Features and Outcomes of Methamphetamine-associated Pulmonary Arterial Hypertension

Abstract

Rationale: Although amphetamines are recognized as “likely” agents to cause drug- and toxin-associated pulmonary arterial hypertension (PAH), (meth)amphetamine-associated PAH (Meth-APAH) has not been well described.

Objectives: To prospectively characterize the clinical presentation, histopathology, and outcomes of Meth-APAH compared with those of idiopathic PAH (iPAH).

Methods: We performed a prospective cohort study of patients with Meth-APAH and iPAH presenting to the Stanford University Pulmonary Hypertension Program between 2003 and 2015. Clinical, pulmonary angiography, histopathology, and outcomes data were compared. We used data from the Healthcare Cost and Utilization Project to estimate the epidemiology of PAH in (meth)amphetamine users hospitalized in California.

Measurements and Main Results: The study sample included 90 patients with Meth-APAH and 97 patients with iPAH. Patients with Meth-APAH were less likely to be female, but similar in age, body mass index, and 6-minute-walk distance to patients with iPAH. Patients with Meth-APAH reported more advanced heart failure symptoms, had significantly higher right atrial pressure (12.7 ± 6.8 vs. 9.8 ± 5.1 mm Hg; P = 0.001), and had lower stroke volume index (22.2 ± 7.1 vs. 25.5 ± 8.7 ml/m²; P = 0.01). Event-free survival in Meth-APAH was 64.2%, 47.2%, and 25% at 2.5, 5, and 10 years, respectively, representing more than double the risk of clinical worsening or death compared with iPAH (hazard ratio, 2.04; 95% confidence interval, 1.28–3.25; P = 0.003) independent of confounders. California data demonstrated a 2.6-fold increase in risk of PAH diagnosis in hospitalized (meth)amphetamine users.

Conclusions: Meth-APAH is a severe and progressive form of PAH with poor outcomes. Future studies should focus on mechanisms of disease and potential therapeutic considerations.

At a Glance Commentary

Scientific Knowledge on the Subject

Drug- and toxin-associated pulmonary arterial hypertension (PAH) has historically been characterized by exposure to anorexigens and chemotherapeutic agents. Although amphetamines are recognized as “likely” agents associated with PAH, the clinical details and outcome of (meth)amphetamine-associated PAH (Meth-APAH) have not been well studied despite a recent surge of illicit (meth)amphetamine use.

What This Study Adds to the Field

To our knowledge, this is the first prospective cohort study to characterize the presentation, clinical phenotype, histopathology, and long-term outcomes of patients with Meth-APAH compared to those with idiopathic PAH. Patients with Meth-APAH had a worse prognosis compared to those with idiopathic disease. We have shown the burden of PAH in the setting of (meth)amphetamine use in a statewide database of hospital admissions.

Since the late 1990s, a global wave of amphetamine and methamphetamine (collectively termed “[meth]amphetamine”) abuse has emerged. Worldwide prevalence of (meth)amphetamine use was estimated at 14.3–52.5 million in 2010, surprisingly more than cocaine and second only to cannabis as the most common illicit substance of use (1). Up to 3.8% of the European Union population (12.5 million people) reported lifetime use (2), as did 2.2–5.8% of the U.S. population (3) with 12.3 million lifetime (meth)amphetamine users in 2013. The epidemic of (meth)amphetamine use specifically in California peaked in 2006 and was associated with an incidence of 12–18 cases per 10,000 hospital admissions between 2006 and 2013 (4).

(Meth)amphetamine can be inhaled (vaporized), smoked, snorted (intranasal), orally ingested, or injected. Cardiovascular toxicity of (meth)amphetamine includes myocardial ischemia, infarction, and cardiomyopathy. Respiratory sequelae include pulmonary hemorrhage, pulmonary edema, acute lung injury, pneumothorax, and pulmonary hypertension (5). In 1993, a case report first suggested that pulmonary hypertension in a young man might be due to prior methamphetamine use (6). In a retrospective cohort study, Chin and colleagues (7) showed that patients with idiopathic pulmonary arterial hypertension (iPAH) had much higher rates of (meth)amphetamine use (29%) than did patients with chronic thromboembolic pulmonary hypertension (4.3%; odds ratio = 10.1) or pulmonary hypertension due to a known associated condition (3.8%; odds ratio = 7.6), although selection bias could have affected these results. Current guidelines recognize (meth)amphetamines as a “likely” cause of drug-induced PAH (8).

Using prospectively collected data, we sought to compare the clinical presentation, disease characteristics, and outcomes of patients with (meth)amphetamine-associated PAH (Meth-APAH) to those of iPAH. We hypothesized that patients with Meth-APAH would have more severe hemodynamic abnormalities and worse survival compared with patients with iPAH. Using the largest state-level, longitudinal hospital care database in the United States, we further evaluated the incidence of PAH in admitted patients who carried a diagnosis of (meth)amphetamine use. We hypothesized that the risk of a PAH diagnosis would be higher among patients with (meth)amphetamine-related hospitalizations.

