly different between 56 patients with CACP and 56 age- and gender-matched normal control subjects; early repolarization was common in both groups.54 Thus, ECGs are poorly associated with acute MI in patients with CACP.

Cardiac Biomarkers

Of 49 cocaine-using patients admitted to the hospital for psychiatric disturbances or suspected cardiac disease, none had MI (CK-MB elevation, 0%), yet 39% had an elevated CK, mostly resulting from rhabdomyolysis, muscular trauma, or intramuscular injection.55 CK was elevated in 47% to 65% of patients with CACP without MI (CK-MB not elevated).9,10 The specificities of cardiac biomarkers for diagnosing MI (World Health Organization criteria) varied, depending on cocaine use. The specificities in patients without cocaine use were 94% for cardiac troponin I, 88% for CK-MB, and 82% for CK; in patients with cocaine use, the specificities were 94%, 75%, and 50%, respectively.56 Therefore, troponins are the preferred cardiac biomarker for cocaine-using patients. CK-MB is superior to CK, which is nonspecific.

Evaluation of Patients With CACP

Diagnosing MI in cocaine-using patients is challenging and differs in several ways from non–cocaine-using patients. 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 patients. Cocaine-using patients with versus without acute MI cannot be distinguished by demographics, medical history, clinical presentation, route or timing of cocaine administration, ECG, or CK. Diagnostic uncertainty has prompted unnecessary hospitalization in many cocaine-using patients.5,9

A 12-Hour Observation Unit

Given that complications rarely occur >12 hours after arrival in the emergency department,5,49 Weber et al8 proposed a 12-hour observation period for patients with CACP. They prospectively categorized 344 patients with CACP into high-risk and non–high-risk groups. Forty-two patients were directly admitted and excluded because they were deemed high risk, defined as an “initial ECG suggested the presence of ischemia or acute MI, ST-segment elevation or depression of 1 mm or more that persisted for at least 1 minute; elevated serum levels of cardiac biomarkers; recurrent ischemic chest pain; or hemodynamic instability.”8 Of the 42 high-risk patients, 10 had an acute MI and 10 had unstable angina. Patients not meeting criteria for high risk (n=302) were enrolled in a 12-hour observation protocol, during which patients underwent measurement of cardiac troponin I at the time of presentation and after 3, 6, and 9 hours and had continuous 12-lead ST-segment monitoring. None of the 302 non–high-risk patients developed MI, congestive heart failure, or arrhythmias in the observation unit, and all were discharged from the unit. At 30 days after presentation, none of the 302 patients sustained ventricular dysrhythmias or died of cardiovascular causes (1 died as a result of homicide, 1 as a result of heroin overdose). Twenty-five percent experienced recurrent chest pain, and 4 (1.3%) developed nonfatal MI (all 4 continued to use cocaine and had at least 2 cardiac risk factors).8 Hollander et al49 also described 130 patients with cocaine-associated MI: 90% of patients with complications developed their first complication within 12 hours, and the other 10% had either CK-MB elevation within 12 hours or an initial ECG indicating ischemia or infarction.

Diagnostic Testing

Stress testing and myocardial imaging have been suggested to facilitate safe, rapid discharge of patients with CACP. Stress testing in patients with CACP rarely indicated ischemia (only 4 of 189 tests were positive), even in patients with MI (0 of 20 were positive; Table 4).4,8,10,48 Holter monitoring revealed frequent episodes of ST-segment elevation in 8 of 21 patients with cocaine addiction, yet only 1 of the same 20 patients had an exercise treadmill stress test that indicated ischemia.57 Computed tomography scanning identified coronary calcification in only 9.6% of persons 33 to 45 years of age, and coronary calcification was not related to cocaine use.58 Rest myocardial perfusion imaging indicated myocardial ischemia in only 5 of 216 patients with CACP, and only 2 of 5 patients with a positive test had MI.59 In 59 patients with CACP, coronary computerized tomography angiography indicated significant coronary artery disease in 6 patients (10%) but did not alter management in any patients.60

