Study results

TitleAuthor(s)YearResultsFundingReported harmsConclusionsEffect due to factor under investigation?Consistent with other studies?Applicable to guideline population?Notes
Comparative efficacy and safety of pravastatin, nicotinic acid and the two combined in patients with hypercholesterolemiaDavignon J; Roederer G; Montigny M; Hayden MR; Tan MH; Connelly PW; Hegele R; McPherson R; Lupien PJ; Gagné C;19948 week results: Placebo: NS change from baseline; Nicotinic acid: LDL −16.11%; HDL 12.20%; TC −11.25%; TG − 11.43%. Pravastatin: −32.72%; HDL 13.46%; TC −23.08%; TG − 14.38%. Combination of prava and nicotinic acid: LDL −41.50%; HDL 16.14%; TC −31.62%; TG − 34.85%. There were significant differences between the pravastatin and pravastatin and nicotinic acid combination (p<0.05).Bristol Myers SquibbOf 158 patients randomized to treatment, 5 discontinued treatment due to adverse events in the first 8 weeks, 4 in the nicotinic acid group and 1 in the combination group. No patient receiving pravastatin alone discontinued treatment.This study indicates that a combination of nicotinic acid and pravastatin is significantly more effective than either treatment on its own.Not clear why 12 patients did not participate.
Clinical experience with simvastatin compared with cholestyramineErkelens DW; Baggen MG; Van Doormaal JJ; Kettner M; Koningsberger JC; Mol MJ;1988TC baseline 12mmol/l; percent change with simva −36%, cholestyramine −23% and combination −45%. LDL baseline 10mmol/l; percent change with simva −43%, cholestyramine − 30% and combination −64%.HDL baseline 1.11mmol/l; percent change with simva +16%, cholestyramine +9% and combination +20%.TG baseline 1.85 mmol/l; percent change with simva −21%, cholestyramine +11% and combination −17%. Apo A baseline 99mmol/l; percent change with simva +21%, cholestyramine +9% and combination +15%. Apo B baseline 303 mmol/l; percent change with simva −47%, cholestyramine −32% and combination −64%.UnknownClinical adverse effects were primarily GI symptoms in the cholestyramine group. Eleven patients could not tolerate cholestyramine. Transaminase increases were observed with both drugs and CPK increases occurred in the simva group only.The study indicates that the combination of simva and cholestyramine has an additive effect.It appears that the effect is due to the treatment.YesYes
Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemiaGagne C; Gaudet D; Bruckert E; Ezetimibe S;2002Changes in lipid levels from baseline simva 40 (mmol/l): Direct LDL absolute change 0.5 statin-80 and 1.7 in ezetimibe plus statin 40/80 (p =0.007); TC absolute change .49 statin-80 and 1.9 in ezetimibe plus statin 40/80 (p<0.01). There were no other significant differences between the two treatment groups. There were reductions of at least 14% to 20.5% in LDL-C when ezetimibe was coadministered with a moderate (40 mg) or maximal (80 mg) dose statin therapy compared with maximal therapy with statins alone. Ezetimibe plus statin 80 reduced LDL 26.6% compared to statin 80 reduction of 5.6% from baseline of simva 40.Schering-Plough Research Institute and Merck/Schering-Plough PharmaceuticalsTwo patients in the ezetimibe group discontinued treatment - one due to epigastric and chest pain and another due to increase liver enzymes. There were no significant differences between treatment groups on another other measures of safety.It appears that ezetimibe is an effect lipid lowering agent in the HoFH populationThis study appears to be well designed and the results are plausible.No other studiesYesThere may be differences between sites
The efficacy and safety of pravastatin, compared to and in combination with bile acid binding resins, in familial hypercholesterolaemia.Hoogerbrugge N; Mol MJ; Van D; Rustemeijer C; Muls E; Stalenhoef AF; Birkenhager JC;1990Changes in serum lipid concentrations (%): TC: placebo group week 8–2 +/−9; Resins week 24–17 +/− 12; pravastatin week 8–28 +/− 7. LDL: placebo group week 8–2 +/−9; Resins week 24–22 +/− 15; pravastatin week 8–33 +/− 8. HDL: placebo group week 8–5 +/−14; Resins week 24 7 +/− 15; pravastatin week 8 8 +/− 13. TG: placebo group week 8 4 +/38; Resins week 24 17 +/54; pravastatin week 8–14 +/30. When pravastatin was supplemented with resins, there was an additional reduction in TC of 8% by week 24 (p<0.01) and 12% in LDL (p<0.01).UnknownNone of the patients had to discontinue medication because of side effects Symptomatic adverse effects or major abnormalities of laboratory values did not occur.The mean reduction in LDL cholesterol after 8 weeks of treatment with pravastatin was 33%; with resins was 22% and by 42% with pravastatin and resin combination.The results appear to be due to treatment. There were two resins used but the researchers assumed that these reduced cholesterol levels to the same extent and by the same mechanism.YesYes
