- Email: [email protected]
Effect of Propionyl-L-Carnitine on Quality of Life in Intermittent Claudication
Effect of Propionyl-L-Carnitine on Quality of Life in Intermittent Claudication Gregorio Brevetti, MD, Sergio Perna, MD, Carlo Sabba, MD, Vincenzo Domenico Martone, MD, Antonietta Di Iorio, MD, and Giuseppe Barletta,
MD
A double-blind, dose titration study was designed to assess the efficacy of propionyl-L-carnitine in intermittent claudication. The effect on walking capacity was described in a previous article. This study reports on the effect on quality of life, assessed by the McMaster Health Index Questionnaire (MHIQ). After 24 weeks of treatment, the global MHIQ score did not show any difference from baseline in patients randomized to placebo (n Å 102). Conversely, it increased from 0.59 { 0.12 to 0.64 { 0.12 in those taking propionyl-L-carnitine (n Å 85). Analysis of variance showed a significant difference between treatments (p Å 0.018). Stepwise multiple regression analysis identified baseline maximal walking capacity (cutoff point 250 m) as a predictor of treatment
outcome. In patients walking õ250 m, propionyl-L-carnitine significantly improved physical function (p Å 0.027), emotional function (p Å 0.002), and global MHIQ score (p Å 0.002) compared with placebo. Also, for maximal walking capacity, group difference significantly favored propionyl-L-carnitine (p Å 0.009). In patients with baseline maximal walking capacity ¢250 m, propionyl-L-carnitine did not affect the MHIQ scores, nor improve walking performance. These data indicate that propionyl-L-carnitine exerts beneficial effects on quality of life and walking performance in patients with more severely limited walking capacity. Q1997 by Excerpta Medica Inc. (Am J Cardiol 1997;79:777–780)
recent multicenter study1 reported that propionyl-L-carnitine is effective in improving walking capacity in patients with intermittent claudication and is well tolerated with minimal untoward effects. An additional aim of the trial was to evaluate the effect of treatment on quality of life by a selfadministered questionnaire. The results are described in the present report.
months, severe venous insufficiency, and peripheral neuropathy. Study design: A double-blind, dose-titration design was adopted by 13 centers for the study. All patients gave written informed consent before participation. After a screening visit, current treatments for intermittent claudication were discontinued and patients entered a 2-week washout phase during which they were familiarized with the treadmill. A 2-week runin period followed, during which stability of the maximal walking capacity was assessed. At the end of this period, patients who met the inclusion criteria were randomly allocated to orally administered placebo or propionyl-L-carnitine. The initial dose of 500 mg twice daily was increased at 2-month intervals to 2 g/day and then to 3 g/day in patients with an improvement in treadmill performance õ30% over baseline; patients showing an improvement of ¢30% continued with the same dose as in the previous 2 months. The double-blind medication lasted 6 months. Initial claudication distance (i.e., distance walked before onset of claudication) and maximal walking capacity were measured throughout the study. Quality of life was assessed by the McMaster Health Index Questionnaire (MHIQ) at the end of the run-in period and at the last control visit, before the patient performed the treadmill test. Drug compliance was assessed by tablet count without the patient’s knowledge every 2 months. Patients receiving õ70% of the prescribed dose were considered noncompliant and excluded from the efficacy analysis. Patients were advised of the beneficial effects of therapeutic walking program and abstinence from nicotine, but no persistent or aggressive effort was made to change their lifestyle while they participated in the study. McMaster Health Index Questionnaire: This instrument is a self-administered generic questionnaire of
A
METHODS Patients: Patients with history of intermittent claudication for at least 1 year were selected. The diagnosis of peripheral arterial disease was established on the basis of Doppler examination and decrease in ankle/arm systolic blood pressure ratio of at least 20% after exercise. After the screening visit, only patients aged ¢40 years with a maximal walking capacity between 30 and 400 m (treadmill speed 4 km/hour, inclination 77) were included in the study. To ensure that patients admitted to the study had a stable maximal walking capacity, 3 treadmill tests were conducted at weekly intervals during a 2-week run-in period, and only patients whose maximal walking capacity among the 3 tests varied õ20% were included. The only drugs allowed during the study were oral antidiabetic agents and diuretics. Patients with any other condition that limited exercise capacity were excluded. Other major exclusion criteria were reconstructive vascular surgery, sympathectomy or angioplasty during the previous 6 From the Department of Medicine, University Federico II, Naples; and Department of Medicine, University of Bari, Bari, Italy. This study was supported in part by a grant from Sigma-Tau SpA, Pomezia, Rome, Italy. Manuscript received June 25, 1996; revised manuscript received and accepted October 23, 1996. Address for reprints: Gregorio Brevetti, MD, via G. Iannelli 45/ A, 80131 Naples, Italy. Q1997 by Excerpta Medica, Inc.