Patients with CACP are at low risk for cardiovascular events,8,53 so an extensive diagnostic workup may not be cost-effective. The number needed to treat with computerized tomography coronary angiography to identify 1 case of clinically significant coronary artery disease was 59 in one study.61 Compared with a brief observation period, length of stay was only minimally shortened by diagnostic testing.61,62 Diagnostic testing has little influence on therapy because the benefit of percutaneous coronary intervention is unproven in cocaine-using patients and risk factors should be modified in all cocaine-using patients with chest pain or MI. Cessation of cocaine is the most important therapy.8,53,63

Therapy for CACP and MI

The treatment of chest pain and acute coronary syndromes 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 (Figure 2).

Figure 2. Treatment algorithm for patients with cocaine-associated chest pain. β-Blockers (not included in the figure) should be avoided in the acute setting and initiated at discharge only in select patients. If hypertension persists after benzodiazepine administration, first-line treatment is nitrates; second-line treatment is phentolamine or calcium channel blockers. STEMI indicates ST-segment elevation myocardial infarction; NSTEMI, non-STEMI; and ACE I, angiotensin-converting enzyme inhibitor.

Benzodiazepines

In a dog model of acute cocaine toxicity, pretreatment with diazepam prevented the cocaine-induced increases in blood pressure, heart rate, acidemia, and hyperthermia.64 In a trial of 40 patients with CACP randomized to diazepam, nitroglycerin, or both, chest pain severity improved similarly in all 3 groups,65 whereas greater pain relief was observed with the combination of lorazepam plus nitroglycerin compared with nitroglycerin alone in a randomized study of 27 patients.66 Benzodiazepines are thought to relieve CACP though their antianxiety effects. Benzodiazepines should be administered intravenously to patients with CACP to relieve chest pain and to attenuate the hemodynamic manifestations of cocaine.67,68 If hypertension or tachycardia persists despite benzodiazepines or if the patient has evidence of myocardial injury, then additional therapies are indicated.

Nitroglycerin

Nitroglycerin relieves chest pain in approximately half of cocaine-using patients.65,69 Nitroglycerin reversed the coronary vasoconstriction induced by cocaine.70 Nitroglycerin abolished acetylcholine-induced coronary vasoconstriction in 8 of 8 long-term cocaine-users and dilated the coronary artery beyond baseline diameter in 7 of 8.29 If chest pain or hypertension does not resolve with benzodiazepines, then nitroglycerin should be administered.

Calcium Channel Blockers

In mongrel dogs, verapamil prevented cocaine-induced ventricular fibrillation and attenuated the effects of cocaine on heart rate, blood pressure, and myocardial contractility.71 Verapamil abolished the effects of cocaine on blood pressure and coronary vasoconstriction in humans.72 Because calcium channel blockers have not benefitted important clinical end points in randomized trials involving traditional patients with MI, their role in cocaine-using patients with chest pain may be limited to second-line therapy for hypertension or coronary artery vasospasm.67 As in non–cocaine-using patients, short-acting nifedipine should not be used. In patients with heart failure, systolic dysfunction, bradycardia, or heart block, verapamil and diltiazem should be avoided.

Phentolamine

Phentolamine, an α-antagonist used predominantly in the treatment of hypertensive emergencies, appears to benefit cocaine-using patients with ischemia. In 45 patients undergoing cardiac catheterization for the evaluation of chest pain, phentolamine abolished the detrimental effects of cocaine on heart rate, blood pressure, coronary artery diameter, and coronary sinus blood flow.25 A case report describes the successful use of phentolamine in reducing chest pain and ST-segment elevation in a cocaine-using patient with normal coronary arteries.73 A short half-life and significant side effects limit the clinical utility of phentolamine in the general population, but its mechanism of action is ideal for the treatment of cocaine-induced vasoconstriction.

Antiplatelet and Antithrombin Agents

Cocaine promotes thrombus formation, so antiplatelet and antithrombin agents are probably beneficial, although they have not been well studied in cocaine-using patients. Aspirin should be routinely administered immediately for patients with CACP and continued indefinitely for patients with MI or coronary artery disease. Other agents, including clopidogrel, heparin, and glycoprotein IIb/IIIa inhibitors, should be administered as indicated by published guidelines.