Comparative Efficacy and Safety of Pravastatin and Cholestyramine Alone and Combined in Patients with HypercholesterolemiaKnopp RH; Brown WV; Corder CN; Dobs AS; Dujovne CA; Goldberg AC; Hunninghake DB; Insull W; Mellies MJ; Smith DA; Stein EA;1993Pravastatin 20 mg bid: TC − baseline 7.9 +/− 0.14; week 8 6.0 +/− 0.14; −24% +/− 1.2. LDL − baseline 6.1 +/− 0.13; week 8 4.2+/− 0.13; −31.3 % +/− 1.6. Pravastatin 40 mg bid: TC − baseline 8.0 +/− 0.15; week 8 5.7 +/− 0.12; −28.7% +/− 1.2. LDL − baseline 6.1 +/− 0.14; week 8 3.8 +/− 0.11; −37.7% +/− 1.5. Cholestyramine 12 g bid: TC − baseline 8.1 +/− 0.17; week 8 6.3 +/− 0.18; −22.0% +/− 1.3. Cholestyramine 12 g bid + pravastatin 20 mg bid: LDL − baseline 6.1 +/− 0.17; week 8 4.2 +/− 0.17; −32.1% +/− 1.7. Placebo: TC − baseline 8.0 +/− 0.16; week 8 7.9 +/− 0.18.LDL − baseline 6.0 +/− 0.15; week 8 5.9 +/− 0.18; −2.3% +/− 2.4.”Bristol Meyers SquibbFrequencies of adverse experiences attributable to the drugs were similar in all treatment groups. The most common adverse reaction were gastrointestinal. Mean levels of liver enzymes remained within the normal range throughout the trial.This study indicates that both pravastatin, cholestyramine and cholestyramine and pravastatin in combination are effective treatments for cholesterol and LDL.Only about half of the patients had FH.
Efficacy and safety of a combination fluvastatin-bezafibrate treatment for familial hypercholesterolemia: comparative analysis with a fluvastatin-cholestyramine combinationLeitersdorf E; Muratti EN; Eliav O; Meiner V; Eisenberg S; Dann EJ; Sehayek E; Peters TK; Stein Y;1994Percent change from baseline was reported in both groups. Total cholesterol in Group 1 changed by 23.9% + 10.7 and in Group 2, 28.6% +11.7; TG increased in Group 1 by 14.2 % +35.8 and decreased in Group 2, 25.1% + 29.7; HDL increased in Group 1 2.9 % + 11.0 and in Group 2 13.0% + 13.4; LDL decreased by 21.3% + 7.9 in Group 1 and 25.0% + 13.5. There was no significant difference in total cholesterol or LDL between groups; however, there were significant differences between triglyceride and HDL levels (p<0.001 and p<0.05 respectively).SandozNone of the patients discontinued the study because of adverse events. GI events occurred in five cases from Group 1 and four from Group 2. No notable abnormalities were observed in laboratory values.This study demonstrates that the addition of fibrates or resins did not result in a significant difference in LDL or TC but that fibrates were more effective in treating TG and HDL levels.
Effectiveness of Low-Dose Lovastatin Combined with Low-Dose Colestipol in Moderate to Severe Primary HypercholesterolemiaTonstad S; Ose L; Gorbitz C; Harrison EM; Gans HJD;1993Mean baseline values (SD): TC mmol/l -Placebo 7.6 (0.9); lovastatin 20 mg & 5 g colestipol 5.8 (0.7): lovastatin 20 mg and 10 g colestipol 5.5 (0.9); LDL mmol/l -Placebo 5.6 (0.7); lovastatin 20 mg & 5 g colestipol 3.9 (0.7): lovastatin 20 mg and 10 g colestipol 3.6 (0.); TG − Placebo 1.5 (0.7); lovastatin 20 mg & 5 g colestipol 1.4 (0.7): lovastatin 20 mg and 10 g colestipol 1.2 (0.4); HDL − Placebo 1.3 (0.3); lovastatin 20 mg & 5 g colestipol 1.3 (0.4): lovastatin 20 mg and 10 g colestipol 1.4 (0.3); Apo A- Placebo 1.2 (0.1); lovastatin 20 mg & 5 g colestipol 1.2 (0.2): lovastatin 20 mg and 10 g colestipol 1.3 (0.2);Apo B - Placebo 1.2 (0.3); lovastatin 20 mg & 5 g colestipol .9 (0.2): lovastatin 20 mg and 10 g colestipol .9 (0.1). Compared to placebo 20 mg lovastatin and 5 g and 10 g of colestipol reduced TC significantly (p<0.0001), Apo B levels(p<0.01), LDL levels (p<0.0001). There was a 34% and 35% reduction in LDL levels at 8 weeks with 5 g and 10 g colestipol respectively.UnknownThe incidence of GI events possibly or probably attributed to drug treatment was 32% and 30% in the lovastatin 5 g colestipol and 10 g groups respectively and 50% in the placebo group (p>0.05). Six of the 39 participants (15%) on active therapy reported abdominal side effects that lasted 3 weeks or longer. There were no clinically significant changes in lab safety tests.The combination of low dose lovastatin with low dose colestipol in this study resulted in significant reductions in total cholesterol, LDL and Apo B levels.Yes, it appears that the treatment was responsible for the effect.YesYes
