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Propionyl-L-carnitine for intermittent claudication.
Cochrane Database Syst Rev. 2021 12 26; 12:CD010117.CD

Abstract

BACKGROUND

Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis. Intermittent claudication is a symptomatic form of PAD that is characterized by pain in the lower limbs caused by chronic occlusive arterial disease. This pain develops in a limb during exercise and is relieved with rest. Propionyl-L-carnitine (PLC) is a drug that may alleviate the symptoms of PAD through a metabolic pathway, thereby improving exercise performance.

OBJECTIVES

The objective of this review is to determine whether propionyl-L-carnitine is efficacious compared with placebo, other drugs, or other interventions used for treatment of intermittent claudication (e.g. exercise, endovascular intervention, surgery) in increasing pain-free and maximum walking distance for people with stable intermittent claudication, Fontaine stage II.

SEARCH METHODS

The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and the ClinicalTrials.gov trials register to July 7, 2021. We undertook reference checking and contact with study authors and pharmaceutical companies to identify additional unpublished and ongoing studies.

SELECTION CRITERIA

Double-blind randomized controlled trials (RCTs) in people with intermittent claudication (Fontaine stage II) receiving PLC compared with placebo or another intervention. Outcomes included pain-free walking performance (initial claudication distance - ICD) and maximal walking performance (absolute claudication distance - ACD), analyzed by standardized treadmill exercise test, as well as ankle brachial index (ABI), quality of life, progression of disease, and adverse events.

DATA COLLECTION AND ANALYSIS

Two review authors independently selected trials, extracted data, and evaluated trials for risk of bias. We contacted study authors for additional information. We resolved any disagreements by consensus. We performed fixed-effect model meta-analyses with mean differences (MDs) and 95% confidence intervals (CIs). We graded the certainty of evidence according to GRADE.

MAIN RESULTS

We included 12 studies in this review with a total number of 1423 randomized participants. A majority of the included studies assessed PLC versus placebo (11 studies, 1395 participants), and one study assessed PLC versus L-carnitine (1 study, 26 participants). We identified no RCTs that assessed PLC versus any other medication, exercise, endovascular intervention, or surgery. Participants received PLC 1 grams to 2 grams orally (9 studies) or intravenously (3 studies) per day or placebo. For the comparison PLC versus placebo, there was a high level of both clinical and statistical heterogeneity due to study size, participants coming from different countries and centres, the combination of participants with and without diabetes, and use of different treadmill protocols. We found a high proportion of drug company-backed studies. The overall certainty of the evidence was moderate. For PLC compared with placebo, improvement in maximal walking performance (ACD) was greater for PLC than for placebo, with a mean difference in absolute improvement of 50.86 meters (95% CI 50.34 to 51.38; 9 studies, 1121 participants), or a 26% relative improvement (95% CI 23% to 28%). Improvement in pain-free walking distance (ICD) was also greater for PLC than for placebo, with a mean difference in absolute improvement of 32.98 meters (95% CI 32.60 to 33.37; 9 studies, 1151 participants), or a 31% relative improvement (95% CI 28% to 34%). Improvement in ABI was greater for PLC than for placebo, with a mean difference in improvement of 0.09 (95% CI 0.08 to 0.09; 4 studies, 369 participants). Quality of life improvement was greater with PLC (MD 0.06, 95% CI 0.05 to 0.07; 1 study, 126 participants). Progression of disease and adverse events including nausea, gastric intolerance, and flu-like symptoms did not differ greatly between PLC and placebo. For the comparison of PLC with L-carnitine, the certainty of evidence was low because this included a single, very small, cross-over study. Mean improvement in ACD was slightly greater for PLC compared to L-carnitine, with a mean difference in absolute improvement of 20.00 meters (95% CI 0.47 to 39.53; 1 study, 14 participants) or a 16% relative improvement (95% CI 0.4% to 31.6%). We found no evidence of a clear difference in the ICD (absolute improvement 4.00 meters, 95% CI -9.86 to 17.86; 1 study, 14 participants); or a 3% relative improvement (95% CI -7.4% to 13.4%). None of the other outcomes of this review were reported in this study.

AUTHORS' CONCLUSIONS

When PLC was compared with placebo, improvement in walking distance was mild to moderate and safety profiles were similar, with moderate overall certainty of evidence. Although In clinical practice, PLC might be considered as an alternative or an adjuvant to standard treatment when such therapies are found to be contraindicated or ineffective, we found no RCT evidence comparing PLC with standard treatment to directly support such use.

Authors+Show Affiliations

Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium. Cardiovascular Center, Ghent University Hospital, Ghent, Belgium.Department of Public Health, Ghent University, Ghent, Belgium.Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium.Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium. Cardiovascular Center, Ghent University Hospital, Ghent, Belgium.

