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Smith MEB, Lee NJ, Haney E, et al. Drug Class Review: HMG-CoA Reductase Inhibitors (Statins) and Fixed-dose Combination Products Containing a Statin: Final Report Update 5 [Internet]. Portland (OR): Oregon Health & Science University; 2009 Nov.

Cover of Drug Class Review: HMG-CoA Reductase Inhibitors (Statins) and Fixed-dose Combination Products Containing a Statin

Drug Class Review: HMG-CoA Reductase Inhibitors (Statins) and Fixed-dose Combination Products Containing a Statin: Final Report Update 5 [Internet].

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Children

Key Question 1. How do statins and fixed-dose combination products containing a statin and another lipid-lowering drug compare in their ability to reduce low-density lipoprotein cholesterol?

Summary of findings

  • Trials of statins in children have been conducted primarily in children with heterozygous or homozygous familial hypercholesterolemia, or other familial dyslipidemias.
  • Eight trials of various statins showed improvement in low-density lipoprotein compared with placebo.
  • In meta-analysis, statins reduced low-density lipoprotein cholesterol in children taking a statin by 32% (95% CI, 37 to 26).
  • One trial compared ezetimibe/simvastatin to simvastatin alone and demonstrated a 54% reduction in low-density lipoprotein cholesterol for combination compared to 38% reduction for simvastatin alone.

Key Question 1a. Are there doses for each statin or fixed-dose combination product containing a statin and another lipid-lowering drug that produce similar percent reduction in low-density lipoprotein cholesterol?

All the trials of statin drugs compared to placebo, including 1 trial of atorvastatin 285 2 of lovastatin,286, 287 2 of pravastatin,288, 289 and 3 of simvastatin,290–292 demonstrated improvement in total cholesterol and low-density lipoprotein cholesterol among children and adolescents with familial hypercholesterolemia. For all trials, the change in total cholesterol ranged from −17% to −32% from baseline for treatment groups compared with changes of +3.6% to −2.3% for placebo groups. The decreases in low-density lipoprotein cholesterol ranged from 19% to 41% for treatment groups compared with changes of +0.67% to −3% for placebo groups.

The 1 trial of atorvastatin compared to rosuvastatin included patients with homozygous familial hypercholesterolemia. Eight of the 44 patients enrolled were under age 18 and results were not separated out by age group. The trial started with open label dose titration of rosuvastatin for 18 weeks and then randomized patients to atorvastatin or rosuvastatin (both at 80 mg/day doses) in a crossover design for 6 weeks. After the first 18-week dose titration phase, there was a 21% difference in low-density lipoprotein cholesterol levels compared to baseline (P<0.0001). At the end of the first 6-week period of the crossover phase there was no difference in low-density lipoprotein cholesterol from baseline between groups (19% decrease for rosuvastatin 80 mg/day and 18% decrease for atorvastatin 80 mg/day).293

We conducted a meta-analysis of the percent change from baseline in low-density lipoprotein levels in placebo-controlled trials (Figure 2). Seven trials provided sufficient information to be included in the meta-analysis (mean percent change from baseline and standard deviation, or data to calculate these).285–289, 291, 292 Of these, 1 was rated good quality,286 1 was rated poor quality,291 and the rest were fair quality. A sensitivity analysis excluding the poor quality study did not change results of the meta-analysis. One study included atorvastatin,285 2 lovastatin,286, 287 2 pravastatin,288, 289 and 2 simvastatin.291, 292 The meta-analysis included 472 patients taking a statin and 320 taking a placebo. Overall, statins reduced low-density lipoprotein cholesterol in children taking a statin by 32% (95% CI, 37 to 26). The mean percent change from baseline was greater for atorvastatin (10 mg) and simvastatin (40 mg) than lovastatin (40 mg) and pravastatin (20 to 40 mg). These results are similar to percent reductions seen in adults at these doses. With the exception of pravastatin 20 to 40 mg compared with simvastatin 40 mg, confidence intervals for the different statins overlapped, suggesting similar percent low-density lipoprotein cholesterol lowering. However, because this body of evidence is indirect, and studies were heterogenous, it cannot be used to draw strong conclusions about the comparative effectiveness of the different statins.

Figure 2. Low-density lipoprotein cholesterol lowering in placebo-controlled trials of statins in children with familial hypercholesterolemia.

Figure 2

Low-density lipoprotein cholesterol lowering in placebo-controlled trials of statins in children with familial hypercholesterolemia.

Key Question 1b. Do statins or fixed-dose combination product containing a statin and another lipid-lowering drug differ in the ability to achieve National Cholesterol Education Program goals?

