- Email: [email protected]
“A real world” dose comparison of lovastatin and pravastatin
READERS’ COMMENTS Lovastatin Versus Pravastatin for Hypsrcholesterolemia
The multicenter comparative trial of lovastatin and pravastatin in the treatment of hypercholesterolemia (sponsored by Merck, manufacturer of lovastatin) did an injustice to pravastatin.’ The Lovastatin Pravastatin Study Group concluded that lovastatin was more effective than was pravastatin in reducing total and low-density lipoprotein (LDL) cholesterol acrossthe recommended dosageranges.Closer scrutiny of the data reveals that milligram for milligram, pravastatin was as effective as was lovastatin in reducing total and LDL cholesterol, and at lower dosageswas more effective than was lovastatin in raising high-density lipoprotein (HDL) cholesterol. The recommended daily dosages of pravastatin and lovastatin are 10 to 40 mg2 and 20 to 80 mg,3respectively. Efficacy of the drugs was determined by comparing 10, 20 and 40 mg/day of pravastatin with 20,40 and 80 mg/day of lovastatin, respectively. On this basis, it was concluded that lovastatin was more effective in reducing total and LDL cholesterol. However, if one compares 20 and 40 mg/day of pravastatin with 20 and 40 mg/day of lovastatin, respectively,there is no significant difference in total and LDL cholesterol lowering. Ten mg/day of pravastatin was as effective as 20 mg/day of lovastatin in raising HDL cholesterol. Most LDL cholesterol lowering with lovastatin occurs at dosagesup to 40 mg/day, and not much added lowering occurs in the 40 to 80 mg dosage range.4 It is unusual to prescribe lovastatin in dosages >40 mg/day and also very costly. In fact, pravastatin is cheaper than is lovastatin, milligram for milligram.5 I feel this study supports the increased use of pravastatin over lovastatin. Milligram for milligram, both drugs are equally effective in Letters (from the United States) concerning a particular article in the Journal must be received within 2 months of the article’s publication, and should be limited (with rare exceptions) to 2 double-spaced typewritten pages. Two copies must be submitted.
416
question on the clinical differences between hydroxymethylglutaryl coenzyme A reductaseinhibitors. The study design, however, is not optimally designed to reflect the real world usage of these agents. By forcing the dosage upward regardless of response, the authors are placing artificial constraints on the data, and clinicians may make inappropriate decisions based on the authors’ conclusions that “lovastatin was more effective than pravastatin at reducing total and LDL (low-density lipoprotein) cholesterol over their usually recommended dosage ranges.” The authors’ own data indicate that pravastatin on a milligram-per-milligram basis is about 30% more potent than is lovastatin in lowering LDL, and clinical experience suggeststhat it is most likely much greater. We recently converted all patients at our hospital on lovastatin to pravastatin (n = 169).The target dosage of pravastatin was 50% of that for lovastatin. Patientshad 22 lipid profiles performed at their most recent Mark R. Goldstein, MD dosage of lovastatin and Y lipid Upland, Pennsylvania profile after conversion to pravas18 May 1993 tatin. All patients have received 26 months of therapy on each drug. 1. The Lovastatin Pravastatin Study Group. A multiCompliance was assessedutilizing center comparative trial of lovastatin and pravastatin in the treatment of hypercholesterolemia. Am J Carrefill records and was similar dial 1993:71:8lt&815. throughout the study period. Our re2. Physicians’ Desk Reference. Supplement A. 46th sults indicated that patients coned. Montvale, NJ: Medical Economics Books, 1992: A53-A55 trolled on lovastatin could be suc3. Phvsicians’ Desk Reference. 