Methods

Stanford Cohort

Design

We performed a prospective cohort study of adults evaluated at the Stanford Adult Pulmonary Hypertension Program between January 2003 and December 2015. The study sample included patients with iPAH or Meth-APAH who were newly evaluated at our center. Patients underwent echocardiography, pulmonary function testing, chest imaging, and right-heart catheterization. Date of hemodynamic confirmation of PAH was used as the diagnosis date. We included patients with mean pulmonary artery pressure of 25 mm Hg or greater and pulmonary arterial wedge pressure 15 mm Hg or less at rest (9). We excluded patients with significant obstructive (defined as FEV₁/FVC ratio below 70%) or restrictive (defined as FVC or TLC <65% predicted) ventilatory defects. We also excluded patients with significant left-ventricular (left ventricular ejection fraction < 45%) and valvular heart diseases, chronic thromboembolic disease, and other causes of pulmonary hypertension. Patients with concomitant anorexigen and nonamphetamine illicit substance use, such as cocaine (historical or active based on urinary toxicology screen [UTS]), were excluded. We also excluded subjects with HIV infection.

Prior use of (meth)amphetamine was characterized using a comprehensive questionnaire, which included routine and slang terms. Meth-APAH was defined as PAH in the setting of significant (meth)amphetamine exposure, characterized as more than three episodes of use reported per week for greater than 3 months (10). Active (meth)amphetamine use was identified using UTS, performed in all patients at baseline evaluation. Patients with iPAH were required to demonstrate a negative UTS and exposure history, and have no evidence of another form of PAH.

Data collection and variables

All patients underwent a detailed history, physical examination, and laboratory assessment. Digitized echocardiographic studies were acquired using Hewlett Packard Sonos 7500 or Philips IE 33 ultrasound systems. All measures were averaged over three cycles and performed in accordance with the latest guidelines of the American Society of Echocardiography (11, 12) and interpreted by level III echocardiography-certified cardiologists. Right-heart catheterization was performed with inhaled nitric oxide challenge. Pulmonary wedge angiography was obtained by placing the pulmonary artery catheter in the wedge position with an inflated balloon. A sandwich solution of 5 ml iodinated contrast followed by 4–5 ml of heparinized saline was hand injected, the balloon gently deflated, and images captured with routine cineangiography (13, 14). Demographic, clinical, hemodynamic, and outcomes data were captured in the Vera Moulton Wall Center Pulmonary Hypertension Database (see details in the online supplement). County-level socioeconomic data for the patient’s residence were obtained from the U.S. Census Bureau’s publically available Small Area Income and Poverty Estimate (1995–2015) and the American Community Survey (2008–2013) datasets. Medication use data were collected at baseline and subsequent clinical encounters at 3- to 4-month intervals.

Deaths were captured from the medical record and the Social Security Death Index. When patients were admitted to Stanford University Medical Center, hospitalization data were extracted from the inpatient chart. Outside hospitalizations were either self-reported or verified by local physicians. Patients were followed until lung transplantation, death, or January 2016 (whichever came first). We defined nonadherence as active (meth)amphetamine use identified by clinical screening, missed medications for PAH treatment, or missed pulmonary hypertension clinic appointments during the observation period (definition 1). To avoid the confounding effect of exposure definition within adherence, we also evaluated outcomes without the active (meth)amphetamine use component of nonadherence (definition 2).

Outcome

The primary outcome was time to all-cause mortality (verified by Social Security Death Index), transplantation (lung or heart–lung), or hospitalization for right-heart failure. Right-heart failure was defined as progressive symptoms primarily attributed to worsening cardiac function, including, but not limited to, fluid retention (lower extremity or ascites), worsening renal function, hypotension, arrhythmias, or congestive hepatopathy. Initial admission for stabilization and initiation of PAH therapy was not considered a hospitalization end point. Heart failure hospitalizations resulting in death were counted as a mortality event.

Histopathology

Pathologic lung samples were obtained from individuals with Meth-APAH or iPAH either at the time of transplantation or autopsy. For each case, sections from pulmonary tissue blocks were stained with hematoxylin and eosin after proper fixation. Representative areas were analyzed, photographed, and compared across etiologies by experienced pulmonary pathologists (R.T., G.J.B., and J.I.S.).

The Stanford University Institutional Review Board for human studies approved the registry protocols (Institutional Review Board no. 12338), and written consent was obtained.

Statistical analysis

Continuous variables were expressed as median (interquartile range [IQR]) or mean ± SD, and categorical variables were expressed as counts (percentages). Two-sample t tests or Mann-Whitney U tests were used to compare continuous variables, and chi-square or Fisher’s exact tests were used to compare categorical variables, as appropriate.

Kaplan-Meier curves compared event-free survival stratified by diagnosis. We used Cox proportional hazards models to estimate the relationship between diagnosis (Meth-APAH vs. iPAH) and outcomes (see the online supplement). Briefly, multivariable Cox models included several prespecified covariates a priori: age, sex, race, median household income, and use of intravenous or subcutaneous prostacyclin analogs. Medication use, including number of PAH medications and intravenous/subcutaneous prostacyclin analogs, were analyzed as time-varying covariates. We then performed purposeful addition of covariates where we assessed the effect of the inclusion of possible confounders of the effect estimate of diagnosis (Meth-APAH vs. iPAH) in the multivariable model. We considered a 20% change in the effect estimate to be meaningful and retained those covariates (referred to as “a priori plus” models). P values less than 0.05 were considered statistically significant. All analyses were performed in R, version 3.1.3 (R Core Team, 2015). For missing data, multiple imputation was implemented using the R package “mice,” version 2.22 (15). Sensitivity analyses were performed using only treatment-naive patients, alternate definitions of adherence, and the outcome of time to death or transplantation.