National Cholesterol Education Panel goals for children were updated in 2007.294 In that guideline statement, treatment is considered for children 10 years of age or greater, preferably after the onset of menses in girls and ideally after children have reached Tanner stage II or higher. Age and low-density lipoprotein level at which statin therapy is initiated is subject to judgment about presence of risk factors that suggest familial hypercholesterolemia such as cutaneous xanthomas. Authors suggest that patient and family preferences should be considered in decision-making.294

In the only study of simvastatin compared to fixed dose ezetimibe/simvastatin combination (10 mg/40 mg), low-density lipoprotein cholesterol was reduced from a mean of 114 mg/dL to a mean of 103 mg/dL (change of 54%) in the ezetimibe/simvastatin group and reduced from a mean of 144 mg/dL to a mean of to 135 mg/dL (change of 38%) in the simvastatin group.295 At the end of 33 weeks, the percentage of subjects achieving a low-density lipoprotein cholesterol <130 mg/dL were 77% in the ezetimibe/simvastatin group and 53% in the simvastatin group (P<0.01); the number of subjects achieving a low-density lipoprotein cholesterol level <110 mg/dL were 63% in the ezetimibe/simvastatin group and 27% in the simvastatin group (P<0.01).295

Key Question 2. How do statins and fixed-dose combination products containing a statin and another lipid lowering drug compare in their ability to raise high-density lipoprotein cholesterol?

Summary of findings

  • Statins decreased high-density lipoprotein cholesterol in 1 study of atorvastatin and did not change high-density lipoprotein cholesterol in 5 other trials of statins including rosuvastatin, simvastatin, lovastatin, and pravastatin.
  • Overall, the pooled result indicated that statins increased high-density lipoprotein cholesterol by 3% (95% CI, 0.6 to 5.6).

Key Question 2b. Are there doses for each statin or fixed-dose combination product containing a statin and another lipid lower drug that produce similar percent increase in high-density lipoprotein cholesterol between statins?

High-density lipoprotein cholesterol decreased in the 1 trial of atorvastatin285 but did not change in 2 trials of lovastatin,286, 287 1 trial of pravastatin that reported high-density lipoprotein cholesterol,288 and 2 trials of simvastatin.291, 292 Overall, high-density lipoprotein cholesterol increased +1% to +11% for treatment groups compared with –1% to +4.8% for placebo groups.

The trial of atorvastatin compared to rosuvastatin started with open-label dose titration of rosuvastatin for 18 weeks and then randomized patients to atorvastatin or rosuvastatin (both at 80 mg/day doses) in a crossover design for 6 weeks. Eight of 44 patients enrolled in the trial were under age 18; results were not separated out by age group. At the end of the initial dose titration phase (18 weeks) there was no significant difference in high-density lipoprotein levels compared with baseline (3.1% increase in the rosuvastatin group, not significant). After 6 weeks of the crossover comparison phase (prior to crossover), there was no difference between groups in the change in high-density lipoprotein cholesterol from baseline (2.5% increase for rosuvastatin 80 mg/day and 4.9% decrease for atorvastatin 80 mg/day, P=0.24).293

The 1 trial that evaluated simvastatin compared to fixed-dose ezetimibe/simvastatin combination (10 mg/40 mg) demonstrated no change in high-density lipoprotein cholesterol.295

We conducted a random-effects meta-analysis of placebo-controlled trials reporting the change from baseline in high-density lipoprotein cholesterol levels in children with familial hypercholesterolemia (Figure 3). Seven trials contributed data to the meta-analysis,285–289, 291, 292 representing 472 patients taking a statin and 320 taking a placebo. Results are shown in Figure 3. Overall, the pooled result indicated that statins increased high-density lipoprotein cholesterol by 3% (95% CI, 0.6 to 5.6). Among the individual statins, only pravastatin significantly increased high-density lipoprotein cholesterol, with a 5% change (95% CI, 0.1 to 9.7). The mean difference from placebo was nonsignificant for the other statins.

Figure 3. High-density lipoprotein cholesterol increases in placebo-controlled trials of statins in children with familial hypercholesterolemia.

Figure 3

High-density lipoprotein cholesterol increases in placebo-controlled trials of statins in children with familial hypercholesterolemia.

Key Question 3. How do statins and fixed-dose combination products containing a statin and another lipid lowering drug compare in their ability to reduce the risk of nonfatal myocardial infarction, coronary disease (angina), coronary heart disease mortality, all-cause mortality, stroke, hospitalization for unstable angina, or need for revascularization (coronary artery bypass graft, angioplasty, or stenting)?

Summary of findings

  • Studies of statins in children have not been conducted with long enough follow-up to assess for outcomes related to cardiovascular mortality and morbidity.

Detailed assessment

Nonfatal myocardial infarction, coronary disease (angina), coronary heart disease mortality, all-cause mortality, stroke, hospitalization for unstable angina, or need for revascularization (coronary artery bypass graft, angioplasty, or stenting) are outcomes that occur primarily in adults. There were no studies in children that had sufficient follow-up to determine the effect of treatment with statin or fixed-dose combination products containing a statin and another lipid-lowering drug on the risk of these outcomes. However, it is generally assumed by the specialists in this area that treatment of children with familial hypercholesterolemia does postpone or prevent the onset of early cardiovascular disease. As a surrogate end-point, trials have demonstrated the effect of statins on intima-medial thickness, arterial stiffness, and endothelial function.289

Key Question 4. Are there differences in effectiveness of statins and fixed-dose combination products containing a statin and another lipid lowering drug in different demographic groups or in patients with comorbid conditions (e.g. diabetes, obesity)?