β-Blockers

β-Blockers are the most extensively studied and the most controversial drugs relating to cocaine-using patients. In non–cocaine-using patients, β-blockers benefit numerous end points, including mortality, during and after acute MI , and in patients with cardiomyopathy. In cocaine-using patients, however, β- blockade can potentially leave α-stimulation unopposed, resulting in pronounced systemic and coronary vasoconstriction. In animal studies of acute cocaine toxicity, propranolol worsened the seizure threshold and expedited death.64,74 In humans, cocaine-induced coronary artery vasoconstriction was exacerbated by propranolol.75 Esmolol increased blood pressure in 2 of 7 cocaine-using patients.76 In 1 instance, blood pressure increased after esmolol from 200/120 to 230/180 mm Hg.76 Labetalol and carvedilol offer the theoretical advantage of blocking both α- and β-receptors. Labetalol, however, did not reverse cocaine-induced coronary artery vasoconstriction.77 In pheochromocytoma, which features a hypersympathetic state similar to cocaine intoxication, labetalol caused severe hypertension.78 When combined with cocaine, carvedilol 25 mg tended to increase blood pressure consistent with unopposed α-stimulation, whereas carvedilol 50 mg decreased blood pressure and heart rate, suggesting that both α- and β-receptors were blocked.79 Recent, uncontrolled studies of β-blockers in patients with CACP report conflicting results. Death resulting from cocaine-induced MI is rare, which limits the benefit of β-blockers while they increase the risk of hypertension and coronary artery vasoconstriction. An anecdotal report of crushing chest pain, cardiac arrest, and death ensuing minutes after metoprolol administration illustrates the potential risk of mixing β-blockers with cocaine.80 All β-blockers should be avoided in cocaine-using patients in the acute setting. Because most patients continue to use cocaine after hospital discharge,53 postdischarge β-blocker therapy should be considered after careful risk-benefit assessment and perhaps should be withheld until cessation of cocaine has been proven. Patients should be educated on the potential hazards of combining cocaine with β-blockers.

Other Pharmaceutical Agents

Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, and diuretics have not been well studied in cocaine-using patients but are not expected to interact adversely with cocaine. Morphine reversed cocaine-induced coronary vasoconstriction.81 Dexmedetomidine, a potent central sympatholytic agent, abolished the cocaine-induced increases in blood pressure, heart rate, and sympathetic nerve activity.82 A cocaine antidote has been identified in the soil surrounding the coca plant: a bacterial cocaine esterase that hydrolyzes cocaine more efficiently than endogenous esterases.83 When administered to rats before or after cocaine, cocaine esterase prevented or reversed cocaine-induced QRS complex widening, QT prolongation, ST-segment elevation, bradycardia, hypertension, and troponin release.83

Percutaneous Coronary Intervention and Thrombolysis

Compared with non–cocaine-using patients with MI, percutaneous coronary intervention is even more desirable in cocaine-using patients. Two cases in which cocaine-using patients with ST-segment elevations, but without MI, suffered complications from fibrinolytic therapy illustrate that fibrinolytics should be used with caution because of safety concerns, lack of documented efficacy, and poor correlation of ECGs with MI.84 Angiography can define the presence of thrombus and the presence of obstructive disease so that therapy can be tailored accordingly. Coronary thrombectomy and use of glycoprotein IIb/IIIa inhibitors should be advised during percutaneous coronary intervention in patients with cocaine-associated ST-segment elevation MI. Cocaine-using patients are at an increased risk of stent thrombosis (5% to 7.6% incidence), which has been reported in patients compliant and noncompliant with antiplatelet therapy, with and without continued cocaine use, with bare metal and drug-eluting stents, and ranging from 1 to 247 days after stent implantation.85,86 Careful risk-benefit assessment should precede stent implantation, and because of the increased concern for stent thrombosis in cocaine users, it is probably prudent to use bare metal stents.