46th ed. Montvale. NJ: cessfully dose-reducedwith pravasM&al Economics Books, 1992: 1505-1508. 4. Bradford RH, Shear CL, Chremos AN, Du~ovne C, tatin without loss of efficacy (mean Downton M, Franklin FA, Gould AL, Hesney M, Higtotal cholesterol(L,218 mg/dl vs total gins T, Hurley DP, Langendorfer A, Nash DT, Pool cholesterol(p) 222 mg/dl; p = NS). JL, Schnaper H. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. 1. Efficacy in modNine to 12 months following conifvine , -.olasma IiDooroteins and advene event motile in version, only 8.5% of patients ini8,245 patients ‘with moderate hypercholestkrolemia. tially started on pravastatin required Arch Intern Med 199 I : I5 I :4349. 5. Abramowicz M. Choice of cholesterol lowering minor dosage increases,and only 1 drugs. Med Len Dru,qs Ther 1993;35: 19-22. required a higher dosagethan lovas6. Ettinger WH, Wahl PW, Kuller LH. Lipoprotein lipids in older people: results from the Cardiovascular tatin. 1992;86:858&869. Health Study. Circulation Theseresults indicate that the clin7. Denke MA. Why and how should hyperlipidemia ical usage of hydroxymethylglutaiyl in the elderly be treated? Nutr Merah Cardiowsc Dis 1992;2:191-194. coenzyme A reductase inhibitors is I. Wvsowski DK. Kennedv, DL. Grosr TP. Prescribed very complex. Pravastatin and louse of cholesterol-lowering drugs in the United States, vastatin differ in regard to their in1978 through 1988. JAMA 1990;263:2185-2188. herent potencies, protein-binding, lipophilicity and bioavailabilities. “A Real. World” Doss Although the inherent potency of ga:my; of Lovadatin and pravastatin to lovastatin is likely not 2:1, clinical efficacy may well apThe Lovastatin Pravastatin Study proach this. Pravastatin appears to Group’ addressesa very important be more bioavailable at bedtime lowering LDL cholesterol, and at lower dosages, pravastatin is more effective than is lovastatin in raising HDL cholesterol. HDL cholesterol is more predictive of future coronary eventsthan is LDL cholesterol in an elderly population6 and may be the desirable lipoprotein to target for intervention. Lower dosagesof lipidlowering drugs are preferred in the elderly.7 Sincemost prescriptions for reductaseinhibitors are given to the elderly,s lower dosages of pravastatin are cost-effective. Both drugs are equally well-tolerated, and safety and compliance do not seemto be an issue. In summary, this study indicates that pravastatin is as effective as lovastatin in lowering LDL cholesterol and may be more effective in raising HDL cholesterol at lower dosages, thus making it the preferred reductase inhibitor for the elderly. Most importantly, we await data demonstrating that any reductase inhibitor can decreasemorbidity or mortality, or both, in long-term primary and secondarycoronary prevention trials.
THE AMERICANJOURNALOF CARDIOLOGY VOLUME73
FEBRUARY15, 1994
Cost Analysis
Pravastatin Lovastatin Pravastatin Lovastatin Pravastatin Lovastatln
10 20 20 40 40 80
Price of 30-Day SUPPlY
Percentage of Tota I Cholesterol Lowering
Cost per Percentage of Total Cholesterol Lowering
Percentage of LDL Cholesterol Lowering
Cost per Percentage of LDL Cholesterol Lowering
49.18
-13
57.59
-20
3.78 2.87 3.24 4.51 5.46 7.40
-19 -28 -25 -33 -27 -39
2.59 2.05 2.08 3.14 3.84 5.31
-16
51.91
-23 -19 -28
103.65 103.82 207.31
LDL = low-density lipoprotein.