Mediation analysis

Mediation analysis was performed to evaluate whether certain factors mediated the association between diagnosis and event-free survival (16). When possible mediators were identified, we further calculated the “proportion of treatment effect” (17) or the degree of the association between diagnosis and outcome explained by the mediator (see the online supplement).

Healthcare Cost and Utilization Project Cohort

Design and data source

We performed a retrospective cohort study of hospital admissions reported to the Healthcare Cost and Utilization Project (HCUP) sponsored by the Agency for Healthcare Research and Quality (18). We queried HCUP databases, which include all hospitalizations resulting in at least one overnight stay in California medical centers between 2005 and 2011. These databases contain encounter-level information, including patient demographics, diagnoses (International Classification of Diseases, Ninth Revision, Clinical Modification) (19), procedures, discharge status, and cost for all patients, regardless of payer.

Analysis

Using comprehensive, discharge-linked International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic code stratification, we analyzed the incidences of PAH linked to discharges with and without (meth)amphetamine use diagnoses. We also calculated the overall and sex-specific risk ratios for PAH given a (meth)amphetamine use diagnosis (see the online supplement).

Results

Stanford Cohort

Between January 2003 and December 2015, we evaluated 487 patients with PAH from which we identified 90 new patients with Meth-APAH and 97 patients with iPAH who met our inclusion criteria (Figure 1).

Figure 1.

Strengthening the Reporting of Observational Studies in Epidemiology flow diagram. CHD-APAH = congenital heart disease–associated PAH; CTD-APAH = connective tissue–associated PAH; D+T-APAH = drug- and toxin-associated PAH; HPAH = heritable PAH; iPAH = idiopathic PAH; Meth-APAH = (meth)amphetamine-associated PAH; PAH = pulmonary arterial hypertension; PCH = pulmonary capillary hemangiomatosis; PH = pulmonary hypertension; PPHTN = portopulmonary hypertension; PVOD = pulmonary veno-occlusive disease. *Other drugs include concomitant cocaine (n = 8), anorexigens (n = 4), and dasatinib (n = 2).

Patients with Meth-APAH were similar in age and body mass index to patients with iPAH, but were less likely to be female (63.3% vs. 82.5%; P = 0.005), were more likely to be non-Hispanic white (78.9% vs. 52.6%, P < 0.001), and reported a worse functional class (P = 0.022) (Table 1). Time from symptom onset to diagnosis was not different between Meth-APAH and iPAH groups. Patients with Meth-APAH had higher creatinine, but similar N-terminal pro B-type natriuretic peptide levels. Despite similarly reduced 6-minute-walk distance, patients with Meth-APAH demonstrated lower 2-minute heart rate recovery compared with patients with iPAH (19.7 ± 10.7 vs. 24.5 ± 14.4 bpm; P = 0.017). The majority of both diagnostic groups were treatment naive (incident) or on monotherapy at baseline. The characteristics of the counties of residences were similar between the groups, including the median household income and percent of residents below the poverty line, although counties of patients with Meth-APAH had more residents with a high school degree.

Table 1.

Baseline Patient Demographics and Clinical Characteristics

Parameters	iPAH (n = 97)	Meth-APAH (n = 90)	P Value*
Patient-level characteristics
Age, yr	45.2 ± 16.4	44.5 ± 7.3	0.71
Sex, female, n (%)	80 (82.5)	57 (63.3)	0.005
BMI, kg/m2	29.7 ± 7.8	31.2 ± 7.3	0.18
Race, n (%)			0.001†
White, non-Hispanic	51 (52.6)	71 (78.9)
Asian/Pacific Islander	13 (13.4)	3 (3.3)
Hispanic	18 (18.6)	11 (12.2)
Black, non-Hispanic	8 (8.2)	2 (2.2)
Native American	2 (2.1)	1 (1.1)
Other	4 (4.1)	0
Unknown	1 (1.0)	2 (2.2)
Sx onset to diagnosis, mo (n = 157)‡	10.0 (3.0–26.8)	11.0 (6.2–24.0)	0.74
WHO class, n (%)			0.02
I	6 (6.2)	1 (1.1)
II	20 (20.6)	8 (8.9)
III	45 (46.4)	54 (60.0)
Intravenous	24 (24.7)	27 (30.0)
6-min-walk test
6MWD, m (n = 180)	380 (163)	365 (156)	0.54
HRR-2 min, beats (n = 169)	24.5 (14.4)	19.74 (10.7)	0.017
Baseline O2 saturation, % (n = 175)	96.1 ± 2.8	95.6 ± 2.8	0.24
Peak-exercise O2 saturation, % (n = 171)	91.7 ± 7.4	93.6 ± 6	0.02
Laboratory tests‡
NT-pro BNP, pg/dl (n = 110)	811 (190–2,205.3)	1,166.5 (314.5–2,174.3)	0.59§
Creatinine, mg/dl (n = 173)	0.9 (0.8–1.1)	1.0 (0.9–1.2)	0.016§
Hemoglobin, g/dl (n = 168)	14 (12.9–16)	15 (13.5–16.2)	0.079§
Platelets, thousands (n = 162)	207 (175–247)	204 (174–263)	0.83§
RDW, % (n = 163)	14.1 (13.4–15.9)	14.6 (13.7–16.1)	0.16§
Baseline PAH medications, n (%)
Prostacyclin analog	3 (3.1)	4 (4.4)	0.92
Endothelin receptor antagonist	7 (7.2)	11 (12.2)	0.36
Phosphodiesterase-5 inhibitor	20 (20.6)	25 (27.8)	0.33
Baseline no. of PAH therapies, n (%)			0.39†
None	72 (74.2)	59 (65.6)
One	20 (20.6)	24 (26.7)
Two	5 (5.2)	5 (5.6)
Three	0 (0.0)	2 (2.1)
County-level characteristics‡
Median household income, U.S. $	61,228 (50,376–81,378)	67,295 (44,795–84,741)	0.71§
% residents below poverty line	13.5 (10.6–17.1)	12.5 (10.6–18.2)	0.11§
% residents with a high school degree	86.0 (76.6–86.5)	86.5 (83.5–88.4)	0.004§
% residents with a college degree	36.4 (20.6–45.1)	36.5 (19.7–45.5)	0.63§