0002-9149/97/$17.00 PII S0002-9149(96)00867-3
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59 health-related statements covering physical, social, and emotional dimensions.2 The 24 physical function items assess the following areas: physical activities, mobility, self-care activities, communication, and global physical function. The 25 social function items are concerned with general welfare, family and friends support/participation, and global social function. The 25 emotional function items have to do with feeling of self-esteem, attitudes toward personal relationship, thoughts about the future, and global emotional function. The total number of items is 59 because several items address both social and emotional functions. For each index of physical, emotional, and social function, scores were computed for each patient: a score of 1 was assigned to ‘‘good function’’ and 0 to ‘‘poor function’’ responses for each item and the sum was divided by the number of items. Thus, function scores are standardized to index values ranging from 0.0 (extremely poor function) to 1.0 (extremely good function). The MHIQ was translated from the original English into Italian by us. The Italian translation was retranslated into English by an independent psychologist from Great Britain unaware of the original to confirm its accuracy. The MHIQ, previously used to assess quality of life impairment in patients with intermittent claudication,3 has good validity, sensitivity, and reliability.4,5 Statistical analysis: Efficacy analysis was conducted by analysis of variance for patients who completed the study by comparing the effect of placebo and propionyl-L-carnitine on day 180. The choice of an efficacy rather than an intention-to-treat approach was justified by the causal nature of the study6 and the fact that not all patients received the optimal dose throughout the study because of the titration procedure. Stepwise multiple regression analysis was used to assess which patient background variables could predict a favorable treatment outcome. The following variables were examined: center, treatment, age, and baseline values of ankle/brachial pressure index, reduction in this index with exercise, global MHIQ score, and maximal walking capacity. Maximal walking capacity at baseline was used as a dichotomic variable, a treadmill performance of 250 m being the cutoff point. One of the participating centers studied 98 patients, 77 of whom provided data on quality of life. This implies that the sample size of this center was markedly higher than that of each of the remaining 12 centers. Thus, data of these centers were analyzed by combining all 12 centers in one stratum. As a consequence, the center effect had only 2 levels. Data are expressed as mean { SD.
RESULTS A total of 245 patients were included in the double-blind treatment phase: 118 were assigned to propionyl-L-carnitine and 127 to placebo. Thirty-one (19 in the propionyl-L-carnitine group, 12 in the placebo group) did not complete the trial for the reasons reported in the main study.1 Twenty-seven refused to complete the questionnaire. Thus, the efficacy 778
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evaluation of the present study was performed for the remaining 187 patients (85 in the propionyl-Lcarnitine group, 102 in the placebo group). No differences in clinical and demographic characteristics were observed between groups (Table I). Efficacy analysis: In the placebo group, the global MHIQ score was 0.63 { 0.12 before randomization and 0.64 { 0.13 at the end of the study. In the propionyl-L-carnitine group, it increased from 0.59 { 0.12 to 0.64 { 0.12. Analysis of variance showed a significant difference between treatments (p Å 0.018). The effect of treatments on the 3 dimensions explored by the questionnaire and walking capacity is shown in Table II. A significant difference between placebo and propionyl-L-carnitine was found for emotional function, whereas physical function approached statistical significance. With respect to treadmill performance, the effect of propionyl-L-carnitine on maximal walking capacity was significantly greater than that with placebo (p Å 0.026). In contrast, for initial claudication distance, no difference was observed between treatments. As reported in the main study, adverse effects not requiring drug discontinuation were similar in the 2 treatment groups. At the end of the study, 28 patients (33%) were taking 1 g/day, 25 (29%) 2 g/day, and 32 (38%) 3 g/day of propionyl-L-carnitine. Identification of target population: The stepwise multiple regression procedure identified center, treatment, and baseline maximal walking capacity (categorized as ¢250 m and õ250 m) as the predictors entering the model at the 0.05 significance level. There was no treatment-by-center interaction. Conversely, a marked center effect was observed because the 77 patients studied in 1 center were more severely affected than those studied in the remaining 12 centers. Treatment effects were analyzed in patients with baseline maximal walking capacity õ250 m (n Å 127) and in those with maximal walking capacity ¢250 m (n Å 60), separately. With the exception of walking performance, no differences in clinical and demographic characteristics were observed between TABLE I Demographic and Clinical Characteristics Proprionyl-L-Carnitine (n Å 85) Age (yr) Men Diabetes mellitus Cigarette smokers Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Ankle/brachial index at rest Initial claudication distance (m) Maximal walking capacity (m)
Placebo Group (n Å 102)
62.3 { 7.8 80 (94) 10 (12) 83 (98) 149 { 17
58.6 { 8.2 93 (91) 20 (20) 101 (99) 147 { 17
82 { 8
84 { 7
0.63 { 0.11
0.64 { 0.09
128 { 65
129 { 74
215 { 109
223 { 118
Values are expressed as mean { SD or number (%) of patients.
