Clinical profile, anatomical variations, and short-term clinical outcomes in patients with chronic lower limb ischemia

Introduction

Lower extremity peripheral artery disease (PAD) has evolved into a global health crisis, now affecting over 230 million adults worldwide [1,2,3]. It is characterized by the atherosclerotic narrowing of the arteries that supply the limbs. PAD represents a malignant phenotype of systemic vascular disease and serves as a potent indicator of increased risk for myocardial infarction and stroke [3,4]. Despite its significance as a coronary risk equivalent, PAD remains underrecognized compared to other atherosclerotic manifestations [3,4,5,6].

While the absolute number of PAD cases has increased by nearly 25% over the last two decades, a disproportionate share of this burden is now borne by low- and middle-income countries [2,6]. Epidemiological data suggest that over 42% of the global PAD population resides in these regions, where the transition toward urbanization has led to a steep rise in metabolic risk factors [2,7]. However, most data on anatomical distribution and short-term outcomes of PAD are derived from Western cohorts [8]. This leaves significant knowledge gaps regarding the natural history and specific prognostic indicators within South Asian populations, where the disease often carries higher morbidity [1,9].

In the Indian subcontinent, the prevalence of PAD is estimated between 5% and 25%, frequently manifesting with higher anatomical complexity and presenting earlier than observed in European or North American populations [10]. Indian patients often present to specialized centers with advanced stages of the disease, such as Rutherford categories I/Three through III/Five. These categories are characterized by extensive Trans-Atlantic Inter-Society Consensus II (TASC II) Category D lesions. This high-risk profile is exacerbated by a dense burden of modifiable risk factors, specifically smoking, hypertension, and diabetes, which may uniquely influence short-term survival and major adverse cardiovascular events (MACE) in the local tertiary care context [1].

The primary aim of this prospective observational study was to characterize the clinical profile and anatomical variations of newly diagnosed infrarenal PAD in a large cohort at a major Indian cardiology research center. Furthermore, we sought to identify independent predictors of three-month all-cause and cardiovascular mortality, to better inform risk stratification and secondary prevention strategies within this specific population.

Figure 1

Methods

This was a prospective, hospital-based observational study conducted at a specialized tertiary care cardiology research center in Western India over a 24-month period. The study protocol received institutional ethics committee approval (UNMICRC/CARDIO/2022/12), and all participants provided written informed consent prior to enrollment.

A total of 400 consecutive patients with newly diagnosed infrarenal PAD were enrolled. Newly diagnosed PAD was defined as patients who had not previously received a formal PAD diagnosis or undergone prior revascularization for lower extremity arterial disease. Diagnosis was confirmed through objective diagnostic criteria. An ankle-brachial index (ABI) < 0.90 was required as the primary diagnostic threshold, consistent with current American College of Cardiology (ACA)/American Heart Association (AHA) and European Society of Cardiology (ESC) guidelines. All patients underwent color Doppler ultrasound, and computed tomography angiography (CTA) was performed in every patient to characterize the anatomical distribution of disease. Conventional angiography was performed selectively in patients who were deemed suitable for and underwent revascularization. The study excluded patients with acute limb ischemia (symptoms <14 days) and those who had already experienced a primary study outcome, such as limb loss, prior to enrollment. The 14-day symptom threshold distinguished chronic PAD from acute limb ischemia (ALI), which presents with sudden symptoms <14 days and requires emergent management.

A total of 462 consecutive patients with suspected lower extremity PAD were assessed for eligibility. Of these, 400 patients with newly diagnosed infrarenal PAD were enrolled over a 24-month period to follow-up at three months. All 400 patients were included in baseline analyses. For multivariable regression, available-case analysis was used; the number included in each model is reflected in the respective tables. A STROBE participant flow diagram is provided (Figure 2).

Figure 2

Comprehensive baseline data were collected, including demographics (age and gender) and cardiovascular risk factors, such as smoking status, hypertension, diabetes mellitus, coronary artery disease (CAD), chronic kidney disease (CKD), and history of cerebrovascular events. Clinical severity was staged using the Rutherford classification system. Physical examination findings, including the presence of gangrene and ABI, were recorded to evaluate hemodynamic impairment. Laboratory assessments at admission included hemoglobin, white blood cell (WBC) count, serum creatinine, C-reactive protein (CRP), and glycated hemoglobin (HbA1c).