Lovastatin
Versus
Pravastatin
in Reducing
Total and LDL Cholesterol
Lipid/ Lipoprotein
Lovastatin
Total cholesterol LDL cholesterol
-20 -28
(10) (15)
Pravastatin -16 -24
(12) (17)
I
Mean % Change (40 mg/day)
Mean % Change (20 mg/day)
Pravastatln
p Value
(11)
-18 (13)
(15)
-26
p Value
Lovastatin
-23 -32
0.002
(17)
LDL = low-density lipoprotem
than is lovastatin, since lovastatin should be taken with food. Additionally, the Expanded Clinical Evaluation of Lovastatin (EXCEL) study has shown that the efficacy of 40 mg of lovastatin can be increased by 13% by dividing the dosage, rather than giving it once a day.2 There is no difference in the efficacy of pravastatin when the same total dosage is given twice or once daily. In contrast to the conclusions of the Lovastatin Pravastatin Study Group, we found that patients at our institution could be successfully dose-reduced by about 50% when switched from lovastatin to pravastatin. Our real world results are supported by 21 double-blind, doubleplacebo, randomized comparison that demonstrated that the differences in mean reductions of total and LDL cholesterol at 8 weeks were not statistically significant between 20 mg of lovastatin given once daily with the evening meal and 10 mg of pravastatin given at bedtime.’ Our results are significant considering the ever increasing need for cost-effective ways to maintain optimal patient care. Lisa 6. Korman.
PII-D
Newington, Cotkcticut 25 May 1993 1. The Lovastatm Pravastatin Study Group. A multicenter comparative trial of lovastarin and pravastatin
in the treatmentof hypercholesterolemia. 4nr .I Cardid 1993:71:81~~81S. 2. Bradford RH, Shear CL, Chremos AN. Dujovne C, Downton M, Franklin FA, Gould AL, Hesney M, Higgms T, Hurley DP, Langendorfer A, Nash DT, Pool JL, Schnaper H. Expanded Clinical Evaluation of Lovastatin (EXCEL) study resulrs. Amh Intrr-n Med 1991:151:4.~9. 3. McPherson R, Bedard J. Connelly P, Cumew G. Davignon J, Echenberg D, Lavin P, Later L, Lenis J, McQueen M, Montigny M, Munoz C, O’Leary T, Ooi T, Rouleau I, Space D, Tan M, Theroux P. Comparison of the shon-term efficacy and tolerability of lovastatin and pravastatin in the management of priC/in Ther- 1992; 14: mary hypercholesterolemia. 276-29 I.
Lovastatin in Pravastatin Comparative Trial: Cost-Effectiveness In the April 1993 issue of the AJC, the Lovastatin Pravastatin Study Group’ compared the effectiveness of lovastatin and pravastatin in a double-blinded trial. Their final discussion suggests that lovastatin is more effective than is pravastatin across dosing ranges. Unfortunately, I believe that a cost analysis of cholesterol-lowering shows that pravastatin is more effective at the higher dose ranges. The attached table shows a cost breakdown for each percent of cholesterol and lowdensity lipoprotein (LDL) lowering.2 As arranged in the table, one can see the differences in cost per the percentage of total and LDL cholesterol over a 30-day period. This would
suggest that the potency difference is of minimal importance when costeffectiveness is determined. At the lowest dose range, lovastatin would seem to have a cost advantage; however, at higher dose ranges, pravastatin seems to have the more favorable cost. Other analyses of the effects of pravastatin on LDL cholesterol have shown more dramatic results: 22.4, 32.4, and 34.1% at the IO,20 and 40 mg/day doses, respectively.3 If these factors were used in the cost analysis, the cost-effectiveness of pravastatin would be more dramatic. Sam Farbstein,
MD
Chicago Ridge, Illinois 2 July 1993 1. The Lovastatin Pravastarin Study Group. A multicenter comparative trial on lovastatin and pravastatin in the treatment of hypercholesverolemia. Am .I Cardial 1993:71:810-815. 2. MEDLSPAN’s
PrescriptionPricingGuide@,Nation-
al Average Wholesale Prices (AWP), Medispan Inc., March 1993. 3. Jones PH, Farmer JA, Crasman MD, McKenney JM. Wright JT, Proctor JD, Berkson DM, Famham DJ, Wolfson PM, Golfer HT, Rockley CE, Sigmund WR, Schlant RC, Are&erg D, McGovern ME. Oncedaily pravaatatin in patients with primary hyperchole\terolemia: a dose response study. Cli~l C~I&I/ 1991;14:14~151.
