Too much heterogeneity: envisioning a new approach to methamphetamine associated heart failure

Methamphetamine use is rising nationally, 2 and with it the incidence of its many cardiopulmonary complications. Patients with cardiomyopathy and heart failure due to methamphetamine (MethHF) use are at an increased risk of acute care utilisation (eg, emergency department, inpatient hospitalisation), morbidity and mortality. In California, methamphetamine associated admissions increased from 1.2% of all hospitalisations in 2008 to 8% in 2018, a 600% increase. Methamphetamine use was an independent predictor of heart failure readmission (OR 3.62, 95% CI 1.40 to 9.38) at our safetynet hospital in San Francisco. Barriers to effective treatment of cardiomyopathy due to stimulant use are many: the exact pathophysiology, dose– response and incidence are unknown, continued drug use both drives further disease progression and impedes medical care engagement, and there are limited effective treatment options to reduce use. Cooccurring mental health and other substance use issues and underresourced socioeconomic and social support (eg, unstable housing, food insecurity, etc) all obstruct outpatient care delivery. These social determinants of health disproportionately affect this population, playing a large role in the elevated risks of hospitalisation for heart failure, morbidity and mortality. Also, the stigma associated with stimulant use too often negatively biases providers, further estranging the care alliance. Rates of acute care utilisation (urgent care, emergency department) are disproportionately high while rates of standard outpatient engagement are low. Given this predominance of care delivery in the emergency setting, the use of guideline directed medical therapy for patients with heart failure is frequently suboptimal. Although the basics of the pathophysiology associated with methamphetamine use have been described, it is still not known why patients suffer different end organ complications. For example, some patients are predisposed to dilated cardiomyopathy and others to pulmonary arterial hypertension, although seldom both. Furthermore, the dose needed to harm is unknown. Is a single use enough to trigger a cascade leading to heart failure or must an individual use daily for years? In this issue of Heart, Manja et al report on an important and necessary systematic review of the current published literature, seeking to address some of these issues. Their review included 21 studies: 14 retrospective cohort studies, three casecontrol studies, two studies with a prospective cohort and two administrative data studies. They found that MethHF was associated with increased severity of heart failure and more readmissions. Healthcare costs were staggering. Based on inpatient hospitalisation data in California between 2008 to 2018, annual inflation adjusted hospitalisation charges for MethHF increased by 840% (from US$41.5 million to $390.2 million) compared with 82% (from $3.5 billion to $6.8 billion) for all heart failure. A pivotal finding of this analysis was the existence of so much heterogeneity between trials that they could not perform a metaanalysis. Key domains of study variability driving this heterogeneity included inconsistent definitions of MethHF and of methamphetamine exposure history. The inclusion criteria ranged so widely that the various studies included completely different patient populations and yielded often contradictory results; for example, one study reported longer length of stay and another the opposite. Some studies showed greater mortality and readmission risk in MethHF versus nonMethHF, while others found no difference. Understanding this heterogeneity is critical because, as Manja et al have shown, it is very difficult to study something without a clear consensus on a definition. As highlighted in table 4, there is so much more to classifying a patient’s relationship with methamphetamine than simply a positive urine drug screening (UDS). The authors point out that there is neither a clear definition or consensus of how much methamphetamine is necessary to be associated with the development of a cardiomyopathy nor a consensus of who should be included in a clinical MethHF study. Although all of the 21 studies intended to include patients with MethHF, the heterogeneity and frequently contradictory results mandated that there be a standard by which patients in this demographic are assessed and enrolled in clinical studies. Manja et al importantly begin to describe how criteria should be set for future studies. Future prospective studies must explicitly identify a patient’s relationship to methamphetamine (eg, use, abuse, dependence, use disorder) and describe use history (eg, duration and quantity of use). We need to be able to identify specific phenotypes, track the natural history of their disease course, identify treatment option(s) and consistently link each patient with the correct treatment plan. Cardiology providers studying this population must become more familiar with the definitions outlined in table 4. All too often different entities such as 'methamphetamine use', 'methamphetamine use disorder' and 'methamphetamine abuse' are used inappropriately. Certainly, a patient with a single positive UDS will be at a different phase in the disease course than a patient who has used methamphetamine daily for years, with different prognosis, morbidity and social determinants of health. Lastly, screening tests often have false positive amphetamine results, requiring a confirmatory test that can take hours to days to result. The initial UDS alone is thus not the best marker of use or for study inclusion. The thoughtful review and analysis from Manja et al shows that MethHF is not straightforward to study or treat. They clearly demonstrate that with improved understanding of patients’ relationships with methamphetamine and the other factors impacting their care, we will better characterise the pathophysiology of MethHF and better investigate evidence based best practices and treatment strategies. Patients with MethHF are at an increased risk of mortality and associated complications. Given the overlap in comorbidities, it may be difficult to isolate a given risk factor so the whole person must be considered. This complexity obliges a paradigm shift. A multidisciplinary team designed to meet this population’s unique needs and deliver nonstigmatising, patient centred care is mandatory. This model has been shown to be highly effective in increasing engagement and clinic attendance while simultaneously reducing stimulant use and acute care utilisation. Meaningful progress necessitates that healthcare systems financially commit to novel care delivery approaches that Cardiology, University of California San Francisco, San Francisco, California, USA