Postdischarge Therapy

For cocaine-using patients with chest pain or MI, cessation of cocaine is the primary therapeutic goal. For patients who discontinue cocaine, the incidence of recurrent chest pain is reduced and MI and death are rare.8,53 Cardiac risk factors should be modified, especially cigarette smoking. Medications should be provided according to published guidelines, except β-blockers should be prescribed only for select patients.

Summary of Therapy for Patients With CACP and MI

As reviewed here and in a statement by the American Heart Association,67 patients with CACP should be treated in a manner similar to patients with traditional risk factors, with a few exceptions (Figure 2). Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, diuretics, and antiplatelet and antithrombin agents should be administered according to published guidelines. All β-blockers should be avoided in the acute setting and prescribed at discharge only for select patients. Benzodiazepines should be given intravenously to patients with CACP to relieve chest pain and to lower blood pressure and heart rate. In the setting of cocaine, nitrates may have benefits beyond those observed in traditional patients related to coronary vasodilation. The mechanism of action of phentolamine is well suited to counteract the hemodynamic effects of cocaine intoxication, so phentolamine may be useful for persistent hypertension. In patients without a contraindication, calcium channel blockers may be used as second-line therapy for hypertension or coronary artery vasospasm and may attenuate the hemodynamic effects of cocaine. In the setting of possible ST-segment-elevation MI, percutaneous coronary intervention is preferable to thrombolytic therapy and is even more desirable in the setting of cocaine use. At discharge, cessation of cocaine is the primary therapeutic goal.

Stroke

In an analysis of all hospitalized stroke patients in Texas in 2003 (937 hemorrhagic, 998 ischemic), cocaine independently increased the risk of both hemorrhagic (OR, 2.33) and ischemic stroke (OR, 2.03).87 An analysis of 96 cocaine users hospitalized with stroke reported that stroke type differed between current cocaine users, former cocaine users, and the general population, with a higher proportion of hemorrhagic strokes in cocaine users (Table 6).88 Of cocaine users with ischemic strokes, 44% were due to large-artery atherosclerosis, 11% to cardioemboli, and 22% to small-vessel occlusion.88 Acute spikes in blood pressure likely contribute to hemorrhagic strokes, especially among current cocaine users. Twenty-two of 25 (88%) cases of subarachnoid hemorrhage in cocaine users were associated with arterial aneurysms,88 which were also observed to occur with increased frequency in the coronary arteries of cocaine users.23 Compared with cocaine-negative patients, cocaine users with an intracerebral hemorrhage had worse functional outcomes and higher in-hospital mortality (OR, 2.7),89 although no difference in mortality was found in a larger study.87 β-Blockers should be avoided in the acute setting. Data on the use of tissue plasminogen activator for cocaine-induced ischemic stroke are limited, but in 29 such patients, tissue plasminogen activator therapy was used without complications, and despite increased initial stroke severity, cocaine users treated with tissue plasminogen activator had in-hospital outcomes and dispositions similar to those of cocaine users who did not receive tissue plasminogen activator.90

Table 6. Stroke Type in Relation to Cocaine Use Ischemic, % Intracerebral Hemorrhage, % Subarachnoid Hemorrhage, % General population 87 10 3 Former cocaine user 66 9 26 Current cocaine user 36 38 26

