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.

Keywords: methamphetamine; outcomes; pulmonary arterial hypertension.

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).

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).

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.

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).

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.