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TABLE II Effect of Treatments on MHIQ Scores and Walking Capacity Propionyl-L-Carnitine
Placebo
MHIQ score Physical function Social function Emotional function Walking capacity Initial claudication distance (m) Maximal walking capacity (m)
Baseline
Day 180
Baseline
Day 180
p Value
0.68 { 0.18 0.65 { 0.11 0.65 { 0.14
0.72 { 0.19 0.65 { 0.13 0.63 { 0.16
0.65 { 0.17 0.60 { 0.13 0.61 { 0.17
0.73 { 0.17 0.63 { 0.12 0.64 { 0.17
0.082 0.151 0.018
128 { 65 223 { 118
199 { 165 308 { 198
129 { 74 215 { 109
233 { 194 372 { 133
0.167 0.026
Values are expressed as mean { SD. MHIQ Å McMaster Health Index Questionnaire.
TABLE III Effect of Treatments on MHIQ Scores and Walking Capacity in Patients With Baseline Maximal Walking Capacity õ250 m Propionyl-L-Carnitine (n Å 55)
Placebo (n Å 71) Baseline MHIQ scores Physical function Social function Emotional function Global Walking capacity Initial caludication distance (m) Maximal walking distance (m)
0.67 0.66 0.66 0.64
{ 0.18 { 0.11 { 0.13 { 0.12
94 { 35 158 { 48
Day 180 0.70 0.65 0.62 0.63
{ 0.19 { 0.13 { 0.16 { 0.14
143 { 83 228 { 116
Baseline 0.64 0.60 0.60 0.59
{ 0.18 { 0.12 { 0.18 { 0.13
94 { 38 158 { 57
Day 180 0.73 0.63 0.65 0.64
{ 0.16 { 0.11 { 0.17 { 0.12
175 { 151 282 { 186
p Value 0.027 0.113 0.002 0.002 0.084 0.009
Values are expressed as mean { SD. Abbreviation as in Table II.
Different results were observed in the subpopulation with mild claudication. In these patients (baseline maximal walking capacity ¢250 m), propionyl-Lcarnitine did not affect the MHIQ scores, nor improve the walking performance. As shown by the 95% confidence intervals, a large variation in results was observed in this subset of patients compared with those with more severe claudication (Figure 1).
DISCUSSION The present study is the first to report the effect of a pharmacologic treatment on quality of life in patients with intermittent claudication. We used the MHIQ, a standardized, generic measure.2 This questionnaire, already used to assess quality of life in patients with chronic diseases,7,8 is an appropriate instrument with which to assess several aspects of FIGURE 1. The 95% confidence intervals for mean treatment diffunctional status in patients with intermittent clauferences on day 180. Hatched bars, patients with baseline maxidication.3 At the end of the trial, patients who remal walking capacity õ250 m; open bars, patients with baseline ceived propionyl-L-carnitine showed a higher global maximal walking capacity ¢250 m. MHIQ Å McMaster Health Index Questionnaire; ICD Å initial claudication distance; MWC Å MHIQ score than those who received placebo. The maximal walking capacity; PLC Å propionyl-L-carnitine. emotional state (the ability to remain in good spirits most of the time and to be usually happy and satisfied the 2 groups. In the subset of patients walking õ250 with one’s own life) was beneficially affected by m at baseline, propionyl-L-carnitine significantly im- treatment. Conversely, no difference between treatproved physical function (p Å 0.027), emotional ments was observed for social function. Physical function (p Å 0.002), and global MHIQ score (p Å function showed an improvement that approached 0.002) compared with placebo (Table III). Also, for statistical significance, although the increase in maximal walking capacity, group differences signif- treadmill maximal walking capacity with propionylicantly favored propionyl-L-carnitine (p Å 0.009), L-carnitine was significantly greater than that with whereas no difference between treatments was ob- placebo. Such a discrepancy is probably due to the served for initial claudication distance (Table III). fact that many of the items assessing physical funcMISCELLANEOUS/PROPIONYL-L-CARNITINE IN INTERMITTENT CLAUDICATION
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tion concern areas such as self-care activities and communication, which are not affected by the disease.3 Actually, physical mobility, expected to be more affected by claudication, was significantly improved by active treatment compared with placebo. Target population: Arfviderson et al9 reported that patients with maximal walking capacity õ70 W have significant reduction in everyday life function as opposed to those performing a higher treadmill work. As a consequence, a treatment aimed at improving quality of life is expected to be beneficial in patients with severe functional impairment rather than in those with less pronounced walking disability, because the overall function status in the latter is only slightly different from that occurring in a general population.9 In effect, the stepwise multiple regression procedure indicated that treadmill maximal walking capacity at baseline (cutoff point 250 m) identifies a population in whom the probability for a successful treatment outcome is higher than in a general population of claudicants. In patients who