Congestive Heart Failure and Cardiomyopathy

Cocaine causes systolic dysfunction in long-term users and with acute intoxication. In a dog model, acute cocaine intoxication caused left ventricular dilation, decreased contractility, and increased end-diastolic pressure.91 Rabbits demonstrated regional wall motion abnormalities (mostly anteroseptal) associated with decreased left ventricular fractional shortening and increased systolic dimension in response to acute cocaine intoxication.92 After 2 weeks of abstinence from cocaine, 6 of 84 (7%) asymptomatic cocaine users (mean age, 36 years) had an ejection fraction <55%.93 In 33 cocaine-using patients undergoing coronary angiography (indication: chest pain, 28; congestive heart failure, 4), ejection fraction was abnormal in 18 patients (55%) and ≤30% in 6 patients (18%).47 Moreover, 4 patients had an ejection fraction <30% with global hypokinesis. Dilated cardiomyopathy is more common among cocaine users,63 but a case of left ventricular apical ballooning (Takotsubo cardiomyopathy) has also been described.94 In a registry including 83 hospitals nationally, stimulant drug use (96% cocaine, 5% methamphetamine) was self-reported in 594 of 11 258 patients (5.3%) who presented to the emergency department with acute decompensated heart failure.95 Patients with stimulant drug use were more likely to have ≥3 hospitalizations within 6 months (28% versus 11%) and had lower ejection fractions (median, 23% versus 40%).

Acute cocaine intoxication decreases myocardial contractility and ejection fraction35,36 and increases left ventricular end-diastolic pressure and end-systolic volume.36 Long-term cocaine use is associated with left ventricular hypertrophy37 and prolonged deceleration time.38 The pathophysiology of cocaine-associated cardiomyopathy, however, remains unclear. Of 18 cocaine users undergoing coronary angiography with an ejection fraction <55%, 12 had coronary artery disease and regional wall motion abnormalities suggesting recent or remote MI; however, 6 did not have coronary artery disease and demonstrated global hypokinesis (4 of 6 with an ejection fraction <30%).47 Thus, a manifestation of coronary artery disease can explain cocaine-induced ventricular dysfunction in some patients, but cocaine also has a direct toxic effect on cardiac myocytes. Factors contributing to cocaine-induced cardiomyopathy may include the blocking of sodium and potassium channels within the myocardium,35 alterations in calcium ion handling,36 myocardial inflammation with necrosis and fibrosis,38,93 left ventricular hypertrophy,37,38 alterations in gene expression,95 and concomitant alcohol consumption.47

Cessation of cocaine is the primary therapeutic goal in cocaine-induced cardiomyopathy. Cocaine-induced heart failure improved dramatically with cessation of cocaine and recurred with resumption of cocaine.63 As with CACP, medical therapy for cocaine-induced heart failure and cardiomyopathy should follow published guidelines, except all β-blockers should be avoided in the acute setting. Thereafter, β-blockers should be considered for each patient individually, after careful risk-benefit assessment, and maybe after cocaine cessation has been documented. Continued cocaine use precludes eligibility for cardiac transplantation.

Arrhythmias

Bauman and colleagues96 hypothesized that because MI with ventricular fibrillation is the most frequent cause of sudden death in the general population, cocaine users may succumb to this same disease mechanism. In 84 of 107 (81%) deaths attributable to cocaine, no definitive cause of death was identified at autopsy, so deaths were presumed to be due to arrhythmias.96 Cocaine precipitated arrhythmias in experimental models, especially in the setting of ischemia.39,40,71 Arrhythmias occur in cocaine-using patients with MI, including sustained ventricular tachycardia in 8% to 13% (Table 4).48,49 Cocaine has also been associated with arrhythmias in the absence of ischemia, including ventricular tachycardia, torsade de pointes, ventricular fibrillation, idioventricular rhythms, atrioventricular block, asystole, and sinus arrest.96,97 Cocaine users have presented with ECG findings typical of Brugada syndrome; subsequent pharmacological challenge tests have been both positive and negative.98

Ventricular arrhythmias that occur within hours of cocaine use result from the effects of cocaine on sodium channels and are treated preferably with sodium bicarbonate.67,99,100 Beyond several hours from cocaine use, ventricular arrhythmias usually result from ischemia. Treatment should focus on managing ischemia.67 For persistent or recurrent ventricular arrhythmias, standard therapy, including lidocaine, should be used.67,101 In some but not all animal studies, lidocaine potentiated the cardiac and central nervous system toxicity of cocaine.67,101 However, no deleterious effects were observed in 29 patients with cocaine-induced MI who received lidocaine in the emergency room.101 Because cocaine prolongs the QT interval, class III antiarrhythmic drugs should be used with caution.102 The QT interval returns to normal after several days of abstinence.103 Compared with non–cocaine-using age-matched control subjects, cocaine-using patients experiencing cardiac arrest were more likely to survive (22% versus 54%).97