Summary of findings

  • No trials have evaluated statins in children with diabetes or obesity. One study demonstrated 21% reduction in low-density lipoprotein with simvastatin in children with neurofibromatosis 1.

Detailed assessment

We identified no trials of statins and fixed-dose combination products in children with diabetes or obesity. One study of simvastatin compared to placebo in children with neurofibromatosis 1 demonstrated a reduction in low-density lipoprotein cholesterol (21% for simvastatin; low-density lipoprotein reduction for placebo group not reported) but no change in high-density lipoprotein.296

Key Question 5. Are there differences in the harms of statins or fixed-dose combination products containing a statin and another lipid lowering drug when used in the general population of children?

Summary of findings

  • Adverse events were variably reported; methods of detection and assessment of adverse events were often not specified.
  • Multiple studies reported no significant elevations in both creatine kinase and aspartate aminotransferase/alanine aminotransferase over the course of the study.
  • Elevations in aspartate aminotransferase/alanine aminotransferase occurred but were either lower than 3 times the upper limit of normal or resolved with interruption/discontinuation of medication.
  • Elevations in creatine kinase occurred with simvastatin and simvastatin plus ezetimibe; all returned to normal with cessation of medication.

Detailed assessment

Information on harms of statins and fixed-dose combination products in children was obtained from randomized-controlled trials, controlled clinical trials, non-controlled case series, and case reports. Data on adverse events from clinical trials is variably reported; methods for detection and assessment of the adverse events were often not specified.

Several studies reported that aspartate aminotransferase and alanine aminotransferase remained below twice or 3 times the upper limit of normal. This was true for 24–48 weeks of treatment lovastatin,286, 287 28 weeks of simvastatin,291 and 12 weeks to 2 years of treatment with pravastatin.288, 289, 297 Reports of elevations in transaminases occurred with atorvastatin,285 simvastatin-ezetimibe combinations,295 and rosuvastatin (in a trial that included both adults and children with homozygous familial hypercholesterolemia).293 In studies that reported increased transaminase levels during statin treatment, these levels returned to normal with treatment interruption or discontinuation of the statin.285, 291, 295

Similarly, multiple studies reported no significant elevations in creatine kinase over the study period.285–287, 289, 293 One study reported a 1.6% incidence of creatine kinase elevation (>10 times the upper limit of normal) in the treatment (simvastatin plus ezetimibe) group compared to 9% in the control group (simvastatin alone).295 Another study reported a single child with creatine kinase elevation (>10 times the upper limit of normal) without muscled symptoms, which occurred with concomitant administration of simvastatin and erythromycin and returned to normal after completion of the antibiotics, and 2 children with increases in creatine kinase (>5-fold the upper limit of normal) that returned to normal in repeat tests.292

Several studies also cited “no significant” or “no serious” adverse events, or even “no adverse events”.286, 291, 298 Such statements in these studies lack rigorous definitions of the methods used to monitor for and detect adverse events. Other studies stated that the incidence of reporting any adverse events was equal between the treatment and control (placebo) groups287, 288, 291 or reported the incidence of adverse events to demonstrate that point.285, 292, 295 Treatment-related adverse effects were reported as 8.6% for lovastatin compared with 5% for placebo;286 4.7% compared with 3.4% (clinical) and 1.2% compared with 1.7% (laboratory);288 18.2% for rosuvastatin in the open-label titration period and in the crossover period; and 2.6% for atorvastatin compared with 0% for rosuvastatin.293

Key Question 6. Are there differences in the harms of statins or fixed-dose combination products containing a statin and another lipid lowering drug when used in special populations or with other medications (drug-drug interactions)?

Summary of findings

  • One study of fluvastatin in children with minimal change glomerulonephritis demonstrated decrease in total cholesterol and reported no side effects.

Detailed assessment

One study of children with minimal change glomerulonephritis (MCGN) assigned 36 patients to 20 mg of fluvastatin or dipyridamole for 2 years.299 The main study outcome was bone mineral density, for which there was no change over the course of the study. Hematuria decreased significantly, and creatinine clearance, total protein, and albumin increased compared to baseline in the statin group, but not the dipyridamole group. Total cholesterol decreased from 4.43±0.57 mmol/L to 3.68±0.52 mmol/L and triglycerides decreased from 1.04±0.57 g/L to 0.66±0.26 g/L (P<0.001 compared with baseline for both; P>0.001 compared with dipyridamole for both after treatment). The authors observed no side effects in any of the patients over the treatment period.

Copyright © 2009, Oregon Health & Science University, Portland, Oregon.
Bookshelf ID: NBK47279

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