Use of intravenous alprostadil in patients with severe critical ischemia of the lower limbs

Introduction

Peripheral arterial disease (PAD) is a term that includes partial or complete obstruction of at least one artery in the extremities, ¹ and the lower limbs are mainly affected. It occurs frequently; the estimated prevalence of PAD in adults is up to 10.6%, while the prevalence of critical limb ischemia (CLI) is only 1.3%. ¹ This last stage is a serious public health problem^1,2 due to its potential implications for morbidity and mortality, and especially due to the high risk of requiring amputation of the limb. Amputation is associated with cardiovascular death because perfusion is severely compromised, reducing the viability of the tissue. ³

The main risk factors for the development, progression, and lack of therapeutic response in PAD are smoking, diabetes mellitus, hypertension, dyslipidemia, obesity, and alcohol consumption, which also influence cardiovascular diseases such as coronary ischemic heart disease and heart failure.^1,4 However, diabetes mellitus is one of the main factors that increases the severity of the pathology due to poor collateral circulation.

The diagnosis of critical ischemia is mainly based on clinical criteria, including pain present at rest (although claudication pain may be absent in up to 50% of patients), an ulceration or gangrene in the lower limb, and the presence or absence of blood pressure values in the ankle of less than 50–70 mmHg (normal value >120 mmHg), less than 40 mmHg in the presence of pain at rest, or less than 60 mmHg in the presence of trophic disorders. ⁵

In patients with advanced stages of PAD with tissue loss, ulcers that do not heal, or gangrene with ischemia in the feet and who are at risk of losing the limb, elective revascularization is the preferred treatment, but in most cases, rapid medical management is required to improve both the symptoms and the results of the planned procedure.^3,5

Among the drugs available for treatment, acetylsalicylic acid and clopidogrel have been used mainly to reduce the associated risk of myocardial infarction. Cilostazol has been used to reduce platelet aggregation and act as a direct arterial vasodilator, seeking to improve exercise capacity in patients with claudication; however, it has not shown a great impact in patients with critical ischemia. Finally, prostaglandin E₁ or alprostadil, which in general is used for longer than four weeks, has shown improvement in pain at rest and ulcerations,^6–8 and it is also indicated in patients who are not candidates for revascularization. However, adverse events, such as headache, facial flushing, phlebitis, nausea, vomiting, and diarrhea, have been reported.^3,5

Because critical ischemia of the extremities has potentially serious implications for patients ² and few national studies have been published regarding the use of prostaglandin E₁ in these patients, ⁹ we proposed to determine indications for use, the potential benefits, and the adverse reactions of alprostadil present in a group of Colombian patients during a period from 2011 to 2017.

Methods

Results

A total of 61 patients who were treated with intravenous alprostadil for CLI or PAD were evaluated during their hospitalization. The gender distribution was equivalent, with 50.8% men, and the mean age was 72.5 ± 10.7 years (range: 47–90 years). According to the hospital center, 27 patients were treated in Buga (44.3%), 19 were treated in Pereira (31.1%), 9 were treated in Ibagué (14.8%), 4 were treated in Cali (6.6%), and 2 were treated in Manizales (3.3%).

All patients presented a diagnosis of severe ischemia of the lower extremities; in addition, 81.9% of patients presented some type of ulceration or skin necrosis, and in 57.4% of the patients, this condition was considered as a complication associated with the critical condition of a diabetic foot. Evaluation of the classification of arterial obstruction using Fontaine stages showed that the majority of patients were classified as stage 4 (n = 50, 81.9%), and the remaining 11 patients were classified as stage 3 (18.1%). The main reason for consulting a physician was pain at rest, which was present in 58 patients (95.1%). Ankle brachial index was not available.

Regarding comorbidities, a significant prevalence of chronic conditions was observed, including hypertension (n = 53, 86.9%), diabetes mellitus (n = 40, 65.6%), dyslipidemia (n = 27, 44.3%), stable coronary disease (n = 24, 30.3%) a history of an acute coronary events (n = 12, 19.7%), chronic renal failure (stage 3 or greater) (n = 15; 24.6%), obesity (n = 5, 8.2%), smoking (n = 5, 8.2%), previous smoking (n = 8; 13.1), and a history of cancer (n = 2, 3.3%, pancreas and peritoneal leiomyosarcoma).

Information on the hospital stay, admission to the intensive care unit, and management of limb salvage of this cohort of patients are listed in Table 1. A total of 60.7% of patients received the therapy as it had been initially indicated, and in the remaining patients who did not complete the recommended number of days, early suspension was related to reasons such as partial improvement of symptoms, premature discharge from the hospital, the suspicion or appearance of adverse reactions associated with alprostadil (such as chemical phlebitis (n = 2, 3.2%), pain associated with the application (n = 1, 1.6%), hypotension (n = 2, 3.2%), emesis (n = 2, 3.2%), pruritus (n = 1, 1.6%)), the amputation of the limb, or the placement of a stent (n = 3); the placement of this device was not successful in any of these patients.

