Fluvastatin for lowering lipids

Stephen P Adams; Sarpreet S Sekhon; Michael Tsang; James M Wright

doi:10.1002/14651858.CD012282.pub2

. 2018 Mar 6;2018(3):CD012282. doi: 10.1002/14651858.CD012282.pub2

Fluvastatin for lowering lipids

Stephen P Adams ^1,^✉, Sarpreet S Sekhon ¹, Michael Tsang ², James M Wright ¹

Editor: Cochrane Hypertension Group

PMCID: PMC6494196 PMID: 29508377

Abstract

Background

Fluvastatin is thought to be the least potent statin on the market, however, the dose‐related magnitude of effect of fluvastatin on blood lipids is not known.

Objectives

Primary objective  To quantify the effects of various doses of fluvastatin on blood total cholesterol, low‐density lipoprotein (LDL cholesterol), high‐density lipoprotein (HDL cholesterol), and triglycerides in participants with and without evidence of cardiovascular disease.

Secondary objectives  To quantify the variability of the effect of various doses of fluvastatin.    To quantify withdrawals due to adverse effects (WDAEs) in randomised placebo‐controlled trials.

Search methods

The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to February 2017: the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 1), MEDLINE (1946 to February Week 2 2017), MEDLINE In‐Process, MEDLINE Epub Ahead of Print, Embase (1974 to February Week 2 2017), the World Health Organization International Clinical Trials Registry Platform, CDSR, DARE, Epistemonikos and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. No language restrictions were applied.

Selection criteria

Randomised placebo‐controlled and uncontrolled before and after trials evaluating the dose response of different fixed doses of fluvastatin on blood lipids over a duration of three to 12 weeks in participants of any age with and without evidence of cardiovascular disease.

Data collection and analysis

Two review authors independently assessed eligibility criteria for studies to be included, and extracted data. We entered data from placebo‐controlled and uncontrolled before and after trials into Review Manager 5 as continuous and generic inverse variance data, respectively. WDAEs information was collected from the placebo‐controlled trials. We assessed all trials using the 'Risk of bias' tool under the categories of sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other potential biases.

Main results

One‐hundred and forty‐five trials (36 placebo controlled and 109 before and after) evaluated the dose‐related efficacy of fluvastatin in 18,846 participants. The participants were of any age with and without evidence of cardiovascular disease, and fluvastatin effects were studied within a treatment period of three to 12 weeks. Log dose‐response data over doses of 2.5 mg to 80 mg revealed strong linear dose‐related effects on blood total cholesterol and LDL cholesterol and a weak linear dose‐related effect on blood triglycerides. There was no dose‐related effect of fluvastatin on blood HDL cholesterol. Fluvastatin 10 mg/day to 80 mg/day reduced LDL cholesterol by 15% to 33%, total cholesterol by 11% to 25% and triglycerides by 3% to 17.5%. For every two‐fold dose increase there was a 6.0% (95% CI 5.4 to 6.6) decrease in blood LDL cholesterol, a 4.2% (95% CI 3.7 to 4.8) decrease in blood total cholesterol and a 4.2% (95% CI 2.0 to 6.3) decrease in blood triglycerides. The quality of evidence for these effects was judged to be high. When compared to atorvastatin and rosuvastatin, fluvastatin was about 12‐fold less potent than atorvastatin and 46‐fold less potent than rosuvastatin at reducing LDL cholesterol. Very low quality of evidence showed no difference in WDAEs between fluvastatin and placebo in 16 of 36 of these short‐term trials (risk ratio 1.52 (95% CI 0.94 to 2.45).

Authors' conclusions

Fluvastatin lowers blood total cholesterol, LDL cholesterol and triglyceride in a dose‐dependent linear fashion. Based on the effect on LDL cholesterol, fluvastatin is 12‐fold less potent than atorvastatin and 46‐fold less potent than rosuvastatin. This review did not provide a good estimate of the incidence of harms associated with fluvastatin because of the short duration of the trials and the lack of reporting of adverse effects in 56% of the placebo‐controlled trials.

Plain language summary

Fluvastatin for lowering lipids

Review question

What is the effect of various doses of fluvastatin on blood lipids?

The effects of various doses of fluvastatin on blood lipids were quantified in 145 studies.

Background

Fluvastatin is thought to be the least potent statin but the precise dose‐related effect of fluvastatin on lipids is unknown. It would be interesting to know how much fluvastatin lowers blood lipids in the 145 studies retrieved.

Search date

The evidence is current to February 2017.

Study characteristics

Randomised placebo‐controlled and uncontrolled before and after trials of different fixed doses of fluvastatin. The studies were of three to 12 weeks duration.

Participants could be of any age and gender with or without evidence of cardiovascular disease.

One‐hundred and forty‐five included trials involved 18,846 participants.

Key results

Fluvastatin 10 mg/day to 80 mg/day reduced LDL cholesterol by 15% to 33%. There were strong linear dose‐related effects on blood total cholesterol and LDL cholesterol and a weak linear dose‐related effect on blood triglycerides. There was no dose‐related effect of fluvastatin on blood HDL cholesterol.

Based on the effect on LDL cholesterol, fluvastatin is 12‐fold less potent than atorvastatin and 46‐fold less potent than rosuvastatin.

Of the 36 placebo‐controlled trials only 16 reported withdrawals due to adverse effects (WDAEs). WDAEs were higher, risk ratio 1.52 (95% confidence interval (CI) 0.94 to 2.45), demonstrating uncertainty, but the possibility of an increase in adverse effects.

Quality of the evidence

The quality of evidence was high for the lipid levels. For WDAEs the quality of evidence was very low because 20 (55.6%) out of 36 placebo‐controlled trials did not report WDAEs.

Summary of findings

Background

Description of the condition

Cardiovascular disease is the major cause of death and disability in the developed world (Eisenberg 1998). Existing evidence shows a weak association in young adults between adverse cardiovascular events and concentration of total cholesterol or low‐density lipoprotein (LDL) cholesterol in the serum (NCEP 1993).

The current recommended treatment for secondary prevention of adverse cardiovascular events after diet and lifestyle changes is drug therapy with the drug class widely known as "statins".

Description of the intervention

Fluvastatin is the least potent widely prescribed statin in the world. Fluvastatin and the seven other statins are prescribed to prevent adverse cardiovascular events and to lower total cholesterol and LDL cholesterol. Importantly, statins have been shown in individual randomised controlled trials (RCTs), and in a systematic review and meta‐analysis of RCTs to reduce mortality and major vascular events in people with occlusive vascular disease (CTT 2005).

How the intervention might work

Statins act on the liver by inhibiting the rate‐limiting enzyme for cholesterol synthesis, 3‐hydroxy‐3‐methyl‐glutaryl‐CoA (HMG Co‐A) reductase. This enzyme is the first step in a sequence of reactions resulting in the production of cholesterol and its derivatives, LDL cholesterol and very low‐density lipoprotein (VLDL cholesterol) particles. The prevailing hypothesis is that statins reduce mortality and morbidity in people with occlusive vascular disease by reducing the production of cholesterol. However, the HMG Co‐A reductase enzyme is also responsible for the production of coenzyme Q₁₀, vitamin D, steroid hormones, and many other compounds. It therefore remains possible that the beneficial effects of statins are due to an action other than the reduction of cholesterol, often referred to as the pleiotropic effects of statins (Liao 2005).

Most important for this review is the fact that a fasting blood lipid profile consisting of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides is used clinically to monitor the effect of a prescribed statin. The outcome therefore in this review, presented as the percentage reduction in the five serum lipids, represents the best available pharmacological marker of the magnitude of the statin effect.

