Comorbid microvascular disease in patients with peripheral artery disease: an escalating issue

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12 March 2024

Using data from over 33 million hospital admissions in the USA, over 25% of patients admitted with peripheral artery disease (PAD) had comorbid microvascular disease. This group was at higher risk of adverse limb and cardiovascular events.

Grubman S, Algara M, Smolderen KG, et al. Examining outcomes in patients admitted with comorbid peripheral artery disease and microvascular disease. J Am Heart Assoc 2024;13:e030710.

STUDY SUMMARY

Objective:

To characterise patients with peripheral artery disease (PAD) and microvascular disease and determine the impact of these comorbid conditions on cardiovascular and limb outcomes.

Study design:

Observational data using data for hospital admissions from the US National Readmissions Database.

Study population:

Adults (≥18 years) admitted to hospital with PAD and/or microvascular disease (2011-2018). Subjects with nonatherosclerotic causes of leg injury were excluded.

Study outcomes:

Primary: major and minor amputations, major adverse cardiovascular outcomes (MACE), in-hospital all-cause mortality, and readmission. Major amputations were defined as amputations above the level of the ankle joint, and minor amputations were considered at or below this level. MACE was defined as one or more of the following events: ST-segment elevation myocardial infarction (MI), non–ST-segment elevation MI, or ischaemic stroke. Readmissions for any cause were considered within 1 calendar year or up to death.
Secondary: lower extremity endovascular or surgical revascularisation procedure, median length-of-stay, and costs associated with the index admission.

Methods:

Patients were categorised as 1) diagnosed with PAD only, 2) diagnosed with microvascular disease only, or 3) diagnosed with both conditions. Multiple logistic regression was used to evaluate associations between disease group and major amputations, minor amputations, MACE, and in-hospital mortality. The models were adjusted for sociodemographic data and comorbidities including hypertension, valvular disease, diabetes, coronary artery disease, heart failure, chronic lung disease, renal failure, anaemia, hypothyroidism, obesity, smoking status, dyslipidaemia, and depression. A Cox proportional hazard model was used to assess the association between readmission risk at 1 year and disease group.

Results

Data from 33,972,772 admissions (53%) were analysed, ~9.1 million admissions with PAD only, 21.3 million with microvascular disease only, and 3.6 million with both conditions. Median age for the three cohorts ranged between 72.9 (PAD only cohort) and 67.5 (microvascular disease only cohort). Compared with patients with PAD alone, those with both PAD and microvascular disease had over 2-fold higher rates of diabetes (relative risk [RR] 2.1) and renal failure (RR 2.5), as well as higher risks of anaemia and obesity.

Patients with both PAD and microvascular disease had higher rates of major or minor amputation compared with those with either PAD alone (RR 1.8 and 3.0) or microvascular disease alone (RR 25.2 and 11.5), as well as a higher risk of MACE versus those with microvascular disease only (10.6% versus 7.4%) (Table 1). In-hospital mortality did not substantially differ across the three groups. Rates of surgical or endovascular revascularisation were higher in the groups with either PAD alone or both conditions versus those with microvascular disease (11.2%, 8.8% and 0.3%, respectively).

Table 1. Outcomes stratified by cohort.

Event; n (%)	PAD alone N=9,133,257	Microvascular disease alone N=21,270,667	Both conditions N=3,568,848
Major amputation	235183 (2.6)	38235 (0.2)	162009 (4.5)
Minor amputation	223241 (2.4)	135477 (0.6)	262930 (7.4)
MACE	902192 (9.9)	1584635 (7.4)	379912 (10.6)
In-hospital mortality	368142 (4.0)	694932 (3.3)	130858 (3.7)

Even after adjustment for patient- and hospital-level characteristics, diagnosis of microvascular disease with PAD versus PAD alone was more strongly associated with major or minor amputations, MACE, in-hospital mortality, and 1-year adjusted readmission risk (Table 2).

Table 2. Adjusted odds ratio (95% confidence interval) for adverse outcomes.

	Major amputation	Minor amputation	MACE	In-hospital mortality
PAD only (reference)
Microvascular disease only	0.05 (0.05)	0.15 (0.14-0.15)	0.66 (0.61-0.70)	0.73 (0.73-0.74)
Both conditions	1.30 (1.28-1.32)	2.15 (2.12-2.18)	1.04 (1.03-1.04)	1.07 (1.05-1.09)

Author conclusion

Comorbid microvascular disease is present in a large and growing number of patients with PAD and is associated with augmented risk for adverse outcomes.

COMMENT

Peripheral artery disease is the third largest cardiovascular disease, affecting more than 200 million people worldwide (1), and prevalence is expected to increase in the future with the aging of the global population. PAD is associated with an increased risk for cardiovascular morbidity and mortality , as well lower limb amputations (1,2). Both macrovascular and microvascular disease are implicated in the pathophysiology of PAD (1,3).

This study highlights the prevalence of microvascular disease in patients admitted to hospital with PAD, with over one-quarter having comorbid microvascular disease. These individuals were also at higher risk for major and minor amputation, MACE, and in-hospital mortality, than those with PAD without microvascular disease. Moreover, the study also shows that annual hospital admission for PAD in the USA increased by over 30% over the period 2011-2018, with a similar magnitude of increase for individuals with comorbid PAD and microvascular disease; the latter group also had an increase in major and minor amputations compared with the group with PAD alone.

While the study has limitations inherent in the retrospective, observational design, as well as issues with capturing microvascular disease in diagnostic codes, it also has important clinical implications. Given the increased risk for both cardiovascular and limb adverse events associated with comorbid PAD and microvascular disease, there is a need for greater emphasis on detection and management of microvascular disease, in addition to established risk factors, among patients with PAD. Finally, the study highlights the need for further study to investigate the mechanisms driving the greater morbidity and mortality of this patient group.

References

1. Fowkes FGR, Rudan D, Rudan I, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 2013;382:1329–40.
2. Anand SS, Caron F, Eikelboom JW, et al. Major adverse limb events and mortality in patients with peripheral artery disease: the COMPASS trial. J Am Coll Cardiol 2018;71:2306–15.
3. Feuer DS, Handberg EM, Mehrad B, et al. Microvascular dysfunction as a systemic disease: a review of the evidence. Am J Med 2022;135:1059–10.

Key words

peripheral artery disease; microvascular disease; amputation; cardiovascular events