Definition of abbreviations: 6MWD = 6-minute-walk distance; BMI = body mass index; HRR-2 min = heart rate recovery at 2 minutes; iPAH = idiopathic pulmonary arterial hypertension; Meth-APAH = (meth)amphetamine-associated pulmonary arterial hypertension; NT-pro BNP = N-terminal pro B-type natriuretic peptide; PAH = pulmonary arterial hypertension; RDW = red blood cell distribution width; Sx = symptom; WHO = World Health Organization.

All values are expressed as mean ± SD, and total number of observations is 187, unless otherwise noted.

^*P values calculated using t test for continuous variables or chi-square test for categorical variables unless otherwise noted.

^†Fisher’s exact test used.

^‡Values expressed are median (interquartile range).

^§Mann-Whitney test used.

Although both groups had similarly low rates of comorbidities, reflecting our conservative phenotyping, patients with iPAH had higher rates of concomitant thyroid disease and systemic hypertension (see Table E1 in the online supplement). The self-reported median duration of continuous exposure to (meth)amphetamine in the Meth-APAH group was 60 months (IQR, 21–120), and was similar between male (72 mo; IQR, 20–156) and female (60 mo; IQR, 24–120) users (P > 0.5). Only 18 (20%) subjects with Meth-APAH were found to have positive urine toxicology screen for (meth)amphetamines. The majority (63 [70%]) of the users reported daily use. When route of exposure was clinically documented, inhalation/smoking was the most common (n = 9 out of 13 subjects).

Despite higher rates of smoking history (Meth-APAH 70 [77.8%] vs. iPAH 31 [32%], P < 0.001; Table E1), patients with Meth-APAH had comparable pulmonary function to patients with iPAH, but significantly higher Dl_CO (Table 2). Interestingly both groups had remarkably well preserved Dl_CO. Patients with Meth-APAH were more likely to have moderate to severe right-ventricular (RV) dilatation and dysfunction on echocardiography. Left-ventricular morphology, size, and function were similar between the groups.

Table 2.

Baseline Pulmonary Function, Echocardiography, and Hemodynamics

Parameters	iPAH (n = 97)	Meth-APAH (n = 90)	P Value
Pulmonary function tests
FVC % predicted (n = 168)	87.9 ± 15.9	89.7 ± 14.5	0.44
FEV1 % predicted (n = 168)	85.8 ± 16.4	87.4 ± 16.1	0.51
FEV1/FVC (n = 168)	0.78 ± 0.09	0.77 ± 0.07	0.54
DlCO % predicted (n = 168)	75.8 ± 23.1	82.7 ± 20.9	0.04
Echocardiography
RVSP, mm Hg	81.3 ± 22.6	88.5 ± 35.2	0.11
RAP, mm Hg (n = 165)	9.8 ± 5.6	12.5 ± 9.8	0.03
LV size, n (%)			0.52
Small	26 (26.8)	29 (32.2)
Normal	70 (72.2)	60 (66.7)
Dilated	1 (1.0)	0 (0.0)
LV mass, n (%)			1
Normal	82 (84.5)	76 (84.4)
LVH	15 (15.5)	14 (15.6)
LV function, n (%)			0.12
Normal	92 (94.8)	79 (87.8)
Reduced	5 (5.2)	11 (12.2)
Septum, n (%)			0.46
Normal	27 (27.8)	18 (20.0)
Flattened	66 (68.0)	68 (75.6)
Leftward bowing	4 (4.1)	4 (4.4)
RV size, n (%)			<0.001
Normal	6 (6.2)	1 (1.1)
Dilated (mild)	27 (27.8)	9 (10.0)
Dilated (moderate–severe)	64 (66.0)	80 (88.9)
RV function, n (%)			<0.01
Normal	16 (16.5)	5 (5.6)
Reduced (mild)	20 (20.6)	8 (8.9)
Reduced (moderate–severe)	61 (62.9)	77 (85.6)
LA size, n (%)			0.33
Normal	71 (73.2)	71 (78.9)
Dilated	26 (26.8)	18 (20.0)
Small	0 (0.0)	1 (1.1)
RA size, n (%)			<0.01
Normal	24 (24.7)	7 (7.8)
Dilated	73 (75.3)	83 (92.2)
Pericardial effusion, n (%)	21 (21.6)	28 (31.1)	0.19
Hemodynamics
Heart rate, bpm (n = 175)	81.4 ± 14.1	80.8 ± 13.2	0.81
RAP, mm Hg (n = 180)	9.8 ± 5.1	12.7 ± 6.8	0.001
mPAP, mm Hg	54.9 ± 14.6	54.1 ± 11.9	0.71
PAWP, mm Hg	10.6 ± 3.9	10.4 ± 4.7	0.74
CO, L/min	3.7 ± 1.1	3.5 ± 1.0	0.19
PVR, dyn ⋅ s ⋅ cm−5	1,056 ± 496	1,120 ± 480	0.39
SVi, ml/m2 (n = 175)	25.5 ± 8.7	22.2 ± 7.1	0.01
PAC, ml/mm Hg (n = 174)	1.05 ± 0.64	0.96 ± 0.48	0.28
Vasoreactive, n (%) (n = 141)	7 (9.6)	1 (1.5)	0.064