walked õ250 m at baseline, propionyl-L-carnitine significantly improved quality of life compared with placebo, whereas in those with a baseline maximal walking capacity ¢250 m, no difference was observed between treatments. These 2 subpopulations also showed a different response to treatment in walking performance. In the group with more severely limited treadmill performance at baseline, the improvement in maximal walking capacity with propionyl-L-carnitine was greater than that with placebo. In the other group, statistical analysis did not show a difference between treatments. This finding is consistent with the previous observation that, in intermittent claudication, only the most affected patients require carnitine supplementation, because they, and not those with mild functional impairment, have reduced availability of endogenous carnitine to meet the increased metabolic demand induced by walking.10 Propionyl-L-carnitine, used in this trial, is easily converted into free carnitine and propionyl coenzyme A within the mitochondria.11 Indeed, it increases carnitine levels in the ischemic muscles of patients with severe peripheral arterial disease.12 Furthermore, propionyl-L-carnitine increases the walking capacity of patients with claudication to a greater
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extent than that observed with an equimolar dose of L-carnitine.13
APPENDIX List of participating centers: I Clinica Medica, Universita’ di Bari: Ottavio Albano, MD, Carlo Sabba’ MD; Cattedra di Angiologia, Ospedale Garibali, Catania: Giuseppe Maria Andreozzi, MD; Ospedale citta’ di Pavia: Vittorio Bianchi, MD; Dipartimento di Medicina Interna, Universita’ Federico II, Napoli: Antonietta Di Iorio, MD, Vincenzo Domenico Martone, MD, Sergio Perna, MD; Divisione di Cardiologia, Ospedale Piemonte, Messina: Francesco Casella, MD; Istituto di Clinica Medica, Universita’ di Messina: Fausto Consolo, MD, Agatino Manganaro, MD; Chirurgia Vascolare, II Universita’, Napoli: Alberto Marcialis, MD; Reparto di Cardiologia, Ospedale S. Leonardo, Salerno: Bruno Ravera, MD; Istituto di Chirurgia Vascolare, Ospedale Garibaldi, Catania: Salvatore Romeo, MD; Ospedale Sanatrix, Venafro: Pasquale Simonelli, MD; Cattedra di Chirurgia Vascolare, Universita’ di Modena: Giuseppe Tuscano, MD; Divisione di Chirurgia Vascolare, Ospedale di Modena: Pellegrino Vecchiati, MD; Istituto Medicina Domani, Genova: Gianfranco Di Somma, MD.
1. Brevetti G, Perna S, Sabba’ C, Martone VD, Condorelli M. Propionyl-L-
carnitine in intermittent claudication: double-blind, placebo-controlled, dose titration, multicenter study. J Am Coll Cardiol 1995;26:1411–1416. 2. Chambers LW, MacDonald LA, Tugwell P. The McMaster Health Index Questionnaire as a measure of the quality of life for patients with rheumatoid disease. J Rheumatol 1982;9:780–784. 3. Barletta G, Perna S, Sabba’ C, Catalano A, O’Boyle C, Brevetti G. Quality of life in patients with intermittent claudication: relationship with laboratory exercise performance. Vascular Medicine 1996;1:3–7. 4. Sackett DL, Chambers LW, MacPershon AS, Goldsmith CM, McAuley RG. The development and application of indexes of health: general methods and a summary of results. Am J Public Health 1977;67:423–428. 5. Fortin F, Kerouac S. Validation of questionnaires on physical function. Nurs Res 1977;26:128–135. 6. Andersen B. A question of control. In: Andersen B, ed. Methodological Errors in Medical Research: An Incomplete Catalogue. Cambridge, MA: Blackwell Scientific, 1990:70–71. 7. Guyatt GH, Thompson PI, Berman LB, Sullivan MJ, Townsend M, Jones NL, Pugsley SO. How should we measure function in patients with chronic heart and lung disease? J Chron Dis 1985;38:517–524. 8. Rector TS, Francis GS, Cohn JN. Patient’s self-assessment of their congestive heart failure. Part 1. Patient-perceived dysfunction and its poor correlation with maximal exercise testing. Heart Failure 1987;3:192–196. 9. Arfviderson B, Karlsson J, Dahllof AG, Lundholm K, Sullivan M. The impact of intermittent claudication on quality of life evaluated by the Sickness Impact Profile Technique. Eur J Clin Invest 1993;23:741–745. 10. Brevetti G, Di Lisa F, Perna S, Menabo’ R, Barbato R, Martone VD, Siliprandi N. Carnitine-related alteration in patients with intermittent claudication. Indication for a focused carnitine therapy. Circulation 1996;93:1685–1689. 11. Siliprandi N, Di Lisa F, Menabo’ R. Propionyl-L-carnitine: biochemical significance and possible role in cardiac metabolism. Cardiovasc Drugs Ther 1991;(suppl 5)1:11–15. 12. Brevetti G, Angelini C, Rosa M, Carrozzo R, Perna S, Corsi M, Materazzo A, Marcialis M. Muscle carnitine deficiency in patients with severe peripheral vascular disease. Circulation 1991;84:1490–1495. 13. Brevetti G, Perna S, Sabba’ C, Rossini A, Scotto di Uccio V, Berardi E, Godi L. Superiority of L-propionyl carnitine 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.