The anatomical distribution of atherosclerotic lesions was characterized using CTA and/or conventional angiography. Disease involvement was documented across specific segments: the infrarenal abdominal aorta, the renal, common iliac, external iliac, common femoral, superficial femoral, deep femoral, popliteal, and infrapopliteal arteries. For patients undergoing angiography, lesion complexity was staged using the TASC II classification, which was applied to assess the anatomical disease burden across both the aortoiliac and femoropopliteal segments.

All analyses were conducted at the patient level. For patients with bilateral disease (56.0%), the index limb was defined as the more severely affected limb based on the lower ABI and presence of tissue loss. ABI, gangrene, anatomical involvement, and amputation referred to the index limb unless otherwise specified. Bilateral ABI values reported separately represent independent descriptive measurements for each limb.

Participants were followed for a duration of three months to assess short-term outcomes. The primary endpoints were all-cause mortality and MACEs, defined as a composite of cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke. Secondary endpoints comprised lower limb events, including the development of gangrene, major or minor amputation, and the requirement for endovascular or surgical revascularization.

Outcome events are reported as the number and percentage of unique patients experiencing each event. Events are not mutually exclusive; cardiovascular deaths are a subset of all-cause mortality. The composite MACE endpoint includes patients experiencing any component (cardiovascular death, nonfatal MI, or nonfatal stroke). Major amputation: at or above the ankle; minor: below the ankle; combined: owing to limited event numbers. Below are the specific definitions of adverse outcomes used for this study:

• All-cause mortality: Death from any cause during follow-up.

• Major Adverse Cardiovascular Events (MACE): A composite of cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke.

• Lower Limb Events: A composite including the progression of gangrene, major amputation (at or above the ankle), or the requirement for endovascular or surgical revascularization.

Data analysis was performed using descriptive and inferential statistics to evaluate the relationship between clinical profiles and outcomes. Multivariable logistic regression models were employed to identify independent predictors of mortality and limb loss. Normality of continuous variables was assessed using the Shapiro-Wilk test; normally distributed variables were compared using independent-samples t-tests and non-normally distributed variables using the Mann-Whitney U test. Categorical variables were analyzed using Chi-square or Fisher’s exact test. Missing data were minimal (<1%); no imputation was performed. For multivariable logistic regression, candidate predictors were selected based on univariate associations (p < 0.10) and clinical plausibility. Multicollinearity was assessed using the variance inflation factor (VIF > 5 threshold); no significant multicollinearity was detected. An interaction between CAD and CKD was tested but was determined not significant. Model discrimination was assessed using the Receiver Operating Characteristic Area Under the Curve (ROC-AUC) metric, and calibration by the Hosmer-Lemeshow test. Significance was set at two-tailed p < 0.05.

Results

The study cohort consisted of 400 patients, with a significant male predominance of 88.0%. The largest age groups were patients aged 51–60 years (34.0%) and 61–70 years (33.0%). Smoking was the most prevalent risk factor (78.8%), followed by systemic hypertension (59.8%) and diabetes mellitus (52.3%). Additionally, 43.0% of the cohort had established CAD, and 22.0% had experienced prior cerebrovascular events. According to the Rutherford classification, 70.6% of patients presented with advanced disease, specifically categorized as category I/Three (40.3%) or III/Five (30.3%) (Table 1).

The superficial femoral artery was the most common site of involvement (59.0%), followed by the common iliac artery (46.3%). Femoropopliteal involvement predominated overall (70.3%), while 56.0% of patients presented with bilateral disease (Figure 1). Among those assessed by angiography, 54.7% had high-complexity TASC II category D lesions (Table 2).

Subgroup analysis by vascular territory showed that aortoiliac disease was associated with higher mortality (17.8% vs. 9.1%, p = 0.011), as was mixed-territory involvement (19.1% vs. 9.5%, p = 0.002). Femoropopliteal and infrapopliteal involvement were not significantly associated with mortality. No significant differences in amputation were observed across territory subgroups, likely due to limited events (n = 44).

At least one adverse outcome occurred in 78.1% of patients within three months.

All-cause mortality was 13.8% (n=55), with cardiovascular deaths comprising 47.3%. The composite MACE endpoint occurred in 13.0%. Gangrene developed in 13.3% of patients; of these, 66.0% also underwent amputation. Amputation was performed in 11.0% of patients. Revascularization was required in 53.0% (26.5% endovascular, 27.3% surgical), with two patients undergoing both types (Table 3).