Why it is important to do this review

Statins are the most widely prescribed class of drugs in the world. Statin prescribing and the average prescribed doses are increasing. Clinicians currently have an approximate sense of the different potency of the different statins, but a systematic assessment of the potency, the slope of the dose‐response relationship, and the variability of the effect has not been completed for any of the statins. It is possible that in addition to differences in potency, the slope of the dose‐response relationship or the variability of response differs between different statins. A small number of previous systematic reviews have assessed the effect of statins on serum lipids (Bandolier 2004; Edwards 2003; Law 2003; Ward 2007). They have demonstrated that different statins have different potencies in terms of lipid lowering, and that higher doses of statins cause greater lowering of serum lipids than lower doses (Kellick 1997; Schaefer 2004; Schectman 1996). However, none of these systematic reviews has calculated the slope of the dose response or the variability of effect, and none of them is up‐to‐date. The most comprehensive systematic review to date (Law 2003) has the limitation that it presents the data based on the average reduction in LDL cholesterol concentration rather than on the percentage reduction from baseline. The purpose of our systematic review is to build on Law's work. Since fluvastatin is the least potent statin, we have chosen this as the third drug to study in this class, to complement the reviews we published on the lipid‐lowering efficacy of atorvastatin (Adams 2014) and rosuvastatin (Adams 2015). We used the surrogate marker to measure the pharmacological effect of statins, the percentage reduction from baseline, to describe the dose‐response relationship of the effect of fluvastatin on total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides. We plan to use the methodology established for atorvastatin (Adams 2014) and rosuvastatin (Adams 2015) to study the other drugs in the class (cerivastatin, lovastatin, pravastatin, simvastatin, and pitavastatin) in subsequent reviews, and to compare the results with fluvastatin, rosuvastatin and atorvastatin.

Objectives

Primary objective

To quantify the effects of various doses of fluvastatin on the surrogate markers: blood total cholesterol, LDL cholesterol, triglycerides and HDL cholesterol in people with and without evidence of cardiovascular disease.

We recognise that the outcomes important to patients are mortality and cardiovascular morbidity, however, that is not the objective of this systematic review. We want to learn more about the pharmacology of fluvastatin by characterising the dose‐related effect and variability of the effect of fluvastatin on the surrogate markers.

Secondary objective

To quantify the variability of the effect of various doses of fluvastatin on withdrawals due to adverse effects (WDAEs).

Methods

Criteria for considering studies for this review

Types of studies

Randomised placebo‐controlled trials. We have also included uncontrolled before and after trials because it has been shown that there is no placebo effect of statins on lipid parameters. Therefore in this case a placebo control is not essential (Tsang 2002). We did not include cross‐over trials, but if the outcomes were reported for the parallel arms prior to the cross‐over we did include that data.

Types of participants

Participants could be of any age, with and without evidence of cardiovascular disease. They could have normal lipid parameters or any type of hyperlipidaemia or dyslipidaemia. We accepted participants with various comorbid conditions, including type 2 diabetes mellitus, hypertension, metabolic syndrome, chronic renal failure or cardiovascular disease.

Types of interventions

Fluvastatin must have been administered at a constant daily dose compared to placebo or alone for a period of three to 12 weeks. We have chosen this administration time window to allow at least three weeks for a steady‐state effect of fluvastatin to occur and to keep it short enough to minimise participants dropping out. We included studies where fluvastatin was administered once daily in the morning or evening, twice daily or where it was not specified. Trials required a washout baseline dietary stabilisation period of at least three weeks, where all previous lipid‐altering medication was withdrawn. This baseline phase ensured participants follow a standard lipid‐regulating diet and helped to stabilise baseline lipid values prior to treatment. In trials where participants were not receiving lipid‐altering medications or dietary supplements before receiving the test drug, we did not require washout baseline dietary stabilisation periods.

Types of outcome measures

Fluvastatin 10 mg/day, 20 mg/day, 40 mg/day and 80 mg/day are the doses predominantly prescribed. Because of this and because most of the trials studied these doses we have presented these doses in the 'Summary of findings' tables.

Lipid parameters: For the placebo‐controlled trials we present the mean percentage change from baseline for different doses of fluvastatin minus the mean percentage change from baseline with placebo for each of the lipid parameters below. For the before and after trials we present the mean percentage change from baseline of different doses of fluvastatin. RCT data and before and after data were combined because it was shown for most data that there was a lack of difference in the mean differences between the two types of studies.

Primary outcomes

LDL cholesterol.

Secondary outcomes

Total cholesterol.
HDL cholesterol.
Triglycerides.
End of treatment variability (standard deviation (SD)) and coefficient of variation of LDL cholesterol measurements for each dose of fluvastatin. It is important to know whether fluvastatin has an effect on the variability of lipid measures and ultimately to compare this with the effect of other statins.
Withdrawals due to adverse effects (WDAEs) limited to the placebo‐controlled trials.

Search methods for identification of studies

Electronic searches

The Cochrane Hypertension Information Specialist conducted systematic searches in the following databases for randomised controlled trials (RCTs) without language, publication year or publication status restrictions:

the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies (CRS‐Web) (searched 10 February 2017);
MEDLINE Ovid (1946 to February Week 2 2017), MEDLINE Ovid Epub Ahead of Print, and MEDLINE Ovid In‐Process & Other Non‐Indexed Citations (searched 10 February 2017);
Embase Ovid (searched 10 February 2017);
ClinicalTrials.gov (www.clinicaltrials.gov) searched 10 February 2017);
World Health Organization International Clinical Trials Registry Platform (www.who.int/trialsearch) searched 10 February 2017).

The Information Specialist modelled subject strategies for databases on the search strategy designed for MEDLINE. We present search strategies for major databases in Appendix 1.

Searching other resources

The Cochrane Hypertension Information Specialist searched the Cochrane Database of Systematic Reviews (CDSR) via Wiley, the Database of Abstracts of Reviews of Effects (DARE) via Wiley, and Epistemonikos to retrieve existing systematic reviews relevant to this systematic review, so that we could scan their reference lists for additional trials.
We checked the bibliographies of included studies and any relevant systematic reviews identified for further references to relevant trials.
We contacted experts/organisations in the field to obtain additional information on relevant trials.
We contacted original authors for clarification and further data if trial reports were unclear.
We performed an initial search of Web of Science on 4 April 2016 and omitted this database from subsequent searches, as it did not yield any unique included studies.

We included grey literature by searching other resources:

ProQuest Dissertations and Theses (search.proquest.com/pqdtft/);
Novartis (www.novartis.ca/products/en/pharmaceuticals‐az.shtml);
US Food and Drug Administration (www.fda.gov/);
European Patent Office (worldwide.espacenet.com.

Data collection and analysis

Selection of studies

Initial selection of trials involved retrieving and reading the titles and abstracts of each paper found from the electronic search databases or bibliographic citations. We have provided a PRISMA flow diagram (Figure 1). Two review authors (SA and SS) analysed the full‐text papers independently, to decide on the trials to be included. We resolved disagreements by recourse to a third review author (JMW). Two review authors (SA and SS) independently extracted the appropriate data from each of the included trials. If there was disagreement over a value, we reached consensus by data recalculation to determine the correct value.

Data extraction and management

We directly extracted the mean percentage change from the data or calculated it from the baseline and endpoint values. We added the calculated data to the Data and analyses section of the review. When the calculated data differed from the given data by more than 10%, we judged the data set as not being reliable and these data were not included in the review. We extracted standard deviations (SDs) and standard errors (SEs) from the report or calculated them when possible. We entered data from placebo‐controlled and uncontrolled before and after trials into Review Manager 5 (RevMan 2014) as continuous and generic inverse variance data, respectively.

Assessment of risk of bias in included studies

We assessed all trials using the 'Risk of bias' tool under the categories of adequate sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other potential biases. We appreciate that the first three items are inappropriate for before and after trials and that this is a limitation. However, because the lipid parameters were measured in a remote laboratory they were considered unlikely to be affected by the trial design. We produced 'Risk of bias' tables' as outlined in the Cochrane Handbook for Systematic Reviews of Interventions, Chapter 8 (Higgins 2011).

Measures of treatment effect

We analysed the treatment effects as mean difference for each dose in the placebo‐controlled RCTs and generic inverse variance for each dose in the before and after uncontrolled trials separately. In the event that the mean effects from the two trial designs were not different, we re‐analysed all efficacy study data using the generic inverse variance to determine the overall weighted treatment effects and their 95% confidence intervals (CIs) for serum total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides.