Definition of abbreviations: bpm = beats per minute; CO = cardiac output; iPAH = idiopathic pulmonary arterial hypertension; LA = left atrium; LV = left ventricle; LVH = left ventricular hypertrophy; Meth-APAH = (meth)amphetamine-associated pulmonary arterial hypertension; mPAP = mean pulmonary artery pressure; PAC = pulmonary arterial capacitance; PAWP = pulmonary artery wedge pressure; PVR = pulmonary vascular resistance; RA = right atrium; RAP = right atrial pressure; RV = right ventricle; RVSP = RV systolic pressure; SVi = stroke volume index.

All data are expressed as mean ± SD and n (%); n = 187 unless otherwise specified.

Both groups had hemodynamic abnormalities consistent with severe PAH (Table 2), but patients with Meth-APAH had higher mean right-atrial pressures than patients with iPAH (12.7 ± 6.8 vs. 9.8 ± 5.1 mm Hg; P = 0.001), but no differences in mean pulmonary artery pressure, cardiac output, or pulmonary vascular resistance. Meth-APAH had lower stroke volume index (25.5 ± 8.7 vs. 22.2 ± 7.1 ml/m²; P = 0.01). One patient with Meth-APAH (1.5%) had acute vasoreactivity to inhaled nitric oxide compared with seven patients with iPAH (9.6%) (P = 0.06). Patients with Meth-APAH had a less robust reduction in mean pulmonary artery pressure (−5.5 ± 6.6% vs. −13.4 ± 14.9%; P = 0.001) and pulmonary vascular resistance (−10.4 ± 16.3% vs. −20.7 ± 20%; P = 0.002) in response to inhaled nitric oxide challenge (Table 3).

Table 3.

Acute Vasodilator Challenge (Inhaled Nitric Oxide)

	iPAH (n = 73, 7 VR)				Meth-APAH (n = 68, 1 VR)				% Change (iPAH vs. Meth-APAH) P Value
	Baseline	iNO	P Value	% Change	Baseline	iNO	P Value	% Change
mPAP, mm Hg	55.1 ± 12.7	47.9 ± 14.6	<0.0001	−13.4 ± 14.9	53.2 ± 11.2	49.6 ± 12.5	<0.0001	−5.5 ± 6.6	0.001*
PCWP, mm Hg	10.3 ± 3.9	10.4 ± 3.8	0.5	6.6 ± 31.5	10.5 ± 4.3	10.0 ± 4.6	0.04†	−3.7 ± 28.8	0.02*
CO, L/min	3.6 ± 1.1	3.8 ± 1.1	0.0013*	5.6 ± 12.2	3.6 ± 0.9	3.8 ± 1.1	0.0008	7.7 ± 18.6	0.84*
PVR, dyn ⋅ s ⋅ cm−5	1,093 ± 425	871 ± 428	<0.0001	−20.7 ± 20	1,047 ± 455	940 ± 459	<0.0001*	−10.4 ± 16.3	<0.01*

Definition of abbreviations: CO = cardiac output; iNO = inhaled nitric oxide; iPAH = idiopathic pulmonary arterial hypertension; Meth-APAH = (meth)amphetamine-associated pulmonary arterial hypertension; PCWP = pulmonary capillary wedge pressure; mPAP = mean pulmonary artery pressure; PVR = pulmonary vascular resistance; VR = vasoreactive.

All values represent mean ± SD. All analyses are paired t tests unless otherwise specified.

^*Mann-Whitney U test.

^†Wilcoxon matched-pairs signed-ranks test.

Similar to iPAH (Figures 2C and 2D), pulmonary artery wedge angiography in subjects with Meth-APAH (Figures 2E and 2F) demonstrated rapid tapering, reduced monopedial vessels, and substantial loss of capillary blush with a normal levophase (right middle lobe, Video 1A; right lower lobe, Video 1B) consistent with occlusive vasculopathy. Histopathologic sections of lungs from patients with Meth-APAH demonstrated characteristic vascular changes similar to those in iPAH, including angiomatoid plexiform lesions with slit-like vascular channels within the artery (Figures 3C and 3D), as well as proliferative capillaries similar to histopathology of pulmonary capillary hemangiomatosis (Figures 3E and 3F). In one case, we could demonstrate aberrant pulmonary arteries with scattered intravascular collections of microcrystalline cellulose (Figure 3H)—a filler commonly used in vitamins, which is also used to “cut” illicit injectable amphetamines. More pathology samples can be found in the online supplement (Figure E1).

Figure 2.

Pulmonary artery wedge angiography comparing idiopathic pulmonary arterial hypertension (iPAH) with (meth)amphetamine-associated PAH (Meth-APAH). Normal pulmonary arteries are characterized by a dense concentration of monopedial supernumerary vessels (A) and healthy-appearing capillary blush (B). Severe pulmonary arterial tapering, monopedial vascular drop-out, and loss of capillary blush characterize Meth-APAH (E and F), as seen in iPAH (C and D). Right upper, middle, and lower lobe pulmonary artery branches are identified according to their anatomic labels, A3–A5 and A7–A10.