Aortic Dissection

Retrospective analyses in 2 urban centers reported aortic dissection to be attributable to cocaine in 16 of 146 cases (10%)104 and in 14 of 38 cases (37%),105 respectively. In contrast, the International Registry for Aortic Dissection, which included 17 aortic centers worldwide, reported cocaine use in only 5 of 921 cases (0.5%) of aortic dissection.106 Thus, the incidence of cocaine-induced aortic dissection varies widely, depending on the population served. Cocaine-using patients were younger and more likely to smoke cigarettes.104,105 The presenting symptoms and type of aortic dissection did not differ depending on cocaine use.104,105 Cocaine-using patients were more likely to undergo surgical repair because surgery was more often deferred in nonusers of cocaine owing to advanced age, severe comorbidities, and patient/family hesitation.105 Cocaine users were more likely to suffer postoperative pulmonary complications.104 Thirty-day mortality did not differ, but 1-year mortality was higher in cocaine-using patients (31% versus 22%) because of deaths caused by drug overdose, MI, and stroke.104

Endocarditis

Risk factors for endocarditis were analyzed retrospectively in 115 intravenous drug users hospitalized for a febrile illness.107 Bacterial endocarditis was diagnosed in 23 (20%) and involved the tricuspid valve in 15 (75%). Forty-four patients used cocaine; 73 used heroin. By univariate analysis, cocaine was the only drug associated with endocarditis (cocaine, P<0.001; heroin, P=0.051). The association of cocaine with endocarditis was strengthened by logistic regression analysis (OR, 138). The marked association between cocaine and endocarditis may be related to overall worse addiction, more frequent injections, worse hygiene, and “dirtier” needles in intravenous cocaine users, or it may be related to the physiological effects of cocaine, including endothelial damage and thrombus formation.107

Endothelial Dysfunction and Erectile Dysfunction

Cocaine affects the vasculature at least in part by impairing endothelial function.15 Through a series of in vivo and in vitro experiments, Mo and colleagues15 demonstrated that cocaine reduced nitric oxide production by 20% and that pretreatment with NG-monomethyl-l-arginine (a nitric oxide blocker) blunted the cocaine-induced increase in blood pressure by 80% and blocked cocaine-induced vasoconstriction. In addition, arteries denuded of endothelium failed to respond to cocaine.15 Levels of endothelin-1, a potent endothelium-derived vasoconstrictor, were markedly elevated in cocaine-intoxicated patients compared with control patients.14 Long-term cocaine users demonstrated endothelial dysfunction in response to intra-arterial acetylcholine in both the brachial and coronary arteries.29 Endothelial dysfunction may be especially important in the setting of cocaine intoxication because arterial segments with endothelial dysfunction show increased vasoconstriction in response to catecholamines.30 Clinically, this effect of cocaine translates into coronary vasoconstriction25 that is more prominent in atherosclerotic arterial segments27 and enhanced with cigarette smoking.28 Moreover, cocaine causes erectile dysfunction through impaired endothelial function. Impotence was reported in 36% to 52% of cocaine abusers.108 In a rat model, acute cocaine intoxication significantly impaired erectile responses, increased endothelin-1 levels, and decreased nitric oxide production.109

Other Vascular Complications

Intraventricular thrombus has been reported with cocaine-induced MI.110 Left ventricular thrombus is common in the setting of anterior MI and may be even more prevalent in cocaine-induced MI because cocaine enhances thrombus formation.110 Renal infarction, acute peripheral arterial occlusion,111 and at least 18 cases of bowel ischemia112 have been reported in association with cocaine. An unusual case of intracranial hemorrhage occurred in a woman who mixed cocaine with her prescribed enoxaparin because it facilitated intravenous injection.113