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MD
A double-blind, dose titration study was designed to assess the efficacy of propionyl-L-carnitine in intermittent claudication. The effect on walking capacity was described in a previous article. This study reports on the effect on quality of life, assessed by the McMaster Health Index Questionnaire (MHIQ). After 24 weeks of treatment, the global MHIQ score did not show any difference from baseline in patients randomized to placebo (n Å 102). Conversely, it increased from 0.59 { 0.12 to 0.64 { 0.12 in those taking propionyl-L-carnitine (n Å 85). Analysis of variance showed a significant difference between treatments (p Å 0.018). Stepwise multiple regression analysis identified baseline maximal walking capacity (cutoff point 250 m) as a predictor of treatment
outcome. In patients walking õ250 m, propionyl-L-carnitine significantly improved physical function (p Å 0.027), emotional function (p Å 0.002), and global MHIQ score (p Å 0.002) compared with placebo. Also, for maximal walking capacity, group difference significantly favored propionyl-L-carnitine (p Å 0.009). In patients with baseline maximal walking capacity ¢250 m, propionyl-L-carnitine did not affect the MHIQ scores, nor improve walking performance. These data indicate that propionyl-L-carnitine exerts beneficial effects on quality of life and walking performance in patients with more severely limited walking capacity. Q1997 by Excerpta Medica Inc. (Am J Cardiol 1997;79:777–780)
recent multicenter study1 reported that propionyl-L-carnitine is effective in improving walking capacity in patients with intermittent claudication and is well tolerated with minimal untoward effects. An additional aim of the trial was to evaluate the effect of treatment on quality of life by a selfadministered questionnaire. The results are described in the present report.
months, severe venous insufficiency, and peripheral neuropathy. Study design: A double-blind, dose-titration design was adopted by 13 centers for the study. All patients gave written informed consent before participation. After a screening visit, current treatments for intermittent claudication were discontinued and patients entered a 2-week washout phase during which they were familiarized with the treadmill. A 2-week runin period followed, during which stability of the maximal walking capacity was assessed. At the end of this period, patients who met the inclusion criteria were randomly allocated to orally administered placebo or propionyl-L-carnitine. The initial dose of 500 mg twice daily was increased at 2-month intervals to 2 g/day and then to 3 g/day in patients with an improvement in treadmill performance õ30% over baseline; patients showing an improvement of ¢30% continued with the same dose as in the previous 2 months. The double-blind medication lasted 6 months. Initial claudication distance (i.e., distance walked before onset of claudication) and maximal walking capacity were measured throughout the study. Quality of life was assessed by the McMaster Health Index Questionnaire (MHIQ) at the end of the run-in period and at the last control visit, before the patient performed the treadmill test. Drug compliance was assessed by tablet count without the patient’s knowledge every 2 months. Patients receiving õ70% of the prescribed dose were considered noncompliant and excluded from the efficacy analysis. Patients were advised of the beneficial effects of therapeutic walking program and abstinence from nicotine, but no persistent or aggressive effort was made to change their lifestyle while they participated in the study. McMaster Health Index Questionnaire: This instrument is a self-administered generic questionnaire of
A
METHODS Patients: Patients with history of intermittent claudication for at least 1 year were selected. The diagnosis of peripheral arterial disease was established on the basis of Doppler examination and decrease in ankle/arm systolic blood pressure ratio of at least 20% after exercise. After the screening visit, only patients aged ¢40 years with a maximal walking capacity between 30 and 400 m (treadmill speed 4 km/hour, inclination 77) were included in the study. To ensure that patients admitted to the study had a stable maximal walking capacity, 3 treadmill tests were conducted at weekly intervals during a 2-week run-in period, and only patients whose maximal walking capacity among the 3 tests varied õ20% were included. The only drugs allowed during the study were oral antidiabetic agents and diuretics. Patients with any other condition that limited exercise capacity were excluded. Other major exclusion criteria were reconstructive vascular surgery, sympathectomy or angioplasty during the previous 6 From the Department of Medicine, University Federico II, Naples; and Department of Medicine, University of Bari, Bari, Italy. This study was supported in part by a grant from Sigma-Tau SpA, Pomezia, Rome, Italy. Manuscript received June 25, 1996; revised manuscript received and accepted October 23, 1996. Address for reprints: Gregorio Brevetti, MD, via G. Iannelli 45/ A, 80131 Naples, Italy. Q1997 by Excerpta Medica, Inc.
0002-9149/97/$17.00 PII S0002-9149(96)00867-3
All rights reserved.