Regarding major limb outcomes, the presence of gangrene at initial presentation was the most potent predictor of subsequent amputation, with an odds ratio of 52.75 (95% CI: 19.28–144.37; p < 0.001). Furthermore, hemodynamic impairment was a primary indicator for gangrene, and a lower ABI was significantly associated with gangrene outcomes (Table 4). Systemic hypertension was identified in the multivariable model (OR: 0.340, p = 0.022), though this counterintuitive finding requires cautious interpretation due to potential residual confounding (see Discussion).

Multivariable regression identified elevated serum creatinine (OR: 2.260, p = 0.016) and higher C-reactive protein quantitative (CRPQ) levels (OR: 1.012, p < 0.001), which were significantly associated with mortality. Additionally, established CAD (OR: 4.667, p < 0.001) and prior cerebrovascular accidents (CVA) (OR: 2.975, p = 0.015) were potent predictors of mortality.

Unilateral lesion involvement (OR: 0.338, p = 0.013) was associated with lower mortality. Endovascular (OR: 0.037, p = 0.002) and surgical revascularization (OR: 0.108, p < 0.001) appeared protective, but are likely subject to survivorship and treatment selection bias. They should not be interpreted as causal protective effects (Table 5).

Discussion

Our prospective analysis of an Indian cohort reveals a clinical profile defined by high anatomical complexity and a significant burden of tissue loss, with nearly 70.6% of patients presenting in advanced Rutherford categories. We identified that femoropopliteal involvement (70.3%) predominated, and more than half of the angiographically staged cases (54.7%) demonstrated TASC II Category D lesions, representing the most extensive form of macrovascular disease. These findings were coupled with a 13.8% three-month mortality rate, suggesting that PAD in this setting may be associated with a systemic atherosclerotic phenotype extending beyond limb manifestations.

Multivariable logistic regression identified established CAD as the most formidable independent predictor of all-cause mortality, with affected patients facing over four times the odds of death (OR: 4.667, p < 0.001). This potent association is corroborated by global literature, such as the Reduction of Atherothrombosis for Continued Health registry and the Examining Use of Ticagrelor in Peripheral Artery Disease trial. The latter describes a “Big MAC” (Myocardial infarction, Amputation, and Cerebrovascular events) risk framework, where polyvascular disease leads to a stepwise increase in fatal outcomes [3,11,12]. Similarly, a history of CVA emerged as a significant mortality predictor in our cohort (OR: 2.975, p = 0.015), reinforcing that survival in PAD is primarily dictated by the total systemic extent of atherosclerotic disease.

The most formidable finding in our regression analysis was that the presence of gangrene at initial presentation increased the odds of subsequent amputation by over 52-fold (OR: 52.75, 95% CI: 19.28–144.37, p = 0.000). This potent association aligns with the observations of Lipsky et al., who characterized established infection and necrosis as the decisive drivers of limb loss in dysvascular patients [13].

International cohorts, such as the Eurodiale study, also report significantly higher amputation rates in patients with the presence of PAD and infection. The magnitude of the risk of amputation in our population, however, suggests a “point of no return,” where biological compensatory mechanisms have been completely exhausted by the time patients reach specialized care [3,13].

The anatomical variations observed in our cohort further explain these poor outcomes, with femoropopliteal involvement (70.3%) predominating and more than half of angiographically staged cases (54.7%) demonstrating complex TASC II Category D lesions. Nearly half of the participants (49.8%) showed mixed territory involvement across the aortoiliac, femoropopliteal, and infrapopliteal segments, representing an extensive macrovascular disease burden.

Hemodynamic status, quantified via an ABI, served as a primary indicator for the development of gangrene in our study. Lower ABI values showed significant univariate associations with gangrene (right ABI OR: 0.063, p < 0.001; left ABI OR: 0.048, p < 0.001), though these did not retain independent significance in the multivariable model (left ABI multivariable OR: 0.177, p = 0.061). The literature establishes that an ABI below 0.50 typically signals the transition to critical limb-threatening ischemia, where resting perfusion is insufficient to maintain tissue viability [4]. Our cohort’s mean ABI (0.48–0.52) falls precisely within this danger zone, reinforcing that objective physiological screening remains an essential tool for identifying limbs at immediate risk of irreversible necrosis.

In the multivariable regression model of amputation, systemic hypertension was identified as a significant independent predictor with an odds ratio of 0.340 (p = 0.022). This counterintuitive finding warrants cautious interpretation. Potential explanations include residual confounding, treatment bias, and collider bias. While the possibility that hypertensive patients receive earlier intensive therapy is plausible, it remains speculative and is not directly tested by the present data. This finding should be considered hypothesis-generating [12,14].