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Table 1.

Pharmacological and hospitalization variables in 61 patients with critical limb ischemia treated in five hospitals in Colombia (2011–2017).

Variable	N=61	%
Hospitalization days (mean ± SD)	21.5	9.5
Admission to ICU (n, %)	10	16.4
Days of stay in ICU (mean ± SD)	2.9	2.3
Alprostadil utilization
Used dose (n, %)
40 µg/day	4	6.6
60 µg/day	6	9.8
80 µg/day	51	83.6
Days initially prescribed (mean ± SD)	24.3	4.7
Administered days (mean ± SD)	19.0	8.2
Patient who completed prescribed therapy (n, %)	37	60.7
Patient who did not complete the therapy
Early discharge for pain or  ulcer improvement	12	19.7
By amputation	5	8.2
By adverse drug reactions	3	4.9
Due to complications of the disease	1	1.6
By coronary event	1	1.6
By death	2	3.2
Other adjunctive medications
Cilostazol (n, %)	43	70.5
Dose used mg/day (mean ± SD)	144.1	50.2
Acetylsalicylic acid (n, %)	46	75.4
Dose used mg/day (mean ± SD)	100	0.0
Clopidogrel (n, %)	6	9.8
Dose used mg/day (mean ± SD)	75	0.0
Low molecular weight heparins (n, %)	33	54.1

ICU: intensive care unit.

Regarding the outcomes presented during hospitalization, almost all patients exhibited clinical improvement, which was mainly assessed by the control of pain at rest associated with critical ischemia. However, some adverse outcomes associated with the pathology were found, such as amputation in less than one-quarter of patients who had no therapeutic option for limb salvage other than the use of alprostadil. The results related to pain improvement and amputation are shown in Table 2.

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Table 2.

Outcomes obtained with medical and pharmacological treatment of 61 patients with critical limb ischemia treated in five hospitals in Colombia (2011–2017).

Variable	N=61	%
Outcomes during hospitalization
Closure of the ulcer or trophic lesion  (patients with ulceration on  admission, n = 50)	7	14.0
Reported improvement of the ulcer a  (patients with ulceration on  admission, n = 50)	29	58.0
Improvement of pain at rest b (patients  with pain at admission, n = 58)	50	86.2
Patients with salvaged limb	44	72.1
Amputation at the level of the toes	3	4.9
Limb amputation	14	22.9
Infracondylar amputation	5	35.7
Supracondylar amputation	9	64.3
Death	6	9.8
Adverse drug reaction	13	21.3
Directly associated with alprostadil c	8	13.1

^aImprovement reported in the clinical history: control of the infection, start of closure, closure of the ulcer.

^bImprovement of the pain reported in the clinical history by the attending physicians.

^cChemical phlebitis, pain associated with the application, hypotension, emesis.

Approximately 10% of the patients evaluated died during the hospital stay due to complications associated with the underlying pathologies, including two patients who died due to superinfection and sepsis (n = 2, 3.2%), one patient who died due to a hemorrhagic cerebrovascular event (n = 1, 1.6%), one patient who died due to an acute coronary event (n = 1, 1.6%), one patient who died due to pneumonia associated with health care (n = 1, 1.6%), and one patient who died due to a pulmonary thromboembolism (n = 1, 1.6%).

The clinical results achieved, such as pain improvement, salvaging of extremities, clinical improvement, or closure of the ulcer according to the Fontaine stage, are listed in Table 3.

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Table 3.

Outcomes reached according to the Fontaine stage in 61 patients treated with alprostadil with a diagnosis of critical limb ischemia in five hospitals in Colombia (2011–2017).

Fontaine stage at admission	Total patients	Improvement of pain at rest	Salvaged limb	Patients with ulceration or trophic lesion on admission	Improvement of the ulcer (at hospital discharge)	Ulcer closure (at hospital discharge)
		(n/%)	(n/%)		(n/%)	(n/%)
3	11	10 (90.9)	8 (72.7)	0	0 (0.0)	0 (0.0)
4	50 a	40 (85.1)	36 (72.0)	50	29 (58.0)	7 (14.0)

^aThe number of stage 4 patients with pain at rest was 47.

Discussion

The present study described the clinical characteristics, therapeutic strategies, and the most interesting outcomes in a group of patients with critical lower limb ischemia due to atherosclerotic disease who were treated with alprostadil for the purpose of limb salvage.