Reply: All 3 letters above address issues raised by our study, conceming the comparative lipid-altering efficacy and cost of lovastatin and
READERS’ COMMENTS
417
The multicenter comparative trial of lovastatin and pravastatin in the treatment of hypercholesterolemia (sponsored by Merck, manufacturer of lovastatin) did an injustice to pravastatin.’ The Lovastatin Pravastatin Study Group concluded that lovastatin was more effective than was pravastatin in reducing total and low-density lipoprotein (LDL) cholesterol acrossthe recommended dosageranges.Closer scrutiny of the data reveals that milligram for milligram, pravastatin was as effective as was lovastatin in reducing total and LDL cholesterol, and at lower dosageswas more effective than was lovastatin in raising high-density lipoprotein (HDL) cholesterol. The recommended daily dosages of pravastatin and lovastatin are 10 to 40 mg2 and 20 to 80 mg,3respectively. Efficacy of the drugs was determined by comparing 10, 20 and 40 mg/day of pravastatin with 20,40 and 80 mg/day of lovastatin, respectively. On this basis, it was concluded that lovastatin was more effective in reducing total and LDL cholesterol. However, if one compares 20 and 40 mg/day of pravastatin with 20 and 40 mg/day of lovastatin, respectively,there is no significant difference in total and LDL cholesterol lowering. Ten mg/day of pravastatin was as effective as 20 mg/day of lovastatin in raising HDL cholesterol. Most LDL cholesterol lowering with lovastatin occurs at dosagesup to 40 mg/day, and not much added lowering occurs in the 40 to 80 mg dosage range.4 It is unusual to prescribe lovastatin in dosages >40 mg/day and also very costly. In fact, pravastatin is cheaper than is lovastatin, milligram for milligram.5 I feel this study supports the increased use of pravastatin over lovastatin. Milligram for milligram, both drugs are equally effective in Letters (from the United States) concerning a particular article in the Journal must be received within 2 months of the article’s publication, and should be limited (with rare exceptions) to 2 double-spaced typewritten pages. Two copies must be submitted.
416
question on the clinical differences between hydroxymethylglutaryl coenzyme A reductaseinhibitors. The study design, however, is not optimally designed to reflect the real world usage of these agents. By forcing the dosage upward regardless of response, the authors are placing artificial constraints on the data, and clinicians may make inappropriate decisions based on the authors’ conclusions that “lovastatin was more effective than pravastatin at reducing total and LDL (low-density lipoprotein) cholesterol over their usually recommended dosage ranges.” The authors’ own data indicate that pravastatin on a milligram-per-milligram basis is about 30% more potent than is lovastatin in lowering LDL, and clinical experience suggeststhat it is most likely much greater. We recently converted all patients at our hospital on lovastatin to pravastatin (n = 169).The target dosage of pravastatin was 50% of that for lovastatin. Patientshad 22 lipid profiles performed at their most recent Mark R. Goldstein, MD dosage of lovastatin and Y lipid Upland, Pennsylvania profile after conversion to pravas18 May 1993 tatin. All patients have received 26 months of therapy on each drug. 1. The Lovastatin Pravastatin Study Group. A multiCompliance was assessedutilizing center comparative trial of lovastatin and pravastatin in the treatment of hypercholesterolemia. Am J Carrefill records and was similar dial 1993:71:8lt&815. throughout the study period. Our re2. Physicians’ Desk Reference. Supplement A. 46th sults indicated that patients coned. Montvale, NJ: Medical Economics Books, 1992: A53-A55 trolled on lovastatin could be suc3. Phvsicians’ Desk Reference. 