Figure 3.

Histopathology of cases with idiopathic pulmonary arterial hypertension (iPAH) and (meth)amphetamine-associated PAH (Meth-APAH). (A) Normal muscular pulmonary artery (hematoxylin and eosin [H&E]). (B) Plexiform lesion in a patient with iPAH who underwent lung transplantation (H&E). (C) Plexiform arteriopathy in Meth-APAH involving muscular artery (H&E). (D) High-power magnification showing proliferation of slit-like vascular channels within artery (H&E). (E) Pulmonary microvasculopathy in Meth-APAH (H&E). (F) High-power magnification showing proliferation of capillaries within the pulmonary interstitium (H&E). (G) Angiomatoid lesion in Meth-APAH composed of dilated, thin-walled vascular spaces surrounding a plexiform lesion (H&E). (H) The patient in G also exhibited scattered intravascular collections of microcrystalline cellulose causing an intimal proliferative response within the muscular artery (polarized microscopy; H&E).

Video 1A.

Download video file ^{(51.2MB, mp4)}

Pulmonary artery wedge angiogram movie. (Videos 1A and 1B [below]) Pulmonary wedge angiography of right middle lobe (RML) (Video 1A) and lower lobe (RLL) (Video 1B [below]) of a patient with (meth)amphetamine-associated pulmonary arterial hypertension (Meth-APAH) demonstrates extensive arterial narrowing, loss of capillary blush, and a normal levophase flow.

Video 1B.

Download video file ^{(88.4MB, mp4)}

(See legend above).

There was a total of 8,605.2 patient-months of follow-up in the entire study. The median follow-up time per patient was 47.2 months (IQR, 19.7–87). A total of 9 (4.8%) of the 187 patients in the cohort ceased follow-up at our center during the study period; however, we confirmed the date of death in three subjects through a Social Security Death Index search and were able to verify the health status of the remaining six at the censor date, resulting in no loss to follow-up.

Although 60.3% of patients with iPAH demonstrated adherence to medical therapy and the care plan, only 46.7% of patients with Meth-APAH were compliant (P = 0.053). The time to initiation of intravenous/subcutaneous prostacyclin analog therapy was greater for patients with Meth-APAH (Figure 4), and patients with Meth-APAH were less commonly prescribed continuous intravenous/subcutaneous prostacyclin analogs compared with iPAH in the long term.

Figure 4.

Proportion of patients on prostacyclin analogs. Proportion of patients with (meth)amphetamine-associated pulmonary arterial hypertension (Meth-APAH; blue) and idiopathic PAH (iPAH; red) on intravenous/subcutaneous prostacyclin analogs during the observation period (years). Patients with Meth-APAH had slower rates of overall prostacyclin analog initiation, and, when prescribed, were more often on inhaled or oral prostacyclin therapies as compared with iPAH counterparts. IV/SQ = intravenous/subcutaneous.

During the observation period, approximately one-half of the cohort (n = 91) had an event. There were 52 (57.8%) events (31 deaths, 3 transplants, and 18 RV failure–associated hospitalizations) in patients with Meth-APAH and 39 (40.2%) events (20 deaths, 7 transplants, and 12 RV failure hospitalizations) in patients with iPAH. Kaplan-Meier analysis showed 5-year and 10-year event-free survival of 47.2% and 25%, respectively, in Meth-APAH versus 64.5% and 45.7% in iPAH (Figure 5, Table E2). In a univariate Cox proportional hazards regression analysis, a diagnosis of Meth-APAH was associated with an increased risk of an event compared with iPAH (hazard ratio, 1.66; 95% confidence interval [CI], 1.09–2.52; P = 0.02; Table E3). In the a priori multivariate model (Table 4), patients with Meth-APAH still had significantly worse outcomes compared with patients with iPAH (hazard ratio, 2.04; 95% CI, 1.28–3.25; P = 0.003), even after adjustment for age, sex, race, median household income, and the use and timing of intravenous/subcutaneous prostacyclin analogs. Adjustment for other potential confounders did not change this result (Table E4). Sensitivity analyses with only treatment-naive patients or using an outcome definition of all-cause mortality or transplantation did not affect the results (Table E5). Of the 10 variables considered as potential mediators of the association between diagnosis group and event-free survival (including adherence), only red cell distribution width (RDW) met all criteria for mediation. Specifically, differences in ventricular function, time to and use of intravenous/subcutaneous prostacyclin analogs between Meth-APAH and iPAH did not fully explain differing outcomes. The “proportion of treatment effect” explained by RDW was only 14%.

Figure 5.

Kaplan-Meier plot of event-free survival for (meth)amphetamine-associated pulmonary arterial hypertension (Meth-APAH) versus idiopathic PAH (iPAH). Kaplan-Meier estimated event-free survival demonstrates worse outcomes for patients presenting with Meth-APAH (dashed line) than for those with iPAH (solid line).

Table 4.

Multivariable Model, A Priori–selected Variables

	HR	95% CI	P Value
Meth-APAH diagnosis (vs. iPAH)	2.04	1.28–3.25	0.003
Age (per year)	0.98	0.96–1.00	0.08
Sex (male vs. female)	1.08	0.68–1.72	0.74
Race (white vs. nonwhite)	0.84	0.52–1.36	0.49
Median household income (per $1,000)	1.00	0.99–1.01	0.91
Prostacyclin analog (intravenous/subcutaneous vs. other)*	1.65	1.03–2.64	0.04

Definition of abbreviations: CI = confidence interval; HR = hazard ratio; iPAH = idiopathic pulmonary arterial hypertension; Meth-APAH = (meth)amphetamine-associated pulmonary arterial hypertension.