Unit of analysis issues

The unit of analysis is the mean values for the people completing the trial for each trial. We expected follow‐up to be reasonably high for these short‐term trials. The data however represent treatment efficacy and not real‐world effectiveness of fluvastatin on these lipid parameters.

Dealing with missing data

When data were missing, we requested them from the authors. The most common type of value that was not reported was the SD of the change.

In the case of a missing SD for the change in lipid parameters, we imputed the SD using the following hierarchy (listed from high to low preference).

SD calculated either from the t statistics corresponding to the exact P value reported or from the 95% CI of the mean difference between treatment groups.
Average weighted SD of the change from other trials in the review (Furukawa 2006).

Because it is common for the SD to be miscalculated, and in order not to overweight trials where it is inaccurately calculated and lower than expected, when SD values were less than 40% of the average weighted SDs, we used the imputed value by the method of Furukawa (Furukawa 2006).

Assessment of heterogeneity

The Chi² test to identify heterogeneity is not appropriate because it has low power when there are few studies, but has excessive power to detect clinically unimportant heterogeneity when there are many studies. The I² is a better statistic. The I² calculates between‐study variance/(between‐study variance + within‐study variance). This measures the proportion of total variation in the estimate of the treatment effect that is due to heterogeneity between studies. This statistic is also independent of the number of studies in the analysis (Higgins 2002).

Assessment of reporting biases

We assessed publication bias using funnel plots, as outlined in the Cochrane Handbook for Systematic Reviews of Interventions, Chapter 10 (Sterne 2011).

Data synthesis

We entered all placebo‐controlled studies into Review Manager 5 (RevMan 2014) as mean difference fixed‐effect model data to determine the weighted treatment effect and 95% CIs for serum total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides. We entered all uncontrolled before and after studies as generic inverse variance fixed‐effect model data to determine the weighted treatment effect. If the effect in the placebo‐controlled trials was not statistically significantly different from the before and after trials, we entered all trials for each dose as generic inverse variance to determine the best overall weighted treatment effect for each dose.

If an I² was ≥50%, we used the random‐effects model to assess whether the pooled effect was statistically significant.

We recorded trial data of each study and dose in GraphPad Prism 4, to yield a weighted least squares analysis based on the inverse of the square of the standard error (SE) for each lipid parameter, to generate weighted log dose response curves. We entered the number of participants in placebo‐controlled trials who prematurely withdrew due to at least one adverse effect in Review Manager 5 (RevMan 2014) as dichotomous data for each dose and all combined doses of fluvastatin.

The relative potency of fluvastatin with respect to atorvastatin and rosuvastatin, was determined as the ratio of the milligram (mg) amount of fluvastatin to the mg amount of atorvastatin or rosuvastatin needed to produce the same specified effect. These values were calculated from the log dose response curves of fluvastatin, atorvastatin and rosuvastatin for total cholesterol, LDL cholesterol and triglycerides. The relative potencies were estimated from these dose ratios.

Data presentation ‐ ’Summary of findings’ tables

We used the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to assess the quality of the supporting evidence behind each estimate of treatment effect (Schünemann 2011a; Schünemann 2011b). We presented key findings of the review, including a summary of the amount of data, the magnitude of the effect size and the overall quality of the evidence, in Table 1. We preselected the following outcomes: LDL cholesterol lowering efficacy of fluvastatin (by dose), and WDAEs.

for the main comparison.

LDL cholesterol lowering efficacy of fluvastatin
Patient or population: participants with normal or abnormal lipid profiles Settings: ambulatory care Intervention: fluvastatin Comparison: LDL cholesterol percentage change from baseline for all trials
Outcomes	Anticipated absolute effects mmol/L (95%CI)		Percent reduction  (95% CI) %	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments

	Before exposure to fluvastatin¹	After exposure to fluvastatin
LDL‐cholesterol fluvastatin 10 mg/day	4.81 (4.44 to 5.17)	4.08 (3.98 to 4.16)	15.2 (17.1 to 13.4)	595  (6)	⊕⊕⊕⊕  high	Effect predicted from log dose‐response equation is 14.8%. Randomised and before and after design not different P = 0.94.
LDL‐cholesterol fluvastatin 20 mg/day	4.87 (4.54 to 5.21)	3.90 (3.88 to 3.91)	20.0 (19.7 to 20.3)	9010  (55)	⊕⊕⊕⊕  high	Effect predicted from log dose‐response equation is 20.8%. Randomised and before and after design not different P = 0.16.
LDL‐cholesterol fluvastatin 40 mg/day	4.74 (4.41 to 5.06)	3.51 (3.48 to 3.54)	25.9 (25.3 to 26.5)	3658  (57)	⊕⊕⊕⊕  high	Effect predicted from log dose‐response equation is 26.8%. Randomised and before and after design not different P = 0.58.
LDL‐cholesterol fluvastatin 80 mg/day	4.80 (4.47 to 5.13)	3.13 (3.10 to 3.15)	34.9 (35.5 to 34.3)	4928  (32)	⊕⊕⊕⊕  high	Effect predicted from log dose‐response equation is 32.8%. Randomised and before and after design not different P = 0.07.
CI: Confidence interval
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Total cholesterol lowering efficacy of fluvastatin
Patient or population: participants with normal or abnormal lipid profiles Settings: ambulatory care Intervention: fluvastatin Comparison: Total cholesterol percentage change from baseline for all trials
Outcomes	Anticipated absolute effects mmol/L (95%CI)		Percent reduction  (95% CI) %	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments

	Before exposure to fluvastatin¹	After exposure to fluvastatin
Total cholesterol fluvastatin 10 mg/day	6.90 (6.47 to 7.33)	6.16 (6.02 to 6.30)	10.7 (12.7 to 8.6)	287  (4)	⊕⊕⊕⊕  high	Effect predicted from log dose‐response equation is 10.9%. Randomised and before and after design not different P = 0.86.
Total cholesterol fluvastatin 20 mg/day	6.99 (6.61 to 7.37)	5.96 (5.94 to 5.98)	14.8 (15.1 to 14.5)	6309  (50)	⊕⊕⊕⊕  high	Effect predicted from log dose‐response equation is 15.2%. Randomised versus before and after design borderline different P = 0.044.
Total cholesterol fluvastatin 40 mg/day	6.91 (6.54 to 7.27)	5.60 (5.57 to 5.64)	18.9 (19.3 to 18.4)	2966  (55)	⊕⊕⊕⊕  high	Effect predicted from log dose‐response equation is 19.4%. Randomised and before and after design not different P = 0.106.
Total cholesterol fluvastatin 80 mg/day	6.97 (6.62, 7.32)	5.24 (5.12 to 5.27)	24.9 (25.5 to 24.4)	3943  (27)	⊕⊕⊕⊕  high	Effect predicted from log dose‐response equation is 23.6%. Randomised and before and after design not different P = 0.595.
CI: Confidence interval
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Triglyceride lowering efficacy of fluvastatin
Patient or population: participants with normal or abnormal lipid profiles Settings: ambulatory care Intervention: fluvastatin Comparison: Triglyceride percentage change from baseline for all trials
Outcomes	Anticipated absolute effects mmol/L (95%CI)		Percent Reduction  (95% CI) %	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments

	Before exposure to fluvastatin¹	After exposure to fluvastatin
Triglycerides fluvastatin 10 mg/day	1.93 (1.63 to 2.22)	1.87 (1.73 to 2.01)	3.0 (10.1 to ‐4.2)	259  (3)	⊕⊕⊕⊕  high	Effect predicted from log dose‐response equation is 5.2%. Only RCT data.
Triglycerides fluvastatin 20 mg/day	1.98 (1.68 to 2.28)	1.76 (1.74 to 1.77)	11.1 (11.8 to 10.3)	7510  (39)	⊕⊕⊕⊕  high	Effect predicted from log dose‐response equation is 9.4%. Randomised and before and after design not different P = 0.277.
Triglycerides fluvastatin 40 mg/day	1.94 (1.70 to 2.17)	1.72 (1.69 to 1.75)	11.1 (12.6 to 9.6)	2646  (48)	⊕⊕⊕⊕  high	Effect predicted from log dose‐response equation is 13.6% Randomised and before and after design not different P = 0.186.
Triglycerides fluvastatin 80 mg/day	1.92 (1.67 to 2.17)	1.59 (1.56 to 1.62)	17.5 (19.1 to 15.9)	3623  (23)	⊕⊕⊕⊕  high	Effect predicted from log dose‐response equation is 17.7% Randomised and before and after design not different P = 0.496.
CI: Confidence interval
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Withdrawal due to adverse events due to fluvastatin
Patient or population: participants with normal or abnormal lipid profiles Settings: ambulatory care Intervention: fluvastatin Comparison: WDAEs fluvastatin versus placebo
Outcomes	*Illustrative Comparative Risks (95%CI)**		Relative effect  (95% CI)	No of Participants  (studies)	Quality of the evidence  (GRADE)	Comments
	Assumed risk	Corresponding risk
	placebo	fluvastatin
WDAEs within 3‐12 weeks			RR 1.52 (0.94 to 2.45)	3023  (16)	⊕⊝⊝⊝  very low^1,2	only 16 out of 36 placebo controlled trials reported withdrawals due to adverse effects.
	18 per 1000	27 per 1000 (17 to 44)




The basis for the assumed risk* is the measure of absolute effect with the placebo group. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk Ratio
GRADE Working Group grades of evidence  High quality: Further research is very unlikely to change our confidence in the estimate of effect.  Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.  Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.  Very low quality: We are very uncertain about the estimate.

Fluvastatin dose (mg/day)	2.5	5	10	20	30	40	80
Total Cholesterol (mean percentage change from control)	‐9.8	‐11.7	‐10.7	‐14.8	‐18.0	‐18.85	‐24.9
95% confidence interval	(‐12.0 to ‐7.7)	(‐14.2 to ‐9.2)	(‐12.7 to ‐8.6)	(‐15.1 to ‐14.5)	(‐19.2 to ‐16.7)	(‐19.3 to ‐18.4)	(‐25.4 to ‐24.4)
LDL‐C^a (mean percentage change from control)	‐12.1	‐14.5	‐15.2	‐20.0	‐25.3	‐25.9	‐34.9
95% confidence interval	(‐14.2 to ‐10.1)	(‐16.3 to ‐12.7)	(‐17.1 to ‐13.3)	(‐20.3 to ‐19.7)	(‐26.9 to ‐23.7)	(‐26.5 to ‐25.3)	(‐35.5 to ‐34.3)
Triglycerides (mean percentage change from control)	‐3.3	‐5.3	‐3.0	‐11.1	‐5.9	‐11.1	‐17.5
95% confidence interval	(‐14.6 to 8.0)	(‐13.1 to 2.5)	(‐10.1 to 4.2)	(‐11.8 to ‐10.3)	(‐20.1 to 8.3)	(‐12.6 to ‐9.6)	(‐19.1 to ‐15.9)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 LDL‐cholesterol	2	338	Mean Difference (IV, Fixed, 95% CI)	‐11.91 [‐14.14, ‐9.69]
2 WDAEs	1	173	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.98]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 LDL‐cholesterol	2	332	Mean Difference (IV, Fixed, 95% CI)	‐15.76 [‐18.91, ‐12.60]
2 LDL‐cholesterol	2	91	Mean Difference (Fixed, 95% CI)	‐13.85 [‐16.02, ‐11.69]
3 WDAEs	1	171	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.01, 8.16]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 LDL‐cholesterol	5	570	Mean Difference (IV, Random, 95% CI)	‐14.49 [‐17.95, ‐11.02]
2 Total cholesterol	3	259	Mean Difference (IV, Random, 95% CI)	‐8.44 [‐13.95, ‐2.93]
3 HDL‐cholesterol	3	259	Mean Difference (IV, Fixed, 95% CI)	1.86 [‐1.28, 5.00]
4 Triglycerides	3	259	Mean Difference (IV, Fixed, 95% CI)	‐2.96 [‐10.19, 4.28]
5 WDAEs	2	211	Risk Ratio (M‐H, Fixed, 95% CI)	0.34 [0.01, 8.16]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 LDL‐cholesterol	14	2329	Mean Difference (IV, Fixed, 95% CI)	‐20.82 [‐21.88, ‐19.77]
2 Total cholesterol	12	2023	Mean Difference (IV, Fixed, 95% CI)	‐15.81 [‐16.75, ‐14.88]
3 HDL‐cholesterol	10	1727	Mean Difference (IV, Fixed, 95% CI)	2.33 [0.90, 3.77]
4 Triglycerides	10	1712	Mean Difference (IV, Fixed, 95% CI)	‐9.67 [‐12.61, ‐6.73]
5 LDL‐cholesterol	41	6681	Mean Difference (Random, 95% CI)	‐20.92 [‐21.83, ‐20.02]
6 Total cholesterol	38	4286	Mean Difference (Random, 95% CI)	‐15.68 [‐16.67, ‐14.68]
7 HDL‐cholesterol	32	6239	Mean Difference (Random, 95% CI)	5.34 [4.51, 6.17]
8 Triglycerides	29	5798	Mean Difference (Random, 95% CI)	‐9.15 [‐11.36, ‐6.94]
9 WDAE	7	1060	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.14, 5.46]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 LDL‐cholesterol	7	336	Mean Difference (Random, 95% CI)	‐24.03 [‐27.72, ‐20.34]
2 Total cholesterol	6	285	Mean Difference (Random, 95% CI)	‐17.23 [‐19.68, ‐14.78]
3 HDL‐cholesterol	2	47	Mean Difference (Random, 95% CI)	7.86 [‐0.36, 16.07]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 LDL‐cholesterol	11	1275	Mean Difference (IV, Random, 95% CI)	‐27.04 [‐30.69, ‐23.40]
2 Total cholesterol	11	1276	Mean Difference (IV, Random, 95% CI)	‐18.21 [‐21.17, ‐15.26]
3 HDL‐cholesterol	6	716	Mean Difference (IV, Fixed, 95% CI)	5.14 [2.86, 7.41]
4 Triglycerides	10	1198	Mean Difference (IV, Fixed, 95% CI)	‐13.53 [‐17.27, ‐9.78]
5 LDL‐cholesterol	46	2383	Mean Difference (Random, 95% CI)	‐26.41 [‐27.67, ‐25.14]
6 Total cholesterol	44	1690	Mean Difference (Random, 95% CI)	‐19.52 [‐20.60, ‐18.45]
7 HDL‐cholesterol	35	1354	Mean Difference (Random, 95% CI)	3.87 [2.06, 5.68]
8 Triglycerides	38	1448	Mean Difference (Random, 95% CI)	‐11.23 [‐14.07, ‐8.40]
9 WDAE	4	236	Risk Ratio (M‐H, Fixed, 95% CI)	3.47 [0.75, 16.11]