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59 health-related statements covering physical, social, and emotional dimensions.2 The 24 physical function items assess the following areas: physical activities, mobility, self-care activities, communication, and global physical function. The 25 social function items are concerned with general welfare, family and friends support/participation, and global social function. The 25 emotional function items have to do with feeling of self-esteem, attitudes toward personal relationship, thoughts about the future, and global emotional function. The total number of items is 59 because several items address both social and emotional functions. For each index of physical, emotional, and social function, scores were computed for each patient: a score of 1 was assigned to ‘‘good function’’ and 0 to ‘‘poor function’’ responses for each item and the sum was divided by the number of items. Thus, function scores are standardized to index values ranging from 0.0 (extremely poor function) to 1.0 (extremely good function). The MHIQ was translated from the original English into Italian by us. The Italian translation was retranslated into English by an independent psychologist from Great Britain unaware of the original to confirm its accuracy. The MHIQ, previously used to assess quality of life impairment in patients with intermittent claudication,3 has good validity, sensitivity, and reliability.4,5 Statistical analysis: Efficacy analysis was conducted by analysis of variance for patients who completed the study by comparing the effect of placebo and propionyl-L-carnitine on day 180. The choice of an efficacy rather than an intention-to-treat approach was justified by the causal nature of the study6 and the fact that not all patients received the optimal dose throughout the study because of the titration procedure. Stepwise multiple regression analysis was used to assess which patient background variables could predict a favorable treatment outcome. The following variables were examined: center, treatment, age, and baseline values of ankle/brachial pressure index, reduction in this index with exercise, global MHIQ score, and maximal walking capacity. Maximal walking capacity at baseline was used as a dichotomic variable, a treadmill performance of 250 m being the cutoff point. One of the participating centers studied 98 patients, 77 of whom provided data on quality of life. This implies that the sample size of this center was markedly higher than that of each of the remaining 12 centers. Thus, data of these centers were analyzed by combining all 12 centers in one stratum. As a consequence, the center effect had only 2 levels. Data are expressed as mean { SD.
RESULTS A total of 245 patients were included in the double-blind treatment phase: 118 were assigned to propionyl-L-carnitine and 127 to placebo. Thirty-one (19 in the propionyl-L-carnitine group, 12 in the placebo group) did not complete the trial for the reasons reported in the main study.1 Twenty-seven refused to complete the questionnaire. Thus, the efficacy 778
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evaluation of the present study was performed for the remaining 187 patients (85 in the propionyl-Lcarnitine group, 102 in the placebo group). No differences in clinical and demographic characteristics were observed between groups (Table I). Efficacy analysis: In the placebo group, the global MHIQ score was 0.63 { 0.12 before randomization and 0.64 { 0.13 at the end of the study. In the propionyl-L-carnitine group, it increased from 0.59 { 0.12 to 0.64 { 0.12. Analysis of variance showed a significant difference between treatments (p Å 0.018). The effect of treatments on the 3 dimensions explored by the questionnaire and walking capacity is shown in Table II. A significant difference between placebo and propionyl-L-carnitine was found for emotional function, whereas physical function approached statistical significance. With respect to treadmill performance, the effect of propionyl-L-carnitine on maximal walking capacity was significantly greater than that with placebo (p Å 0.026). In contrast, for initial claudication distance, no difference was observed between treatments. As reported in the main study, adverse effects not requiring drug discontinuation were similar in the 2 treatment groups. At the end of the study, 28 patients (33%) were taking 1 g/day, 25 (29%) 2 g/day, and 32 (38%) 3 g/day of propionyl-L-carnitine. Identification of target population: The stepwise multiple regression procedure identified center, treatment, and baseline maximal walking capacity (categorized as ¢250 m and õ250 m) as the predictors entering the model at the 0.05 significance level. There was no treatment-by-center interaction. Conversely, a marked center effect was observed because the 77 patients studied in 1 center were more severely affected than those studied in the remaining 12 centers. Treatment effects were analyzed in patients with baseline maximal walking capacity õ250 m (n Å 127) and in those with maximal walking capacity ¢250 m (n Å 60), separately. With the exception of walking performance, no differences in clinical and demographic characteristics were observed between TABLE I Demographic and Clinical Characteristics Proprionyl-L-Carnitine (n Å 85) Age (yr) Men Diabetes mellitus Cigarette smokers Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Ankle/brachial index at rest Initial claudication distance (m) Maximal walking capacity (m)
Placebo Group (n Å 102)
62.3 { 7.8 80 (94) 10 (12) 83 (98) 149 { 17
58.6 { 8.2 93 (91) 20 (20) 101 (99) 147 { 17
82 { 8
84 { 7
0.63 { 0.11
0.64 { 0.09
128 { 65
129 { 74
215 { 109
223 { 118
Values are expressed as mean { SD or number (%) of patients.