Comparison of pravastatin alone and with cholestyramine in the treatment of hypercholesterolemiaTsai CH; Ding YA; Hao KL;1995TC % change at 24 weeks: Pravastatin 5.5 mmol/l +/− .26; pravastatin + cholestyramine 5.4 mmol/l +/− .31; p value NS. LDL % change at 24 weeks: Pravastatin 3.5 mmol/l +/− .28; pravastatin + cholestyramine 3.13 mmol/l +/− .33; p <0.01. HDL % change at 24 weeks: Pravastatin 1.4 mmol/l +/− .15; pravastatin + cholestyramine 1.4 mmol/l +/− .26; p value NS. TG % change at 24 weeks: Pravastatin 2.1 mmol/l +/− .24; pravastatin + cholestyramine 2.5 mmol/l +/− .20; p <0.01.Sankyo Company and Bristol Myers SquibbNo serious adverse drug reactions occurred during the study. No patients withdrew due to side effects.The reduction of LDL of 24% with pravastatin alone is in line with results obtained in a dose response study on primary hypercholesterolemia. There was a higher reduction in LDL (32%) with low dose pravastatin and cholestyramine. The low dose of cholestyramine reduced side effects and improved compliance.The effect appears to be due to the treatmentYesYes
Pravastatin and Gemfibrozil Alone and in Combination for the Treatment of HypercholesterolemiaWiklund O; Angelin B; Bergman M; Berglund L; Bondjers G; Carlsson A; Linden T; Miettinen T; Odman B; Olofsson SO; Saarinen I; Sipila R; Sjostrom P; Kron B; Vanhanen H; Wright I;1993TC: Placebo 7.13 mmol/l (0.12), −1.72% change; pravastatin 5.44 mmol/l (0.11), −26.25% change; gemfibrozil 6.20 mmol/l (0.12),− 15.18% change; combination 5.10 mmol/l (0.12), −28.98% change. LDL: Placebo 5.02 mmol/l (0.13), −1.88% change; pravastatin 3.44 mmol/l (0.11), − 33.54% change; gemfibrozil 4.29 mmol/l (0.11),−16.80% change; combination 3.17 mmol/l (0.10), − 37.06% change. VLDL: Placebo 0.65 mmol/l (0.05), +2.17% change; pravastatin .49 mmol/l (0.04), −21.85% change; gemfibrozil 0.32 mmol/l (0.02),− 49.06% change; combination 0.32 mmol/l (0.03), −49.43 % change. TG: Placebo 1.83 mmol/l (0.10), +1.87% change; pravastatin 1.53 mmol/l (0.08), − 14.17% change; gemfibrozil 1.03 mmol/l (0.05),−42.16% change; combination 1.01 mmol/l (0.06), − 41.68 %change. HDL: Placebo 1.16 mmol/l (0.03), −4.44% change; pravastatin 1.32 mmol/l (0.04), −5.93% change; gemfibrozil 1.39 mmol/l (0.04),15.21% change; combination 1.46 mmol/l (0.05), 16.81% change. Apo A : Placebo 1.37 mmol/l (0.04), − 2.82% change; pravastatin 1.50 mmol/l (0.04), −3.33% change; gemfibrozil 1.49 mmol/l (0.04),5.07% change; combination 1.53 mmol/l (0.05), 5.73 change. Apo B: Placebo 1.61 mmol/l (0.06), −1.81% change; pravastatin 1.13 mmol/l (0.04), −28.76% change; gemfibrozil 1.37 mmol/l (0.04),− 15.29% change; combination 1.06 mmol/l (0.04), −31.61% change.Swedish Medical Research Council, the Swedish Heart and Lung Foundation, the King Gustav V and Queen Victoria Foundation and the Bristol Myers Squibb CompanySafety3-11
A total of 93 patients reported 162 adverse events. The overall frequency did not differ significantly between the groups. 13 patients left the study because of clinical adverse events or asymptomatic elevations in CK (2 patients both receiving combination therapy).
This study shows that when compared with placebo, pravastatin, gemfibrozil and their combination significantly (p<0.01) reduced TC, LDL, VLDL and TG and also increased HDL significantly (p<0.01). C more (p<0.01) than gemfibrozil alone and reduced TG and VLDL and increased HDL (p<0.01) more than pravastatin.The effect appears to be due to the intervention.YesYesIt appears that no account was taken of the 24 drop outs.

From: Appendix C, Clinical data extractions and excluded studies

Cover of Identification and Management of Familial Hypercholesterolaemia (FH)
Identification and Management of Familial Hypercholesterolaemia (FH) [Internet].
NICE Clinical Guidelines, No. 71.
National Collaborating Centre for Primary Care (UK).
Copyright © 2008, Royal College of General Practitioners.

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