Pub Type(s)

Journal Article
Meta-Analysis
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

34954832

Citation

Kamoen, Victor, et al. "Propionyl-L-carnitine for Intermittent Claudication." The Cochrane Database of Systematic Reviews, vol. 12, 2021, p. CD010117.
Kamoen V, Vander Stichele R, Campens L, et al. Propionyl-L-carnitine for intermittent claudication. Cochrane Database Syst Rev. 2021;12:CD010117.
Kamoen, V., Vander Stichele, R., Campens, L., De Bacquer, D., Van Bortel, L., & de Backer, T. L. (2021). Propionyl-L-carnitine for intermittent claudication. The Cochrane Database of Systematic Reviews, 12, CD010117. https://doi.org/10.1002/14651858.CD010117.pub2
Kamoen V, et al. Propionyl-L-carnitine for Intermittent Claudication. Cochrane Database Syst Rev. 2021 12 26;12:CD010117. PubMed PMID: 34954832.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Propionyl-L-carnitine for intermittent claudication. AU - Kamoen,Victor, AU - Vander Stichele,Robert, AU - Campens,Laurence, AU - De Bacquer,Dirk, AU - Van Bortel,Luc, AU - de Backer,Tine Lm, Y1 - 2021/12/26/ PY - 2022/12/26/pmc-release PY - 2021/12/26/entrez PY - 2021/12/27/pubmed PY - 2022/1/7/medline SP - CD010117 EP - CD010117 JF - The Cochrane database of systematic reviews JO - Cochrane Database Syst Rev VL - 12 N2 - BACKGROUND: Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis. Intermittent claudication is a symptomatic form of PAD that is characterized by pain in the lower limbs caused by chronic occlusive arterial disease. This pain develops in a limb during exercise and is relieved with rest. Propionyl-L-carnitine (PLC) is a drug that may alleviate the symptoms of PAD through a metabolic pathway, thereby improving exercise performance. OBJECTIVES: The objective of this review is to determine whether propionyl-L-carnitine is efficacious compared with placebo, other drugs, or other interventions used for treatment of intermittent claudication (e.g. exercise, endovascular intervention, surgery) in increasing pain-free and maximum walking distance for people with stable intermittent claudication, Fontaine stage II. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and the ClinicalTrials.gov trials register to July 7, 2021. We undertook reference checking and contact with study authors and pharmaceutical companies to identify additional unpublished and ongoing studies. SELECTION CRITERIA: Double-blind randomized controlled trials (RCTs) in people with intermittent claudication (Fontaine stage II) receiving PLC compared with placebo or another intervention. Outcomes included pain-free walking performance (initial claudication distance - ICD) and maximal walking performance (absolute claudication distance - ACD), analyzed by standardized treadmill exercise test, as well as ankle brachial index (ABI), quality of life, progression of disease, and adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted data, and evaluated trials for risk of bias. We contacted study authors for additional information. We resolved any disagreements by consensus. We performed fixed-effect model meta-analyses with mean differences (MDs) and 95% confidence intervals (CIs). We graded the certainty of evidence according to GRADE. MAIN RESULTS: We included 12 studies in this review with a total number of 1423 randomized participants. A majority of the included studies assessed PLC versus placebo (11 studies, 1395 participants), and one study assessed PLC versus L-carnitine (1 study, 26 participants). We identified no RCTs that assessed PLC versus any other medication, exercise, endovascular intervention, or surgery. Participants received PLC 1 grams to 2 grams orally (9 studies) or intravenously (3 studies) per day or placebo. For the comparison PLC versus placebo, there was a high level of both clinical and statistical heterogeneity due to study size, participants coming from different countries and centres, the combination of participants with and without diabetes, and use of different treadmill protocols. We found a high proportion of drug company-backed studies. The overall certainty of the evidence was moderate. For PLC compared with placebo, improvement in maximal walking performance (ACD) was greater for PLC than for placebo, with a mean difference in absolute improvement of 50.86 meters (95% CI 50.34 to 51.38; 9 studies, 1121 participants), or a 26% relative improvement (95% CI 23% to 28%). Improvement in pain-free walking distance (ICD) was also greater for PLC than for placebo, with a mean difference in absolute improvement of 32.98 meters (95% CI 32.60 to 33.37; 9 studies, 1151 participants), or a 31% relative improvement (95% CI 28% to 34%). Improvement in ABI was greater for PLC than for placebo, with a mean difference in improvement of 0.09 (95% CI 0.08 to 0.09; 4 studies, 369 participants). Quality of life improvement was greater with PLC (MD 0.06, 95% CI 0.05 to 0.07; 1 study, 126 participants). Progression of disease and adverse events including nausea, gastric intolerance, and flu-like symptoms did not differ greatly between PLC and placebo. For the comparison of PLC with L-carnitine, the certainty of evidence was low because this included a single, very small, cross-over study. Mean improvement in ACD was slightly greater for PLC compared to L-carnitine, with a mean difference in absolute improvement of 20.00 meters (95% CI 0.47 to 39.53; 1 study, 14 participants) or a 16% relative improvement (95% CI 0.4% to 31.6%). We found no evidence of a clear difference in the ICD (absolute improvement 4.00 meters, 95% CI -9.86 to 17.86; 1 study, 14 participants); or a 3% relative improvement (95% CI -7.4% to 13.4%). None of the other outcomes of this review were reported in this study. AUTHORS' CONCLUSIONS: When PLC was compared with placebo, improvement in walking distance was mild to moderate and safety profiles were similar, with moderate overall certainty of evidence. Although In clinical practice, PLC might be considered as an alternative or an adjuvant to standard treatment when such therapies are found to be contraindicated or ineffective, we found no RCT evidence comparing PLC with standard treatment to directly support such use. SN - 1469-493X UR - https://www.unboundmedicine.com/medline/citation/34954832/Propionyl_L_carnitine_for_intermittent_claudication_ L2 - https://doi.org/10.1002/14651858.CD010117.pub2 DB - PRIME DP - Unbound Medicine ER -