Methods	10‐week dietary washout period 12‐week before and after trial
Participants	82 men and women 18‐75 years old with primary hypercholesterolaemia LDL‐C ≥130 mg/dL (≥ 3.4 mmol/L) triglycerides ≤ 400 mg/dL (≤ 4.5 mmol/L) exclusion criteria: congestive heart failure III‐IV; uncontrolled arrhythmia; MI; unstable angina or severe or unstable peripheral artery disease in the preceding 3 months; uncontrolled diabetes; uncontrolled endocrine or metabolic diseases, renal or hepatic dysfunction; myopathic disorders, coagulation disorders; and /or any condition that would make protocol compliance unlikely pregnancy or lactation and confounding drugs 44 participants received fluvastatin 80 mg/day 38 participants received fluvastatin 80 mg/day + ezetimibe 10 mg/day Fluvastatin 80 mg/day baseline TC : 7.7 mmol/L (298 mg/dL)  Fluvastatin 80 mg/day baseline LDL‐C : 5.6 mmol/L (217 mg/dL)  Fluvastatin 80 mg/day baseline HDL‐C : 1.5 mmol/L (58 mg/dL) Fluvastatin 80 mg/day baseline triglycerides: 1.6 mmol/L (142 mg/dL)
Interventions	Fluvastatin XL 80 mg/day Fluvastatin XL 80 mg/day + ezetimibe 10 mg/day
Outcomes	per cent change from baseline at 12 weeks of serum TC, LDL‐C, HDL‐C, and triglycerides
Source of Funding	Novartis
Notes	Fluvastatin XL 80 mg/day + ezetimibe 10 mg/day group was not included in the efficacy analysis
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before and after design
Allocation concealment (selection bias)	High risk	Controlled before and after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAEs	High risk	No comparison possible
Incomplete outcome data (attrition bias)   All outcomes	Unclear risk	11.4% participants were not included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	High risk	Novartis funded the study

Methods	4‐week single‐blind placebo washout period 6‐week before and after trial
Participants	22 elderly women with primary phenotype IIa hypercholesterolaemia LDL‐cholesterol ≥ 160 mg/dL ( ≥ 4.14 mmol/L) triglycerides ≤ 250 mg/dL (≤ 2.82 mmol/L) exclusion criteria: secondary forms of dyslipidaemia, actively treated diabetes mellitus, obesity, liver and renal dysfunction, acute MI, previous coronary bypass surgery or malignancy Fluvastatin 40 mg/day baseline TC : 8.4 mmol/L (325 mg/dL)  Fluvastatin 40 mg/day baseline LDL‐C : 6.1 mmol/L (236 mg/dL)  Fluvastatin 40 mg/day baseline HDL‐C : 1.6 mmol/L (62 mg/dL) Fluvastatin 40 mg/day baseline triglycerides: 1.4 mmol/L (124 mg/dL)
Interventions	fluvastatin 40 mg/day
Outcomes	per cent change from baseline at 3‐6 weeks of serum TC, LDL‐C, HDL‐C, and triglycerides
Source of Funding	unknown
Notes	SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before and after design
Allocation concealment (selection bias)	High risk	Controlled before and after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAEs	High risk	No comparison possible
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All participants were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding was not reported

Methods	4‐week single‐blind placebo washout period 6‐week before and after trial
Participants	39 men and women with type IIA primary hypercholesterolaemia mean age 67 years LDL‐cholesterol ≥ 160 mg/dL ( ≥ 4.14 mmol/L) triglycerides ≤ 250 mg/dL (≤ 2.82 mmol/L) exclusion criteria: secondary dyslipidaemia, diabetes mellitus controlled with drugs, obesity BMI ≥29 abnormal liver and renal function, cancer, MI and coronary bypass surgery Fluvastatin 40 mg/day baseline TC : 8.17 mmol/L (316 mg/dL)  Fluvastatin 40 mg/day baseline LDL‐C : 5.92 mmol/L (229 mg/dL)  Fluvastatin 40 mg/day baseline HDL‐C : 1.5 mmol/L (58 mg/dL Fluvastatin 40 mg/day baseline triglycerides: 1.64 mmol/L (145 mg/dL)
Interventions	Fluvastatin 40 mg/day
Outcomes	per cent change from baseline at 3‐6 weeks of serum TC, LDL‐C, HDL‐C, and triglycerides
Source of Funding	unknown
Notes	SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before and after design
Allocation concealment (selection bias)	High risk	Controlled before and after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAEs	High risk	No comparison possible
Incomplete outcome data (attrition bias)   All outcomes	High risk	15.4% participants were not included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding not reported

Methods	8‐week cholesterol lowering diet 4‐week single‐blind placebo washout period 8‐week before and after trial
Participants	82 male and female patients aged 18‐75 years with primary hypercholesterolaemia received fluvastatin LDL‐cholesterol ≥ 160 mg/dL ( ≥ 4.1 mmol/L) in association with premature CAD or ≥ 2 defined risk factors for CAD or LDL‐cholesterol ≥ 190 mg/dL ( ≥ 4.9 mmol/L) with no CAD and < 2 risk factors and plasma TG levels ≤ 350 mg/dL (4.0 mmol/L) exclusion criteria: familial hypercholesterolaemia, type I, III, IV or V hyperlipoproteinaemia, pregnant or lactating women, child bearing potential secondary dyslipidaemia, GI impairment, MI, angioplasty, major surgery within 6 months of trial, congestive heart failure, severe or unstable angina pectoris untreated hypertension, obesity, medication use that might interfere with study results ingestion of probucol within 1 year of study Fluvastatin 20 mg/day baseline TC : 7.86 mmol/L (304 mg/dL  Fluvastatin 20 mg/day baseline LDL‐C : 5.83 mmol/L (225 mg/dL)  Fluvastatin 20 mg/day baseline HDL‐C : 1.25 mmol/L (48 mg/dL Fluvastatin 20 mg/day baseline triglycerides: 1.71 mmol/L (151 mg/dL)
Interventions	Fluvastatin 20 mg/day for 8 weeks Gemfibrozil 600 mg twice daily for 8 weeks
Outcomes	per cent change from baseline at 8 weeks of plasma TC, LDL‐C, HDL‐C, and triglycerides
Source of Funding	unknown
Notes	Gemfibrozil 600 mg twice daily for 8 weeks group was not analysed sed
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before and after design
Allocation concealment (selection bias)	High risk	Controlled before and after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAEs	High risk	No comparison possible
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All participants were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding was not provided

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 LDL‐cholesterol	10	2727	Mean Difference (IV, Random, 95% CI)	‐34.62 [‐38.60, ‐30.64]
2 Total cholesterol	10	2757	Mean Difference (IV, Random, 95% CI)	‐25.76 [‐28.10, ‐23.41]
3 HDL‐cholesterol	9	2644	Mean Difference (IV, Random, 95% CI)	1.06 [‐2.26, 4.38]
4 Triglycerides	10	2756	Mean Difference (IV, Fixed, 95% CI)	‐17.28 [‐19.63, ‐14.92]
5 LDL‐cholesterol	22	2201	Mean Difference (Random, 95% CI)	‐33.04 [‐35.17, ‐30.90]
6 Total cholesterol	17	1186	Mean Difference (Random, 95% CI)	‐23.27 [‐24.99, ‐21.55]
7 HDL‐cholesterol	13	828	Mean Difference (Random, 95% CI)	3.36 [‐0.50, 7.22]
8 Triglycerides	13	867	Mean Difference (Random, 95% CI)	‐20.04 [‐26.35, ‐13.73]
9 WDAEs	4	1430	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.71, 2.51]

Methods	4‐week washout period 12‐week before and after trial
Participants	23 hypertensive patients with hypercholesterolaemia age 20‐65 years old TC/HDL‐C > 4.5 TC > 5.2 mmol/L (201 mg/dL) with CHD TC > 6.5 mmol/L (251 mg/dL) without CHD BP is 140‐160/90‐110 no exclusion criteria Fluvastatin 40 mg/day baseline TC : 7.98 mmol/L (309 mg/dL)  Fluvastatin 40 mg/day baseline LDL‐C : 5.63 mmol/L (218 mg/dL)  Fluvastatin 40 mg/day baseline HDL‐C : 1.15 mmol/L (44 mg/dL) Fluvastatin 40 mg/day baseline triglycerides: 2.66 mmol/L (236 mg/dL)
Interventions	Fluvastatin 40 mg/day
Outcomes	per cent change from baseline at 12 weeks of blood TC, LDL‐C, HDL‐C, and triglycerides
Source of Funding	unknown
Notes	all lipid parameters were included in the efficacy analysis SDs were determined from P values
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before and after design
Allocation concealment (selection bias)	High risk	Controlled before and after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAEs	High risk	No comparison possible
Incomplete outcome data (attrition bias)   All outcomes	Low risk	4.2% participants were not included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding was not reported