The pathophysiological trajectory toward gangrene in this study’s population likely reflects a “downward-spiralling vicious circle,” where multi-segmental macrovascular stenosis is compounded by microvascular damage [12,15]. With a high prevalence of diabetes mellitus (52.3%) in our cohort, hyperglycemia-induced endothelial dysfunction and impaired vascular repair mechanisms accelerate tissue hypoxia [16,17]. Furthermore, concomitant microvascular disease, such as retinopathy or nephropathy, has been shown to increase amputation risk by 12–22-fold in PAD patients, as it limits the recruitment of endothelial progenitor cells required for angiogenesis and collateral formation [12,15].

An important consideration is the inherent selection bias of our single-center tertiary referral cohort. The high prevalence of advanced Rutherford categories, TASC D lesions (54.7%), gangrene, and revascularization reflects a specialized referral center case-mix and cannot be generalized to the broader PAD population. Additionally, delayed clinical presentation is common in Indian settings. Unlike Western cohorts where claudication is often identified early, patients in low- and middle-income countries frequently present with “masked PAD,” where comorbidities reduce pain perception, allowing ischemia to progress silently until gangrene is established [5,16]. This tertiary care bias ensures that specialists primarily manage patients with diffuse, multi-level disease that has already bypassed the elective window for symptom management, shifting the clinical focus toward urgent limb salvage and systemic stabilization.

Another important methodological consideration is the inclusion of revascularization as a predictor in the mortality model. The apparent protective associations (endovascular OR: 0.037; surgical OR: 0.108) are vulnerable to survivorship and treatment selection bias, as patients must survive long enough to be candidates for revascularization, and the sickest patients may be deemed unsuitable. Without time-dependent analyses, these associations should not be interpreted as causal protective effects.

Clinically, our findings underscore that once gangrene is established, the window for limb preservation narrows dramatically, supporting a multidisciplinary approach that may include metabolic and renal management alongside revascularization [17]. The significant associations between elevated inflammatory markers (CRPQ levels) and mortality further suggest that systemic inflammation drives both local tissue failure and acute cardiovascular instability. Early risk stratification must therefore integrate ABI measurements with metabolic monitoring to intercept the disease before it reaches the “no-option” threshold of extensive gangrene and major amputation [12,16].

Our findings are broadly concordant with the 2024 ACC/AHA Guidelines for the Management of Peripheral Artery Disease, which emphasize that PAD represents a marker of systemic atherosclerotic burden, and that cardiovascular risk reduction is as important as limb-focused intervention. The high prevalence of TASC II D lesions and advanced Rutherford categories in our cohort underscores the guideline recommendation for prompt anatomical assessment and individualized revascularization planning. The 2024 European Society for Vascular Surgery Clinical Practice Guidelines on Chronic Limb-Threatening Ischaemia further recommend a multidisciplinary approach integrating wound care, metabolic optimization, and timely revascularization. This approach aligns with our observation that isolated limb-focused interventions are insufficient in this study’s population [18].

Conclusion

Lower extremity PAD in this tertiary Indian population is characterized by extensive lesions and is associated with a poor short-term prognosis. The powerful predictive value of gangrene, established CAD, and renal dysfunction for mortality and limb loss highlights PAD as a critical indicator of an overburdened systemic vasculature. These findings suggest that limb-focused interventions alone are insufficient. A multidisciplinary approach incorporating metabolic control, renal monitoring, and cardiovascular stabilization may contribute to improved outcomes. However, these conclusions are limited to early (three-month) outcomes and should not be extrapolated to longer-term prognosis.

Limitations

Several limitations should be considered. First, the single-center design at a specialized tertiary referral center introduces significant selection bias. The high prevalence of advanced Rutherford categories, TASC D lesions, and gangrene reflects the referral case-mix and cannot be generalized to the broader PAD population. Second, the three-month follow-up was oriented toward early outcomes; all conclusions apply only to short-term outcomes. Third, the inclusion of revascularization as a time-fixed predictor in the mortality model is vulnerable to survivorship and treatment selection bias. Fourth, with 44 amputations and 55 deaths relative to the number of candidate predictors, the multivariable models may have been subject to overfitting. Fifth, death and amputation are competing risks not formally addressed. Finally, model calibration (Hosmer-Lemeshow) and discrimination (ROC-AUC metric) should be considered when evaluating model reliability.