^*Time-varying covariate.

HCUP Data

We analyzed California hospitalization data from 110,703,804 discharges in 23,347,268 patients included in the HCUP datasets between 2005–2011. The cohort was 54.4% female, median age of 42 (IQR, 25–58) years, and the majority were white (54.5%) or Hispanic (27.4%) (Table E6). Of the total cohort, 105,625 (0.45%) patients had at least one hospitalization linked primarily to (meth)amphetamine use during the observation period, resulting in 4,524 patients per million with at least one hospitalization annually. In patients admitted without the diagnosis of (meth)amphetamine use (n = 23,241,643), we identified 43,680 with a diagnosis of ICD-coded likely pulmonary hypertension, and 12,624 meeting our criteria for ICD-coded likely PAH (Figures E3–E5). During the entire 2005–2011 period, the overall incidence of ICD-coded likely PAH-related hospitalization was 373.2 cases per million non-(meth)amphetamine users, and 984.6 cases per million (meth)amphetamine users (relative risk [RR], 2.64; 95% CI, 2.18–3.2; P < 0.001) (Figure 6, Supplement Table E7). The relative risk of an ICD-coded likely PAH diagnosis in (meth)amphetamine users was higher in women (RR, 3.32; 95% CI, 2.56–4.29, P < 0.001) then in men (RR, 2.16; 95% CI, 1.6–2.9; P < 0.001).

Figure 6.

Healthcare Cost and Utilization Project data. Cumulative incidence of pulmonary arterial hypertension (PAH) diagnosis per 1,000,000 patients hospitalized comparing (meth)amphetamine use–associated hospitalizations (black) with those not associated with a (meth)amphetamine primary diagnosis (gray). Comparisons are described as risk ratios (95% confidence intervals [CIs]), and further stratified by sex.

Discussion

In this first, to our knowledge, prospective cohort study of Meth-APAH, we demonstrate that Meth-APAH is more common in men than iPAH, possibly due to patterns of (meth)amphetamine use. Compared with iPAH, Meth-APAH is characterized by severe pulmonary vascular disease, as evidenced by higher right atrial pressure, lower stroke volume index, and more dilated and dysfunctional RV appearance at baseline. Although similar in angiographic and histopathologic presentation to iPAH, Meth-APAH was associated with an increased risk of heart failure, transplantation, and death, even when accounting for confounders. Differences in hemodynamic, echocardiographic, socioeconomic, or treatment characteristics did not explain the differences in outcomes, potentially suggestive of a (meth)amphetamine-specific factor. Furthermore, using a comprehensive, large, state-wide database, we showed that hospitalized (meth)amphetamine users have a 2.6-fold increased risk of having a ICD-coded PAH diagnosis compared with nonusers, a finding that appears especially prominent in female (meth)amphetamine users.

We found that patients with Meth-APAH lived in areas with similar median household income, rates of poverty, and percent population with a college degree, as did those with iPAH. Patients with Meth-APAH may have lived in areas with a high prevalence of high school graduates than patients with iPAH. Although patients with Meth-APAH had lower rates of adherence with medical therapies and care plan compared with patients with iPAH, lack of adherence did not account for the worse prognosis as demonstrated in our multivariable analysis. Despite the fact that our patients with Meth-APAH were less likely to be treated with intravenous/subcutaneous prostacyclin analogs (and were treated later, when used) than were patients with iPAH, these factors did not explain the worse outcomes in patients with Meth-APAH. Differential prostacyclin analog use in Meth-APAH reflects prescription reluctance by our clinical team due to concern about adherence, appropriate central line/skin site care, and safety.

Hemodynamics were similar between the groups, other than the greater elevation in right atrial pressures and lower stroke volume index in Meth-APAH, which could reflect the potential myocardial impact of (meth)amphetamine exposure leading to diastolic heart failure (20–22). Even so, worse RV function and less vasoreactivity in Meth-APAH did not explain (or mediate) the differences in outcomes. Interestingly, Meth-APAH appears to present with worse hemodynamics than dasatinib-induced PAH (23). It is plausible that chronic (meth)amphetamine use (and potentially intermittent relapse) produce other confounding health consequences, such as systemic, infectious, and neurocognitive diseases, which mediate worse outcomes (24). Our mediation analysis only found a minor contribution of RDW to adverse outcomes, explaining about 14% of the difference in outcomes between Meth-APAH and iPAH. Abnormal RDW may be a reflection of malnutrition (common in [meth]amphetamine users) (25), resulting in iron, folate, and vitamin B12 deficiency. Moreover, hematologic derangements may be the consequence of accidental lead poisoning previously reported in (meth)amphetamine users (26).