Methods	5‐8 week washout period 54‐week before and after trial
Participants	3887 men and women with hypercholesterolaemia LDL‐C 190‐350 mg/dL (4.91‐9.05 mmol/L) in patients with no CHD or peripheral vascular disease and 1 or no risk factors 160‐300 mg/dL (4.14‐7.76 mmol/L) in patients with no CHD or peripheral vascular disease and > 1 risk factor 130‐250 mg/dL (3.36‐6.47 mmol/L) in patients with clinically evident CHD or peripheral vascular disease Triglycerides < 400 mg/dL (4.52 mmol/L) exclusion criteria: statin hypersensitivity, use of prohibited medications, acute liver disease, uncontrolled diabetes mellitus age < 18 and > 80 years Fluvastatin 20 mg/day baseline TC : 6.83 mmol/L (264 mg/dL)  Fluvastatin 20 mg/day baseline LDL‐C : 4.63 mmol/L (179 mg/dL)  Fluvastatin 20 mg/day baseline HDL‐C : 1.21 mmol/L (47 mg/dL) Fluvastatin 20 mg/day baseline triglycerides: 2.14 mmol/L (190 mg/dL)
Interventions	493 patients received Fluvastatin 20 mg/day for 0‐6 weeks 493 patients received Fluvastatin 20‐40 mg/day for 6‐12 weeks 493 patients received Fluvastatin 20‐80 mg/day for 12‐18 weeks 493 patients received Fluvastatin 20‐80 mg/day for 18‐54 weeks 494 patients received Lovastatin 20 mg/day for 0‐6 weeks 494 patients received Lovastatin 20‐40 mg/day for 6‐12 weeks 494 patients received Lovastatin 20‐80 mg/day for 12‐18 weeks 494 patients received Lovastatin 20‐80 mg/day for 18‐54 weeks 478 patients received Pravastatin 10 mg/day for 0‐6 weeks 478 patients received Pravastatin 10‐20 mg/day for 6‐12 weeks 478 patients received Pravastatin 10‐40 mg/day for 12‐18 weeks 478 patients received Pravastatin 10‐40 mg/day for 18‐54 weeks 478 patients received Simvastatin 10 mg/day for 0‐6 weeks 478 patients received Simvastatin 10‐20 mg/day for 6‐12 weeks 478 patients received Simvastatin 10‐40 mg/day for 12‐18 weeks 478 patients received Simvastatin 10‐40 mg/day for 18‐54 weeks 1944 patients received Atorvastatin 10 mg/day for 0‐6 weeks 1944 patients received Atorvastatin 10‐20 mg/day for 6‐12 weeks 1944 patients received Atorvastatin 10‐40 mg/day for 12‐18 weeks 1944 patients received Atorvastatin 10‐80 mg/day for 18‐54 weeks
Outcomes	per cent change from baseline at 6 weeks of blood TC, LDL‐C and HDL‐C
Source of Funding	Pfizer
Notes	Lovastatin, pravastatin, simvastatin, atorvastatin groups were not included in the efficacy analysis Fluvastatin time periods of 6‐12, 12‐18 and 18‐54 weeks were also not included in the efficacy analysis because some participants had a doubling of dose at weeks 6, 12 and 18. blood triglycerides were not included in the efficacy analysis because the calculated value and the given values differed by 29.8%
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before and after design
Allocation concealment (selection bias)	High risk	Controlled before and after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAEs	High risk	No comparison possible
Incomplete outcome data (attrition bias)   All outcomes	Low risk	19/493 (3.9%) participants were not included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	High risk	Pfizer‐funded the trial

Methods	8‐week cholesterol‐lowering diet 6‐week placebo washout period 6‐week before and after trial
Participants	101 men and women aged 18‐75 with primary hypercholesterolaemia received fluvastatin 20 mg/day for 6 weeks then 40 mg/day from 6‐12 weeks 50 men and women aged 18‐75 with primary hypercholesterolaemia received cholestyramine for 12 weeks exclusion criteria:MI in the 6 months preceding the study, unstable anginal pectoris, diabetes, impaired renal and liver function, familial hypercholesterolaemia, type I, III, IV or V hyperlipoproteinaemia excessive alcohol consumption and ingestion of probucol within 1 year of study Fluvastatin 20 mg/day baseline TC : 8.4 mmol/L (325 mg/dL  Fluvastatin 20 mg/day baseline LDL‐C : 6.5 mmol/L (251 mg/dL)  Fluvastatin 20 mg/day baseline HDL‐C : 1.3 mmol/L (50 mg/dL) Fluvastatin 20 mg/day baseline triglycerides: 1.5 mmol/L (133 mg/dL)
Interventions	fluvastatin 20 mg/day for 6 weeks fluvastatin 40 mg/day for 6‐12 weeks cholestyramine 16 g/day for 6 weeks cholestyramine 16 g/day for 6‐12 weeks
Outcomes	per cent change from baseline at 6 weeks of plasma TC and LDL‐C
Source of Funding	unknown
Notes	fluvastatin 40 mg/day for 6‐12 weeks cholestyramine 16 g/day for 6 weeks cholestyramine 16 g/day for 6‐12 weeks groups were not analysed HDL‐C and triglycerides were not included in the efficacy analysis because the calculated values were different by more than 10% from the given data
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before and after design
Allocation concealment (selection bias)	High risk	Controlled before and after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAEs	High risk	No comparison possible
Incomplete outcome data (attrition bias)   All outcomes	Low risk	1% participants were not included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding was not provided

Methods	at least a 4‐week washout period 6‐week before and after trial
Participants	270 men and women mean age 56 years with primary hypercholesterolaemia 136 participants received fluvastatin serum TG < 400 mg/dL (4.52 mmol/L) LDL‐C ≥ 190 mg/dL (4.91 mmol/L) and less than 2 CHD risk factors LDL‐C ≥ 160 mg/dL (4.14 mmol/L) and two or more CHD risk factors LDL‐C ≥ 130 mg/dL (3.36 mmol/L) and definite CHD or other atherosclerotic disease exclusion criteria: none reported Fluvastatin 20 mg/day baseline TC : 7.11 mmol/L (275 mg/dL)  Fluvastatin 20 mg/day baseline LDL‐C : 4.83 mmol/L (187 mg/dL)  Fluvastatin 20 mg/day baseline HDL‐C : 1.21 mmol/L (47 mg/dL) Fluvastatin 20 mg/day baseline triglycerides: 2.34 mmol/L (207 mg/dL)
Interventions	Fluvastatin 20 mg/day Lovastatin 20 mg/day
Outcomes	per cent change from baseline at 6 weeks of serum TC, LDL‐C, HDL‐C, and triglycerides
Source of Funding	unknown
Notes	Lovastatin 20 mg/day group was not included in the efficacy analysis SDs were imputed by the method of Furukawa 2006 for serum HDL‐C and serum triglycerides
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before and after design
Allocation concealment (selection bias)	High risk	Controlled before and after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAEs	High risk	No comparison possible
Incomplete outcome data (attrition bias)   All outcomes	Low risk	all participants were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	First author works for Merck and Co.