46th ed. Montvale. NJ: cessfully dose-reducedwith pravasM&al Economics Books, 1992: 1505-1508. 4. Bradford RH, Shear CL, Chremos AN, Du~ovne C, tatin without loss of efficacy (mean Downton M, Franklin FA, Gould AL, Hesney M, Higtotal cholesterol(L,218 mg/dl vs total gins T, Hurley DP, Langendorfer A, Nash DT, Pool cholesterol(p) 222 mg/dl; p = NS). JL, Schnaper H. Expanded Clinical Evaluation of Lovastatin (EXCEL) study results. 1. Efficacy in modNine to 12 months following conifvine , -.olasma IiDooroteins and advene event motile in version, only 8.5% of patients ini8,245 patients ‘with moderate hypercholestkrolemia. tially started on pravastatin required Arch Intern Med 199 I : I5 I :4349. 5. Abramowicz M. Choice of cholesterol lowering minor dosage increases,and only 1 drugs. Med Len Dru,qs Ther 1993;35: 19-22. required a higher dosagethan lovas6. Ettinger WH, Wahl PW, Kuller LH. Lipoprotein lipids in older people: results from the Cardiovascular tatin. 1992;86:858&869. Health Study. Circulation Theseresults indicate that the clin7. Denke MA. Why and how should hyperlipidemia ical usage of hydroxymethylglutaiyl in the elderly be treated? Nutr Merah Cardiowsc Dis 1992;2:191-194. coenzyme A reductase inhibitors is I. Wvsowski DK. Kennedv, DL. Grosr TP. Prescribed very complex. Pravastatin and louse of cholesterol-lowering drugs in the United States, vastatin differ in regard to their in1978 through 1988. JAMA 1990;263:2185-2188. herent potencies, protein-binding, lipophilicity and bioavailabilities. “A Real. World” Doss Although the inherent potency of ga:my; of Lovadatin and pravastatin to lovastatin is likely not 2:1, clinical efficacy may well apThe Lovastatin Pravastatin Study proach this. Pravastatin appears to Group’ addressesa very important be more bioavailable at bedtime lowering LDL cholesterol, and at lower dosages, pravastatin is more effective than is lovastatin in raising HDL cholesterol. HDL cholesterol is more predictive of future coronary eventsthan is LDL cholesterol in an elderly population6 and may be the desirable lipoprotein to target for intervention. Lower dosagesof lipidlowering drugs are preferred in the elderly.7 Sincemost prescriptions for reductaseinhibitors are given to the elderly,s lower dosages of pravastatin are cost-effective. Both drugs are equally well-tolerated, and safety and compliance do not seemto be an issue. In summary, this study indicates that pravastatin is as effective as lovastatin in lowering LDL cholesterol and may be more effective in raising HDL cholesterol at lower dosages, thus making it the preferred reductase inhibitor for the elderly. Most importantly, we await data demonstrating that any reductase inhibitor can decreasemorbidity or mortality, or both, in long-term primary and secondarycoronary prevention trials.
THE AMERICANJOURNALOF CARDIOLOGY VOLUME73
FEBRUARY15, 1994
Cost Analysis
Pravastatin Lovastatin Pravastatin Lovastatin Pravastatin Lovastatln
10 20 20 40 40 80
Price of 30-Day SUPPlY
Percentage of Tota I Cholesterol Lowering
Cost per Percentage of Total Cholesterol Lowering
Percentage of LDL Cholesterol Lowering
Cost per Percentage of LDL Cholesterol Lowering
49.18
-13
57.59
-20
3.78 2.87 3.24 4.51 5.46 7.40
-19 -28 -25 -33 -27 -39
2.59 2.05 2.08 3.14 3.84 5.31
-16
51.91
-23 -19 -28
103.65 103.82 207.31
LDL = low-density lipoprotein.
