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A systematic review to evaluate the effectiveness of carnitine supplementation in improving walking performance among individuals with intermittent claudication

      Abstract

      Objective

      To evaluate the evidence for the use of carnitine supplementation in improving walking performance among individuals with intermittent claudication.

      Design

      Systematic review.

      Methods

      An electronic search of the literature was performed using MEDLINE (PubMed), Scopus, Cochrane Central Register of Controlled Trials and The Cochrane Library from inception through to November 2012. Search terms included peripheral arterial disease, intermittent claudication and carnitine. Reference lists of review articles and primary studies were also examined. Full reports of published experimental studies including randomized controlled trials and pre-test/post-test trials were selected for inclusion. A quality assessment was undertaken according to the Jadad scale.

      Results

      A total of 40 articles were retrieved, of which 23 did not meet the inclusion criteria. The 17 included articles reported on a total of 18 experimental studies of carnitine supplementation (5 pre-test/post-test; 8 parallel RCT; 5 cross-over RCT) for improving walking performance in adults with intermittent claudication. For pre-test/post-test studies, 300–2000 mg propionyl-l-carnitine (PLC) was administered orally or intravenously for a maximum of 90 days (7–42 participants) with statistically significant improvements of between 74 m and 157 m in pain free walking distance and between 71 m and 135 m in maximal walking distance across 3 out of 5 studies. Similarly, PLC (600 mg-3000 mg) was administered orally in 7 out of 8 parallel RCTs (22–485 participants), the longest duration being 12 months. All but one of the smallest trials demonstrated statistically significant improvements in walking performance between 31 and 54 m greater than placebo for pain free walking distance and between 9 and 86 m greater than placebo for maximal walking distance. A double-blind parallel RCT of cilostazol plus 2000 mg oral l-carnitine or placebo for 180 days (145 participants) did not demonstrate any significant improvement in walking performance. Of 5 cross-over RCTs (8–20 participants), 4 demonstrated significant improvements in walking performance following administration of 300–6000 mg l-carnitine or PLC. Compared to placebo, pain free walking distance and maximal walking distance improved by 23–132 m and 104 m respectively following carnitine intervention.

      Conclusions

      Most trials demonstrated a small or modest improvement in walking performance with administration of PLC or l-carnitine. These findings were largely independent of level or quality of evidence, while there was some evidence that intravenous administration was more effective than oral administration and those with severe claudication may achieve greater benefits than those with moderate claudication. Routine carnitine supplementation in the form of PLC may therefore be a useful adjunct therapy for management of intermittent claudication. Further research is warranted to determine the optimal form, duration, dose and safety of carnitine supplementation across the spectrum of peripheral arterial disease severity and its effect with concurrent supervised exercise programs and best medical therapy. These studies should be supplemented with cost effectiveness studies to ensure that the return on the investment is acceptable.