It is important to highlight that the population evaluated generally consisted of elderly patients with multiple comorbidities and with a diagnosis of CLI who, due to their severity, did not have the option of invasive revascularization; most patients experienced pain at rest and ulcers in the lower limbs, in addition to having a category four classification of limb ischemia according to the Fontaine stage. ¹⁰ This initial description is relevant because it adds important data regarding the approach to this pathology in our country, and our observations are similar to the clinical behavior of patients in a study by Karles-Ernotte et al. in Medellín. ⁹ This study includes subjects with CLI who are treated during the late stages, during which therapeutic options are limited, and alprostadil can be an excellent therapeutic option for these patients. ¹¹

The mean age of the patients evaluated was similar to that reported in studies by Peña-Cortés et al., Karles-Ernotte et al., and Lawell et al., which had similar populations (72 to 74.5 years); however, these studies had a greater proportion of men, which did not occur in our series of cases, which had a symmetric distribution in both sexes.^9,12–15 The discrepancy in results may be related to the high cardiovascular risk and increased peripheral arterial damage in the elderly female population of Colombia.

At the time of hospital admission, the patients exhibited severe critical ischemia, as demonstrated by the entire sample being classified as Fontaine stage 3 or 4. ¹⁰ This situation highlights the good results observed in a large proportion of patients who showed improvement in the pain at rest associated with PAD and that in 72% of the subjects, limb amputation was avoided because, due to the severity of the condition, therapeutic options were limited. ⁷ In addition, among patients who underwent amputation, in approximately 18%, the amputation concerned only the metatarsal phalangeal joint; similar situations have been reported by several studies including a meta-analysis of Ruffolo et al.^7,13,16

It should be noted that most patients showed clinical improvement in the state of ulceration, which was evident by control of the infection, improvement of the fundus and edges of the lesion, and the appearance of scar tissue. A relatively low proportion of complete closure of the ulcer was observed at the time of hospital discharge; however, other publications have reported that total closure of the ulcer can occur up to six months after the end of prostaglandins therapy. Therefore, the follow-up period should be extended to observe this outcome.^6,17 However, the results of the meta-analysis of Creutzig et al., which was performed with few clinical trials and a relatively small sample, should be interpreted with caution.

Surgical management studies performed in patients with ages similar to those of patients in this study, although with a lower proportion of cases of pain at rest (95.1% vs. 73.6%) or ulcers in the extremities (81.2% vs. 26%), showed similar proportions of amputations (22.9% vs. 16.8%) and salvaged limbs,^10,14 which may be evidence of the benefits achieved with conservative management of patients with severe PAD, as performed in this study. However, a recently published clinical trial showed no significant differences between alprostadil and a placebo in the rates of complete cure and amputation, with the exception of the group of patients with diabetes mellitus, in whom the amputation rate was significantly lower. This study also concluded that the rate of patients who exhibited reduction of at least 50% in the size of the ulcer, which can be an indicator of the beginning of the healing process, was slightly higher in the group treated with prostaglandin. ¹⁸ Additionally, it must be taken into account that in this study, more than 65% of the patients had diabetes mellitus.

The additional medications that these patients were receiving, such as platelet antiaggregants and low molecular weight heparins, are indicators of their cardiovascular comorbidities and the need for adequate management of cardiovascular and cerebrovascular risk.^16,19

The doses and time of use of alprostadil prescribed initially by treating physicians in most cases corresponded to those recommended by clinical studies and meta-analyses; ¹⁷ however, therapy was often not completed, and patients used the medication for shorter times, which may affect the final outcome. ²⁰

The present study has important strengths such as the complete monitoring of the clinical variables of interest of patients with critical extremity ischemia and their management with alprostadil in different high-complexity hospitals in our country. However, some limitations should also be recognized, such as the small sample size (associated with a low frequency of the disease and limited use of this therapy), the lack of follow-up after hospital discharge, the difficulty of applying algorithms of causality of adverse reactions, the use of cilostazol as an adjuvant in 75% of patients, and the lack of pain assessment using an analogous visual scale at admission and during hospitalization; in addition, it should be taken into account that the improvement of the ulcer and pain could be due to the best care during hospitalization.

In conclusion, CLI occurred in patients with advanced age and a high cardiovascular risk due to their pathological background, especially those with hypertension and diabetes mellitus, who arrived at hospital centers for care for severe and advanced stages of PAD, for which the therapeutic options are limited. All patients were treated with alprostadil, and the most relevant results were improvements in pain, ulcers, and limb salvage rates. Despite the lack of evidence of the effectiveness of PG1 in patients with CLI for many outcomes, it should be considered as an adjuvant for pain relief and ulcer improvement in addition to all other interventions such as the ulcer care, the use of vasodilators, antiplatelet, analgesics and antibiotics. These findings constitute relevant information for the doctors in charge of and interested in the care of this particular group, as well as for decision makers as a tool that can support the use of this therapy in selected patients who are no longer candidates for stenting and surgical revascularization.