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TABLE II Effect of Treatments on MHIQ Scores and Walking Capacity Propionyl-L-Carnitine
Placebo
MHIQ score Physical function Social function Emotional function Walking capacity Initial claudication distance (m) Maximal walking capacity (m)
Baseline
Day 180
Baseline
Day 180
p Value
0.68 { 0.18 0.65 { 0.11 0.65 { 0.14
0.72 { 0.19 0.65 { 0.13 0.63 { 0.16
0.65 { 0.17 0.60 { 0.13 0.61 { 0.17
0.73 { 0.17 0.63 { 0.12 0.64 { 0.17
0.082 0.151 0.018
128 { 65 223 { 118
199 { 165 308 { 198
129 { 74 215 { 109
233 { 194 372 { 133
0.167 0.026
Values are expressed as mean { SD. MHIQ Å McMaster Health Index Questionnaire.
TABLE III Effect of Treatments on MHIQ Scores and Walking Capacity in Patients With Baseline Maximal Walking Capacity õ250 m Propionyl-L-Carnitine (n Å 55)
Placebo (n Å 71) Baseline MHIQ scores Physical function Social function Emotional function Global Walking capacity Initial caludication distance (m) Maximal walking distance (m)
0.67 0.66 0.66 0.64
{ 0.18 { 0.11 { 0.13 { 0.12
94 { 35 158 { 48
Day 180 0.70 0.65 0.62 0.63
{ 0.19 { 0.13 { 0.16 { 0.14
143 { 83 228 { 116
Baseline 0.64 0.60 0.60 0.59
{ 0.18 { 0.12 { 0.18 { 0.13
94 { 38 158 { 57
Day 180 0.73 0.63 0.65 0.64
{ 0.16 { 0.11 { 0.17 { 0.12
175 { 151 282 { 186
p Value 0.027 0.113 0.002 0.002 0.084 0.009
Values are expressed as mean { SD. Abbreviation as in Table II.
Different results were observed in the subpopulation with mild claudication. In these patients (baseline maximal walking capacity ¢250 m), propionyl-Lcarnitine did not affect the MHIQ scores, nor improve the walking performance. As shown by the 95% confidence intervals, a large variation in results was observed in this subset of patients compared with those with more severe claudication (Figure 1).
DISCUSSION The present study is the first to report the effect of a pharmacologic treatment on quality of life in patients with intermittent claudication. We used the MHIQ, a standardized, generic measure.2 This questionnaire, already used to assess quality of life in patients with chronic diseases,7,8 is an appropriate instrument with which to assess several aspects of FIGURE 1. The 95% confidence intervals for mean treatment diffunctional status in patients with intermittent clauferences on day 180. Hatched bars, patients with baseline maxidication.3 At the end of the trial, patients who remal walking capacity õ250 m; open bars, patients with baseline ceived propionyl-L-carnitine showed a higher global maximal walking capacity ¢250 m. MHIQ Å McMaster Health Index Questionnaire; ICD Å initial claudication distance; MWC Å MHIQ score than those who received placebo. The maximal walking capacity; PLC Å propionyl-L-carnitine. emotional state (the ability to remain in good spirits most of the time and to be usually happy and satisfied the 2 groups. In the subset of patients walking õ250 with one’s own life) was beneficially affected by m at baseline, propionyl-L-carnitine significantly im- treatment. Conversely, no difference between treatproved physical function (p Å 0.027), emotional ments was observed for social function. Physical function (p Å 0.002), and global MHIQ score (p Å function showed an improvement that approached 0.002) compared with placebo (Table III). Also, for statistical significance, although the increase in maximal walking capacity, group differences signif- treadmill maximal walking capacity with propionylicantly favored propionyl-L-carnitine (p Å 0.009), L-carnitine was significantly greater than that with whereas no difference between treatments was ob- placebo. Such a discrepancy is probably due to the served for initial claudication distance (Table III). fact that many of the items assessing physical funcMISCELLANEOUS/PROPIONYL-L-CARNITINE IN INTERMITTENT CLAUDICATION
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tion concern areas such as self-care activities and communication, which are not affected by the disease.3 Actually, physical mobility, expected to be more affected by claudication, was significantly improved by active treatment compared with placebo. Target population: Arfviderson et al9 reported that patients with maximal walking capacity õ70 W have significant reduction in everyday life function as opposed to those performing a higher treadmill work. As a consequence, a treatment aimed at improving quality of life is expected to be beneficial in patients with severe functional impairment rather than in those with less pronounced walking disability, because the overall function status in the latter is only slightly different from that occurring in a general population.9 In effect, the stepwise multiple regression procedure indicated that treadmill maximal walking capacity at baseline (cutoff point 250 m) identifies a population in whom the probability for a successful treatment outcome is higher than in a general population of claudicants. In patients who walked õ250 m at