Methods	4‐week placebo run‐in dietary washout period 20‐week double‐blind randomised placebo‐controlled trial
Participants	48 men and women mean age 59 years with a history of angina pectoris, previous MI or coronary bypass surgery total cholesterol of 200‐300 mg/dL (5.17‐7.46 mmol/L) and concomitant high lipoprotein(a) > 30 mg/dL all women were postmenopausal exclusion criteria: secondary hypercholesterolaemia, serum triglycerides > 300 mg/dL (3.39mmol/L) liver or renal dysfunction, obesity, smoking Placebo baseline TC : 6.34 mmol/L (325 mg/dL)  Placebo baseline LDL‐C : 4.27 mmol/L (236 mg/dL)  Placebo baseline HDL‐C : 1.16 mmol/L (62 mg/dL) Placebo baseline triglycerides: 1.49 mmol/L (124 mg/dL) Fluvastatin 40 mg/day baseline TC : 6.36 mmol/L (325 mg/dL)  Fluvastatin 40 mg/day baseline LDL‐C : 4.47 mmol/L (236 mg/dL)  Fluvastatin 40 mg/day baseline HDL‐C : 1.23 mmol/L (62 mg/dL) Fluvastatin 40 mg/day baseline triglycerides: 1.32 mmol/L (124 mg/dL)
Interventions	placebo 8‐12 weeks placebo 12‐20 weeks fluvastatin 40 mg/day 8‐12 weeks fluvastatin 40 mg/day 12‐20 weeks
Outcomes	per cent change from baseline at 8‐12 weeks of serum TC, LDL‐C, HDL‐C, triglycerides and WDAEs
Source of Funding	Sandoz pharmaceuticals
Notes	placebo 12‐20 weeks fluvastatin 40 mg/day 12‐20 weeks time period was not analysed SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random sequence generation method not reported
Allocation concealment (selection bias)	Unclear risk	Allocation concealment not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind treatment Lipid parameter measurements unlikely influenced by lack of proper blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAEs	Unclear risk	Blinding method was not described
Incomplete outcome data (attrition bias)   All outcomes	Low risk	4.2% participants were not included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	High risk	Sandoz pharmaceuticals funded the trial

Methods	4‐week dietary run‐in period 12‐week before and after trial
Participants	100 men and postmenopausal women age 45‐71 years old with type 2 diabetes mellitus, mixed dyslipidaemia LDL‐C, 150‐300 mg/dL (3.88‐7.76 mmol/L) 50 received fluvastatin triglycerides > 200 mg/dL ( 2.26 mmol/L) and HDL‐C < 50 mg/dL (1.29 mmol/L) exclusion criteria: surgery, MI, or angioplasty during the 6 months before randomisation, uncontrolled hypertension, liver disease, renal dysfunction myopathy, alcohol/drug abuse, statin hypersensitivity, pregnancy or lactation, use of oral contraceptives at the start of the study Fluvastatin 80 mg/day baseline LDL‐C : 3.85 mmol/L (149 mg/dL)  Fluvastatin 80 mg/day baseline HDL‐C : 1.06 mmol/L (41 mg/dL) Fluvastatin 80 mg/day baseline triglycerides: 4.93 mmol/L (437 mg/dL)
Interventions	Fluvastatin XL 80 mg/day for 12 weeks Atorvastatin 20 mg/day for 12 weeks
Outcomes	per cent change from baseline at 12 weeks of serum LDL‐C, HDL‐C, and triglycerides
Source of Funding	unknown
Notes	Atorvastatin 20 mg/day group was not analysed SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before and after design
Allocation concealment (selection bias)	High risk	Controlled before and after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAEs	High risk	No comparison possible
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All participants were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding was not reported

Methods	8‐week dietary run‐in period 8‐week before and after trial
Participants	94 men and women aged 48‐79 years with type 2 diabetes mellitus and the lipid triad triglycerides > 2.3 mmol/L (204 mg/dL) HDL‐C < 1.3 mmol/L (50 mg/dL), and elevated levels of sdLDL exclusion criteria: surgery, MI, or angioplasty during the 6 months before randomisation, uncontrolled hypertension, liver disease, renal dysfunction myopathy, alcohol/drug abuse, statin hypersensitivity, pregnancy or lactation, use of oral contraceptives at the start of the study Fluvastatin 80 mg/day baseline LDL‐C : 4.7 mmol/L (182 mg/dL)  Fluvastatin 80 mg/day baseline HDL‐C : 1.05 mmol/L (41 mg/dL) Fluvastatin 80 mg/day baseline triglycerides: 5.0 mmol/L (443 mg/dL)
Interventions	Fluvastatin XL 80 mg/day for 8 weeks ( 48 participants) Simvastatin 20 mg/day for 8 weeks (46 participants)
Outcomes	per cent change from baseline at 8 weeks of serum LDL‐C, HDL‐C, and triglycerides
Source of Funding	unknown
Notes	Simvastatin 20 mg/day for 8 weeks group was not analysed SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before and after design
Allocation concealment (selection bias)	High risk	Controlled before and after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAEs	High risk	No comparison possible
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Data on all participants were reported
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding was not reported

Methods	no participant was receiving lipid medications known to interfere with the trial washout not required 12‐week before and after trial
Participants	23 women aged 65 years received vitamin C 500 mg/day and 45 women received fluvastatin 40 mg/day and vitamin C 500 mg/day TC > 5.2 mmol/L (201 mg/dL) TC = 7.34 mmol/L (284 mg/dL) LDL‐C = 4.86 mmol/L (188 mg/dL) HDL‐C = 1.89 mmol/L (73 mg/dL) exclusion criteria:BMI > 40, severe or chronic diseases, conditions that may interfere with the trial lack of consent, allergy to statins, participation in another trial within 3 months of the trial
Interventions	Vitamin C 500 mg/day Fluvastatin 40 mg/day + Vitamin C 500 mg/day
Outcomes	per cent change from baseline at 12 weeks of serum TC, LDL‐C and HDL‐C
Source of Funding	Novo Nordisk A/S
Notes	Vitamin C 500 mg/day group was not included in the efficacy analysis SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before and after design
Allocation concealment (selection bias)	High risk	Controlled before and after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAEs	High risk	No comparison possible
Incomplete outcome data (attrition bias)   All outcomes	High risk	36.8% participants were not included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Novo Nordisk A/S funded the trial

Methods	3‐month dietary period none receiving drugs known to affect lipid metabolism 2‐month run‐in period 2‐month before and after trial
Participants	200 hypercholesterolaemic men and women with LDL‐cholesterol levels of 160 mg/dL (4.14 mmol/L) (range 160‐426 mg/dL) (range 4.14‐11.0 mmol/L) or greater age ranged from 24‐75 years mean age 58 years serum triglyceride levels of less than 400 mg/dL (4.52 mmol/L) (range 52‐398 mg/dL) (range 0.59‐4.49 mmol/L) exclusion criteria: diabetes, hypothyroidism,renal and liver dysfunction Fluvastatin 40 mg/day baseline TC : 8.0 mmol/L (309 mg/dL)  Fluvastatin 40 mg/day baseline LDL‐C : 5.8 mmol/L (224 mg/dL)  Fluvastatin 40 mg/day baseline HDL‐C : 1.3 mmol/L (50 mg/dL
Interventions	50 participants received 10 mg/day atorvastatin 50 participants received 40 mg/day fluvastatin 50 participants received 20 mg/day pravastatin 50 participants received 10 mg/day simvastatin
Outcomes	per cent change from baseline at 2 months of serum TC, LDL‐C, and triglycerides
Source of Funding	unknown
Notes	baseline serum triglycerides was reported as a median 10 mg/day atorvastatin 20 mg/day pravastatin 10 mg/day simvastatin groups were not analysed HDL‐C was not included in the efficacy analysis because the calculated value was different by more than 10% from the given value
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before and after design
Allocation concealment (selection bias)	High risk	Controlled before and after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAEs	High risk	No comparison possible
Incomplete outcome data (attrition bias)   All outcomes	Low risk	4% participants were not included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding was not provided

PERMALINK

Fluvastatin for lowering lipids

Stephen P Adams

Sarpreet S Sekhon

Michael Tsang

James M Wright

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

1.

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Data presentation ‐ ’Summary of findings’ tables

for the main comparison.

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Results

Description of studies

Results of the search

Included studies

2.

3.

4.

5.

Excluded studies

Risk of bias in included studies

Allocation

Blinding

Incomplete outcome data

Selective reporting

6.

Other potential sources of bias

Effects of interventions

2.

3.

4.