      Keywords

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      References

        • Norgren L.
        • Hiatt W.R.
        • Dormandy J.A.
        • Nehler M.R.
        • Harris K.A.
        • Fowkes F.G.R.
        Inter-society consensus for the management of peripheral arterial disease (TASC II).
        Eur J Vasc Endovasc Surg. 2007; 33: S1-S75
        • Schainfeld R.M.
        Management of peripheral arterial disease and intermittent claudication.
        J Am Board Fam Prac. 2001; 14: 443-450
        • Hirsch A.T.
        • Haskal Z.J.
        • Hertzer N.R.
        • et al.
        ACC/AHA 2005 practice guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic).
        Circulation. 2006; 113: e463-e465
        • Watson L.
        • Ellis B.
        • Leng G.C.
        Exercise for intermittent claudication.
        Cochrane Database Syst Rev. 2008; (Art. No.: CD000990)https://doi.org/10.1002/14651858.CD000990.pub2
        • Robless P.
        • Mikhailidis D.P.
        • Stansby G.P.
        Cilostazol for peripheral arterial disease.
        Cochrane Database Syst Rev. 2008; (Art. No.: CD003748)https://doi.org/10.1002/14651858.CD003748.pub3
        • Mingorance C.
        • Rodriguez-Rodriguez R.
        • Justo M.L.
        • Herrera M.D.
        • Alvarez de Sotomayor M.
        Pharmacological effects and clinical applications of propionyl-L-carnitine.
        Nutr Rev. 2011; 69: 279-290
        • Brevetti G.
        • Angelini C.
        • Rosa M.
        • et al.
        Muscle carnitine deficiency in patients with severe peripheral vascular disease.
        Circulation. 1991; 84: 1490-1495
        • Hiatt W.R.
        Carnitine and peripheral arterial disease.
        Ann N Y Acad Sci. 2004; 1033: 92-98
        • Hiatt W.R.
        • Wolfel E.E.
        • Regensteiner J.G.
        • Brass E.P.
        Skeletal muscle carnitine metabolism in patients with unilateral peripheral arterial disease.
        J Appl Physiol. 1992; 73: 346-353
        • Brevetti G.
        • Perna S.
        • Sabba C.
        • Martone V.D.
        • Condorelli M.
        Propionyl-L-carnitine in intermittent claudication: double-blind, placebo-controlled, dose titration, multicenter study.
        J Am Coll Cardiol. 1995; 26: 1411-1416
        • Vita J.A.
        • Hamburg N.M.
        Does endothelial dysfunction contribute to the clinical status of patients with peripheral arterial disease?.
        Can J Cardiol. 2010; 26: 45A-50A
        • Jadad A.R.
        • Moore R.A.
        • Carroll D.
        • et al.
        Assessing the quality of reports of randomized clinical trials: is blinding necessary?.
        Contr Clin Trial. 1996; 17: 1-12
        • Taylor D.J.
        • Amato A.
        • Hands L.J.
        • et al.
        Changes in energy metabolism of calf muscle in patients with intermittent claudication assessed by 31P magnetic resonance spectroscopy: a phase II open study.
        Vasc Med. 1996; 1: 241-245
        • Barker G.A.
        • Green S.
        • Askew C.D.
        • Green A.A.
        • Walker P.J.
        Effect of propionyl-L-carnitine on exercise performance in peripheral arterial disease.
        Med Sci Sports Exerc. 2001; 33: 1415-1422
        • Ragozzino G.
        • Mattera E.
        • Madrid E.
        • et al.
        Effects of propionyl-carnitine in patients with type 2 diabetes and peripheral vascular disease: results of a pilot trial.
        Drugs Res Develop. 2004; 5: 185-190
        • Riccioni C.
        • Sarcinella R.
        • Palermo G.
        • et al.
        Evaluation of the efficacy of propionyl-L-carnitine versus pulsed muscular compressions in diabetic and non-diabetic patients affected by obliterating arteriopathy Leriche stage II.
        Int Angiol. 2008; 27: 253-259
        • Allegra C.
        • Antignani P.L.
        • Schachter I.
        • Koverech A.
        • Messano M.
        • Vermani A.
        Propionyl-L-carnitine in Leriche-Fontaine stage II peripheral arterial obstructive disease.
        Ann Vasc Surg. 2008; 22: 552-558
        • Coto V.
        • D’Alessandro L.
        • Grattarola G.
        • et al.
        Evaluation of the therapeutic efficacy and tolerability of levocarnitine propionyl in the treatment of chronic obstructive arteriopathies of the lower extremities: a multicentre controlled study vs. placebo.
        Drugs Exp Clin Res. 1992; 18: 29-36
        • Brevetti G.
        • Diehm C.
        • Lambert D.
        European multicenter study on propionyl-L-carnitine in intermittent claudication.
        J Am Coll Cardiol. 1999; 34: 1618-1624
        • Dal Lago A.
        • De Martini D.
        • Flore R.
        • et al.
        Effects of propionyl-L-carnitine on peripheral arterial obliterative disease of the lower limbs: a double-blind clinical trial.
        Drugs Exp Clin Res. 1999; 25: 29-36
        • Hiatt W.R.
        • Regensteiner J.G.
        • Creager M.A.
        • et al.
        Propionyl-L-carnitine improves exercise performance and functional status in patients with claudication.
        Am J Med. 2001; 110: 616-622
        • Andreozzi G.M.
        • Leone A.
        • Laudani R.
        • Martin R.
        • Deinit G.
        • Cataldi V.
        Levo-propionyl-carnitine improves the effectiveness of supervised physical training on the absolute claudication distance in patients with intermittent claudication.
        Angiol. 2008; 59: 84-89
        • Hiatt W.R.
        • Creager M.A.
        • Amato A.
        • Brass E.P.
        Effect of propionyl-L-carnitine on a background of monitored exercise in patients with claudication secondary to peripheral artery disease.
        J Cardiopulm Rehabil Prev. 2011; 31: 125-132
        • Golderberg N.A.
        • Krantz M.J.
        • Hiatt W.R.
        L-Carnitine plus cilostazol versus cilostazol alone for the treatment of claudication in patients with peripheral artery disease: a multicenter, randomized, double-blind, placebo-controlled trial.
        Vasc Med. 2012; 17: 145-154
        • Brevetti G.
        • Chiarello M.
        • Ferulano G.
        • et al.
        Increases in walking distance in patients with peripheral vascular disease treated with L-carnitine: a double-blind, cross-over study.
        Circulation. 1988; 77: 767-773
        • Brevetti G.
        • Perna S.
        • Sabba C.
        • et al.
        Superiority of L-propionylcarnitine vs. L-carnitine in improving walking capacity in patients with peripheral vascular disease: an acute, intravenous, double-blind, cross-over study.
        Eur Heart J. 1992; 13: 251-255
        • Loffredo L.
        • Pignatelli P.
        • Cangemi R.
        • et al.
        Imbalance between nitric oxide generation and oxidative stress in patients with peripheral arterial disease: effect of an antioxidant treatment.
        J Vasc Surg. 2006; 44: 525-530
        • Arsenian M.A.
        Carnitine and its derivatives in cardiovascular disease.
        Prog Cardiovasc Dis. 1997; 40: 265-286
        • Rebouche C.J.
        Kinetics, pharmacokinetics, and regulation of L-carnitine and acetyl-L-carnitine metabolism.
        Ann N Y Acad Sci. 2004; 1033: 30-41
        • Brass E.P.
        Pharmacokinetic considerations for the therapeutic use of carnitine in hemodialysis patients.
        Clin Ther. 1995; 17: 176-185
        • Evans A.M.
        • Fornasini G.
        Pharmacokinetics of L-carnitine.
        Clin Pharm. 2003; 42: 941-967
        • Ferrari R.
        • Merli E.
        • Cicchitelli G.
        • Mele D.
        • Fucili A.
        • Ceconi C.
        Therapeutic effects of L-carnitine and propionyl-L-carnitine on cardiovascular diseases: a review.
        Ann N Y Acad Sci. 2004; 1033: 79-91
        • Pace S.
        • Longo A.
        • Toon S.
        • Rolan P.
        • Evans A.M.
        Pharmacokinetics of propionyl-L-carnitine in humans: evidence for saturable tubular reabsoprtion.
        Br J Clin Pharmacol. 2000; 50: 441-448