A man developed erythema of the digits on exposure to cold and dry gangrene requiring amputation of the fourth toe.111 He was initially diagnosed with thromboangiitis obliterans (Buerger disease). Lower-extremity angiography was not typical of thromboangiitis obliterans, and the man admitted to frequent cocaine use. The authors suggested that cocaine use can manifest very similarly to thromboangiitis obliterans and may have contributed to the group of 30 young cigarette smokers first described by Leo Buerger in 1908.111

Cocaine and Anesthesia

Cocaine used to be popular for local anesthesia for laryngoscopy because of its intense vasoconstriction.114 However, its topical use for laryngoscopy increases heart rate and systemic blood pressure, reduces coronary blood flow, and precipitates cardiac arrhythmias.25,114 An 18-year-old man undergoing tonsillectomy and nasal polypectomy developed acute MI minutes after topical nasal cocaine and epinephrine in the setting of general anesthesia, intubation, and a surgical incision.115 The combination of stressors probably precipitated a myocardial oxygen supply-demand mismatch. Cocaine is probably not the best choice for local anesthesia, considering the viable alternatives.115

Forty cocaine-abusing patients (with normal heart rate, blood pressure, and temperature) undergoing general anesthesia for elective surgery were compared with 40 drug-free control subjects.116 No patients received β-blockers. No patients developed myocardial ischemia, arrhythmias, changes in heart rate of >30% from baseline, or a >40% increase in blood pressure. Blood pressure decreased 40% from baseline in 3 cocaine abusers and in 4 control subjects.116 Cocaine users were more likely to suffer postoperative pulmonary complications, defined as pneumonia or prolonged mechanical ventilation (63% versus 21%).104

Cocaine Combined With Ethanol

Of 233 cocaine-using patients who presented to the emergency room, 36% also ingested ethanol.3 In patients who died of cocaine overdose, the blood cocaine level at autopsy was lower in patients who also ingested ethanol compared with those who used cocaine alone (0.9 versus 2.8 mg/L; P=0.06), suggesting increased toxicity at lower blood cocaine levels when combined with ethanol; cocaethylene levels were not measured.2 When combined with ethanol, the concentration of cocaine increases, the active metabolite cocaethylene is formed, and hemodynamic effects are prolonged.117,118 Eleven male volunteers ingested ethanol followed by placebo or cocaine (at 2 different doses) in a crossover fashion.118 In the absence of ethanol, only the high dose of cocaine significantly increased heart rate and diastolic blood pressure. When combined with ethanol, both low- and high-dose cocaine significantly increased heart rate, cardiac output, and systolic and diastolic blood pressures. The effects of cocaine, ethanol, and task performance were evaluated in 9 volunteers.119 Heart rate increased by up to 6 bpm with cocaine or ethanol alone, by 20 bpm with cocaine and ethanol combined, by 5 bpm during task performance alone, and by 40 bpm with the combination of cocaine, ethanol, and task performance. Ethanol intensifies and prolongs the cardiovascular effects of cocaine.

Conclusions

Through a variety of mechanisms, cocaine increases the risk of MI, heart failure, cardiomyopathy, arrhythmias, aortic dissection, endocarditis, and other cardiovascular diseases. Identifying the ≈6% of patients with CACP who have acute MI is challenging because demographics, clinical presentation, ECGs, and CK do not differentiate the presence of MI. Twelve-hour observation with serial troponin measurement and ST-segment monitoring identifies acute MI with high accuracy. Benzodiazepines, phentolamine, calcium channel blockers, antiplatelet agents, antithrombotic agents, and cardiac catheterization each play a role in the acute management of chest pain or MI in cocaine-using patients. Severe hypertension and coronary vasoconstriction can result from combining β-blockers with cocaine. β-Blockers should be avoided in the acute setting. Postdischarge management of MI and cardiomyopathy in cocaine-using patients should follow published guidelines, except β-blockers should be prescribed only in select patients. Cessation of cocaine is the primary goal of postdischarge therapy. The use of cocaine should be investigated in patients with cardiovascular disease, especially young patients, because its presence may influence disease diagnosis, management, and therapy.

Disclosures

None.

Footnotes