baseline, propionyl-L-carnitine significantly improved quality of life compared with placebo, whereas in those with a baseline maximal walking capacity ¢250 m, no difference was observed between treatments. These 2 subpopulations also showed a different response to treatment in walking performance. In the group with more severely limited treadmill performance at baseline, the improvement in maximal walking capacity with propionyl-L-carnitine was greater than that with placebo. In the other group, statistical analysis did not show a difference between treatments. This finding is consistent with the previous observation that, in intermittent claudication, only the most affected patients require carnitine supplementation, because they, and not those with mild functional impairment, have reduced availability of endogenous carnitine to meet the increased metabolic demand induced by walking.10 Propionyl-L-carnitine, used in this trial, is easily converted into free carnitine and propionyl coenzyme A within the mitochondria.11 Indeed, it increases carnitine levels in the ischemic muscles of patients with severe peripheral arterial disease.12 Furthermore, propionyl-L-carnitine increases the walking capacity of patients with claudication to a greater
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extent than that observed with an equimolar dose of L-carnitine.13
APPENDIX List of participating centers: I Clinica Medica, Universita’ di Bari: Ottavio Albano, MD, Carlo Sabba’ MD; Cattedra di Angiologia, Ospedale Garibali, Catania: Giuseppe Maria Andreozzi, MD; Ospedale citta’ di Pavia: Vittorio Bianchi, MD; Dipartimento di Medicina Interna, Universita’ Federico II, Napoli: Antonietta Di Iorio, MD, Vincenzo Domenico Martone, MD, Sergio Perna, MD; Divisione di Cardiologia, Ospedale Piemonte, Messina: Francesco Casella, MD; Istituto di Clinica Medica, Universita’ di Messina: Fausto Consolo, MD, Agatino Manganaro, MD; Chirurgia Vascolare, II Universita’, Napoli: Alberto Marcialis, MD; Reparto di Cardiologia, Ospedale S. Leonardo, Salerno: Bruno Ravera, MD; Istituto di Chirurgia Vascolare, Ospedale Garibaldi, Catania: Salvatore Romeo, MD; Ospedale Sanatrix, Venafro: Pasquale Simonelli, MD; Cattedra di Chirurgia Vascolare, Universita’ di Modena: Giuseppe Tuscano, MD; Divisione di Chirurgia Vascolare, Ospedale di Modena: Pellegrino Vecchiati, MD; Istituto Medicina Domani, Genova: Gianfranco Di Somma, MD.
1. Brevetti G, Perna S, Sabba’ C, Martone VD, Condorelli M. Propionyl-L-
carnitine in intermittent claudication: double-blind, placebo-controlled, dose titration, multicenter study. J Am Coll Cardiol 1995;26:1411–1416. 2. Chambers LW, MacDonald LA, Tugwell P. The McMaster Health Index Questionnaire as a measure of the quality of life for patients with rheumatoid disease. J Rheumatol 1982;9:780–784. 3. Barletta G, Perna S, Sabba’ C, Catalano A, O’Boyle C, Brevetti G. Quality of life in patients with intermittent claudication: relationship with laboratory exercise performance. Vascular Medicine 1996;1:3–7. 4. Sackett DL, Chambers LW, MacPershon AS, Goldsmith CM, McAuley RG. The development and application of indexes of health: general methods and a summary of results. Am J Public Health 1977;67:423–428. 5. Fortin F, Kerouac S. Validation of questionnaires on physical function. Nurs Res 1977;26:128–135. 6. Andersen B. A question of control. In: Andersen B, ed. Methodological Errors in Medical Research: An Incomplete Catalogue. Cambridge, MA: Blackwell Scientific, 1990:70–71. 7. Guyatt GH, Thompson PI, Berman LB, Sullivan MJ, Townsend M, Jones NL, Pugsley SO. How should we measure function in patients with chronic heart and lung disease? J Chron Dis 1985;38:517–524. 8. Rector TS, Francis GS, Cohn JN. Patient’s self-assessment of their congestive heart failure. Part 1. Patient-perceived dysfunction and its poor correlation with maximal exercise testing. Heart Failure 1987;3:192–196. 9. Arfviderson B, Karlsson J, Dahllof AG, Lundholm K, Sullivan M. The impact of intermittent claudication on quality of life evaluated by the Sickness Impact Profile Technique. Eur J Clin Invest 1993;23:741–745. 10. Brevetti G, Di Lisa F, Perna S, Menabo’ R, Barbato R, Martone VD, Siliprandi N. Carnitine-related alteration in patients with intermittent claudication. Indication for a focused carnitine therapy. Circulation 1996;93:1685–1689. 11. Siliprandi N, Di Lisa F, Menabo’ R. Propionyl-L-carnitine: biochemical significance and possible role in cardiac metabolism. Cardiovasc Drugs Ther 1991;(suppl 5)1:11–15. 12. Brevetti G, Angelini C, Rosa M, Carrozzo R, Perna S, Corsi M, Materazzo A, Marcialis M. Muscle carnitine deficiency in patients with severe peripheral vascular disease. Circulation 1991;84:1490–1495. 13. Brevetti G, Perna S, Sabba’ C, Rossini A, Scotto di Uccio V, Berardi E, Godi L. Superiority of L-propionyl carnitine 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.
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