Lovastatin
Versus
Pravastatin
in Reducing
Total and LDL Cholesterol
Lipid/ Lipoprotein
Lovastatin
Total cholesterol LDL cholesterol
-20 -28
(10) (15)
Pravastatin -16 -24
(12) (17)
I
Mean % Change (40 mg/day)
Mean % Change (20 mg/day)
Pravastatln
p Value
(11)
-18 (13)
(15)
-26
p Value
Lovastatin
-23 -32
0.002
(17)
LDL = low-density lipoprotem
than is lovastatin, since lovastatin should be taken with food. Additionally, the Expanded Clinical Evaluation of Lovastatin (EXCEL) study has shown that the efficacy of 40 mg of lovastatin can be increased by 13% by dividing the dosage, rather than giving it once a day.2 There is no difference in the efficacy of pravastatin when the same total dosage is given twice or once daily. In contrast to the conclusions of the Lovastatin Pravastatin Study Group, we found that patients at our institution could be successfully dose-reduced by about 50% when switched from lovastatin to pravastatin. Our real world results are supported by 21 double-blind, doubleplacebo, randomized comparison that demonstrated that the differences in mean reductions of total and LDL cholesterol at 8 weeks were not statistically significant between 20 mg of lovastatin given once daily with the evening meal and 10 mg of pravastatin given at bedtime.’ Our results are significant considering the ever increasing need for cost-effective ways to maintain optimal patient care. Lisa 6. Korman.
PII-D
Newington, Cotkcticut 25 May 1993 1. The Lovastatm Pravastatin Study Group. A multicenter comparative trial of lovastarin and pravastatin
in the treatmentof hypercholesterolemia. 4nr .I Cardid 1993:71:81~~81S. 2. Bradford RH, Shear CL, Chremos AN. Dujovne C, Downton M, Franklin FA, Gould AL, Hesney M, Higgms T, Hurley DP, Langendorfer A, Nash DT, Pool JL, Schnaper H. Expanded Clinical Evaluation of Lovastatin (EXCEL) study resulrs. Amh Intrr-n Med 1991:151:4.~9. 3. McPherson R, Bedard J. Connelly P, Cumew G. Davignon J, Echenberg D, Lavin P, Later L, Lenis J, McQueen M, Montigny M, Munoz C, O’Leary T, Ooi T, Rouleau I, Space D, Tan M, Theroux P. Comparison of the shon-term efficacy and tolerability of lovastatin and pravastatin in the management of priC/in Ther- 1992; 14: mary hypercholesterolemia. 276-29 I.
Lovastatin in Pravastatin Comparative Trial: Cost-Effectiveness In the April 1993 issue of the AJC, the Lovastatin Pravastatin Study Group’ compared the effectiveness of lovastatin and pravastatin in a double-blinded trial. Their final discussion suggests that lovastatin is more effective than is pravastatin across dosing ranges. Unfortunately, I believe that a cost analysis of cholesterol-lowering shows that pravastatin is more effective at the higher dose ranges. The attached table shows a cost breakdown for each percent of cholesterol and lowdensity lipoprotein (LDL) lowering.2 As arranged in the table, one can see the differences in cost per the percentage of total and LDL cholesterol over a 30-day period. This would
suggest that the potency difference is of minimal importance when costeffectiveness is determined. At the lowest dose range, lovastatin would seem to have a cost advantage; however, at higher dose ranges, pravastatin seems to have the more favorable cost. Other analyses of the effects of pravastatin on LDL cholesterol have shown more dramatic results: 22.4, 32.4, and 34.1% at the IO,20 and 40 mg/day doses, respectively.3 If these factors were used in the cost analysis, the cost-effectiveness of pravastatin would be more dramatic. Sam Farbstein,
MD
Chicago Ridge, Illinois 2 July 1993 1. The Lovastatin Pravastarin Study Group. A multicenter comparative trial on lovastatin and pravastatin in the treatment of hypercholesverolemia. Am .I Cardial 1993:71:810-815. 2. MEDLSPAN’s
PrescriptionPricingGuide@,Nation-
al Average Wholesale Prices (AWP), Medispan Inc., March 1993. 3. Jones PH, Farmer JA, Crasman MD, McKenney JM. Wright JT, Proctor JD, Berkson DM, Famham DJ, Wolfson PM, Golfer HT, Rockley CE, Sigmund WR, Schlant RC, Are&erg D, McGovern ME. Oncedaily pravaatatin in patients with primary hyperchole\terolemia: a dose response study. Cli~l C~I&I/ 1991;14:14~151.
Reply: All 3 letters above address issues raised by our study, conceming the comparative lipid-altering efficacy and cost of lovastatin and
READERS’ COMMENTS
417