Although our study does not identify the mechanism by which (meth)amphetamine use leads to pulmonary vascular disease and worse outcomes, there is an abundance of substantiating evidence that links (meth)amphetamine use to PAH. The molecular structure of (meth)amphetamine is similar to that of amine-class stimulants, aminorex fumarate (27), 5-methyl-aminorex (28), and fenfluramine (10), all known to cause pulmonary hypertension. Similar to these anorexigens, (meth)amphetamine causes release of dopamine, norepinephrine, and serotonin (5), and promotes the formation of reactive oxygen species (29). A recent study has established that human lungs have the most rapid uptake and the highest accumulation (24%–31% of injected dose) of (meth)amphetamine than other solid organs (30), suggesting an organ-specific vulnerability to (meth)amphetamine toxicity. Furthermore, chronic amphetamine exposure in hypoxic mice leads to suppression of HIF1α (hypoxia-inducible factor 1-α) and disruption of adaptive responses to mitochondrial oxidative stress, resulting in DNA damage and ultimately vascular injury (31). Finally, as with all drug- and toxin-related PAH, a minority of exposed individuals develop PAH, suggesting varying susceptibility from a potential “second hit,” such as genetic (32), epigenetic, and environmental factors, or even route, chronicity, or dose of administration (33).

(Meth)amphetamine can be inhaled (vaporized), smoked, snorted (intranasal), orally ingested, or injected. The preferred route of use varies by geography and sex. In California, most users smoke or inhale vaporized (meth)amphetamine (34). Although older men prefer to inject, women are more likely to inhale or ingest the pill form rather than inject the drug (34, 35). An aspect of our work that will require further study is the implication of route of (meth)amphetamine administration in its potential cardiopulmonary toxicity. With demonstrable acute respiratory toxicity (36), it is possible that chronic and repeated (meth)amphetamine inhalational exposure is associated with significant pulmonary injury. Although we found higher Dl_CO in Meth-APAH, which can be seen with pulmonary hemorrhage, we could not demonstrate signs of acute lung injury to establish the mechanism by which (meth)amphetamine exposure could lead to relatively higher gas transfer factor. Moreover, oxygen saturation at baseline or at peak exercise during 6-minute-walk test were not lower in Meth-APAH. Future studies should evaluate whether route of administration determines the cardiopulmonary manifestation of disease.

Although (meth)amphetamine use should be considered in the workup of PAH in regions where use is high, illicit (meth)amphetamine use is no longer a geographically limited phenomenon. The resurgence of (meth)amphetamine use in the western United States is leading to considerable spread of the epidemic toward the Midwestern and Eastern states (especially in the exurban and rural areas) (4), and is now recognized as a global epidemic (37) led by Southeast Asia, North America, and Europe. Recent data demonstrate that the purity (and thus the addictiveness) of (meth)amphetamine has increased to over 95%, whereas the price has plummeted, spreading the epidemic (1) and increasing the priority for studies of prevention and sequelae of use.

There are several limitations to this study. The prospective cohort reflects a single-center experience. Multicenter, international collaborative studies are necessary to increase the generalizability of our findings. Echocardiographic evaluation, treatment, and follow-up of study subjects was guided by clinical practice and standard of care, and not study-specified protocol. Although the study is limited by some missing data, we had more than 700 patient-years of observation time with no loss to follow-up, and used multiple imputation to address missing data. Nearly 30% of the study population was on active PAH therapies at baseline; however, our sensitivity analysis of treatment-naive patients showed findings similar to the main analysis. Our study was conducted over a 12-year period with different availability of therapies. However, long recruitment and observation periods are a significant strength. Specific exposure thresholds (duration or dose) have not been determined for pulmonary vascular toxicity of (meth)amphetamines, so our definition of significant (meth)amphetamine exposure was based on epidemiologic studies of anorexigen-induced PAH. However, it is unlikely that misclassification could explain our findings. Illicit (meth)amphetamine production occurs in underground, uncontrolled laboratories without strict quality control. Therefore, the actual exposure to the causative agent and duration of use likely varied among the Meth-APAH group. We did not fully capture route of administration, which needs to be addressed in future studies. The potential heterogeneity of methamphetamine synthesis may expose patients to other unrecognized compounds with potentially pulmonary vascular toxic effects. Although we characterized adherence as a binary variable, we must acknowledge that a spectrum of definitions may apply. We considered two definitions of adherence to evaluate whether our results were sensitive to the exact definition, which was not the case.

If patients with apparent iPAH actually had Meth-APAH (or if they started using (meth)amphetamine after the diagnosis without our knowledge), this would have biased to the null, so that the actual differences in outcomes may be even greater than shown. Characterization of phenotypes in the HCUP data is based on billing ICD-9 codes, which may lead to misclassification as a result of miscoding. It is noteworthy that prior studies have used a similar approach to evaluate and report epidemiologic characteristics of PAH (38). To account for such limitations, we included a highly stringent and comprehensive exclusionary code system to remove confounding causes of secondary pulmonary hypertension. Finally, we must note that the annual incidence of ICD-coded likely PAH in hospitalized patients in our HCUP data does not reflect a true patient-based disease incidence, incidence rate, or prevalence, and may be prone to overestimation.

In conclusion, we have shown that, similar to iPAH, Meth-APAH is a severe and progressive phenotype with hemodynamic and histopathologic features of pre–capillary pulmonary vascular disease. Despite these similarities, Meth-APAH has a worse prognosis than iPAH, not attributable to worse baseline right ventricular function, lower socioeconomic status, or lack of adherence. Although these parameters are established prognostic factors in PAH, they do not fully explain the outcome difference of Meth-APAH observed in our study. Furthermore, our epidemiologic data may suggest an increased risk of PAH in (meth)amphetamine users admitted to hospitals in California. Future studies are needed to characterize the symptomatic, angiographic, histopathologic, and clinical presentation of Meth-APAH, as well as to evaluate the prevalence and impact of PAH in (meth)amphetamine users.