1. Fluvastatin Overall Efficacy.

1.1. Analysis.

2.1. Analysis.

2.2. Analysis.

3.1. Analysis.

4.1. Analysis.

4.5. Analysis.

5.1. Analysis.

6.1. Analysis.

6.5. Analysis.

7.1. Analysis.

7.5. Analysis.

Methods	8‐week dietary washout period 4‐week before and after trial
Participants	22 male and female patients with hyperlipidaemia TC > 200 mg/dL (5.17 mmol/L) LDL‐C > 130 mg/dL (3.36 mmol/L) TG < 400 mg/dL (4.52 mmol/L) exclusion criteria: homozygous familial hypercholesterolaemia, hyperlipidaemia type I, III, IV, V, secondary hyperlipidaemia, diabetes, arterial hypertension, obesity BMI 30, renal and hepatic dysfunction, heart failure, systemic diseases, alcohol abuse, acute and chronic inflammation Fluvastatin 80 mg/day baseline TC : 7.0 mmol/L (271 mg/dL  Fluvastatin 80 mg/day baseline LDL‐C : 4.67 mmol/L (181 mg/dL)  Fluvastatin 80 mg/day baseline HDL‐C : 1.48 mmol/L (57 mg/dL Fluvastatin 80 mg/day baseline triglycerides: 1.94 mmol/L (172 mg/dL)
Interventions	Fuvastatin XL 80 mg/day
Outcomes	per cent change from baseline at 4 weeks of serum TC, LDL‐C, HDL‐C, and triglycerides
Source of Funding	unknown
Notes	SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before and after design
Allocation concealment (selection bias)	High risk	Controlled before and after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAEs	High risk	No comparison possible
Incomplete outcome data (attrition bias)   All outcomes	Low risk	all participants were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding was not reported

Methods	4‐week run‐in period 54‐week before and after trial
Participants	318 men and women with documented atherosclerosis age 18‐80 years old BMI not greater than 32 80 participants received fluvastatin LDL‐C ≥ 130 mg/dL (3.36 mmol/L) and ≤ 250 mg/dL (6.5 mmol/L) exclusion criteria: statin or resin hypersensitivities, taking prohibited medications, pregnant or lactation secondary hyperlipoproteinaemia such as uncontrolled hypothyroidism, nephrotic syndrome, severe renal dysfunction or uncontrolled diabetes mellitus; active liver disease or hepatic dysfunction; had a MI, coronary angioplasty, coronary artery bypass graft surgery and/or severe or unstable angina pectoris within 1 month of screening; had participated in another clinical trial within 30 days of screening for this study significant abnormalities that might compromise this study Fluvastatin 20 mg/day baseline TC : 6.465 mmol/L (250 mg/dL)  Fluvastatin 20 mg/day baseline LDL‐C : 4.4 mmol/L (170 mg/dL)  Fluvastatin 20 mg/day baseline HDL‐C : 1.06 mmol/L (41 mg/dL Fluvastatin 20 mg/day baseline triglycerides: 2.15 mmol/L (190 mg/dL)
Interventions	10 mg/day atorvastatin for 0‐12 weeks 20 mg/day atorvastatin for 12‐24 weeks 40 mg/day atorvastatin for 24‐36 weeks 80 mg/day atorvastatin for 36‐48 weeks 80 mg/day atorvastatin + 5 g colestipol twice daily for 48‐54 weeks 10 mg/day simvastatin for 0‐12 weeks 20 mg/day simvastatin for 12‐24 weeks 40 mg/day simvastatin for 24‐36 weeks 40 mg/day simvastatin + 5 g colestipol twice daily for 36‐48 weeks 40 mg/day simvastatin + 10 g colestipol twice daily for 48‐54 weeks 20 mg/day lovastatin for 0‐12 weeks 40 mg/day lovastatin for 12‐24 weeks 40 mg lovastatin twice daily for 24‐36 weeks 40 mg lovastatin twice daily + 5 g colestipol twice daily for 36‐48 weeks 40 mg lovastatin twice daily + 10 g colestipol twice daily for 48‐54 weeks 20 mg/day fluvastatin for 0‐12 weeks 40 mg/day fluvastatin for 12‐24 weeks 40 mg/day fluvastatin + 5 g colestipol twice daily for 24‐36 weeks 40 mg/day fluvastatin + 10 g colestipol twice daily for 36‐54 weeks
Outcomes	per cent change from baseline at 12 weeks of serum TC, LDL‐C, HDL‐C, and triglycerides
Source of Funding	unknown
Notes	10 mg/day atorvastatin for 0‐12 weeks 20 mg/day atorvastatin for 12‐24 weeks 40 mg/day atorvastatin for 24‐36 weeks 80 mg/day atorvastatin for 36‐48 weeks 80 mg/day atorvastatin + 5 g colestipol twice daily for 48‐54 weeks 10 mg/day simvastatin for 0‐12 weeks 20 mg/day simvastatin for 12‐24 weeks 40 mg/day simvastatin for 24‐36 weeks 40 mg/day simvastatin + 5 g colestipol twice daily for 36‐48 weeks 40 mg/day simvastatin + 10 g colestipol twice daily for 48‐54 weeks 20 mg/day lovastatin for 0‐12 weeks 40 mg/day lovastatin for 12‐24 weeks 40 mg lovastatin twice daily for 24‐36 weeks 40 mg lovastatin twice daily + 5 g colestipol twice daily for 36‐48 weeks 40 mg lovastatin twice daily + 10 g colestipol twice daily for 48‐54 weeks 40 mg/day fluvastatin for 12‐24 weeks 40 mg/day fluvastatin + 5 g colestipol twice daily for 24‐36 weeks 40 mg/day fluvastatin + 10 g colestipol twice daily for 36‐54 weeks groups were not analysed
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before and after design
Allocation concealment (selection bias)	High risk	Controlled before and after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAEs	High risk	No comparison possible
Incomplete outcome data (attrition bias)   All outcomes	Low risk	5% participants were not included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding was not reported

Methods	4‐week washout period for those receiving lipid‐lowering agents 2‐month randomised double‐blind placebo‐controlled trial
Participants	1229 men and women aged 70‐85 years with primary hypercholesterolaemia Total cholesterol ≥ 251 mg/dL ( ≥ 6.49 mmol/L) LDL‐cholesterol ≥ 159 mg/dL ( ≥ 4.11 mmol/L) triglycerides ≤ 407 mg/dL (≤ 4.595 mmol/L) exclusion criteria: type I or type V hyperlipoproteinaemia, secondary hyperlipidaemia, renal dysfunction symptomatic heart failure; history of MI, angina pectoris, stroke, severe peripheral artery disease and muscle disease Placebo baseline TC : 7.27 mmol/L (281 mg/dL)  Placebo baseline LDL‐C : 5.17 mmol/L (200 mg/dL)  Placebo baseline HDL‐C : 1.36 mmol/L (53 mg/dL) Placebo baseline triglycerides: 1.43 mmol/L (127 mg/dL Fluvastatin 80 mg/day baseline TC : 7.27 mmol/L (281 mg/dL)  Fluvastatin 80 mg/day baseline LDL‐C : 5.17 mmol/L (200 mg/dL)  Fluvastatin 80 mg/day baseline HDL‐C : 1.37 mmol/L (53 mg/dL) Fluvastatin 80 mg/day baseline triglycerides: 1.63 mmol/L (144 mg/dL)
Interventions	placebo Fluvastatin 80 mg/day
Outcomes	per cent change from baseline at 2 months of serum TC, LDL‐C, HDL‐C, triglycerides and WDAEs
Source of Funding	Novartis Pharma AG
Notes	SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random sequence generation method not reported
Allocation concealment (selection bias)	Unclear risk	Allocation concealment not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind Lipid parameter measurements unlikely influenced by lack of proper blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	all lipids were measured at a central laboratory (Pasteur Institute, Lille, France)
Blinding of outcome assessment (detection bias)   WDAEs	Unclear risk	Blinding method not described
Incomplete outcome data (attrition bias)   All outcomes	High risk	18.7% participants were not included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	High risk	Novartis Pharma AG funded the trial with a grant

Methods	6‐week dietary run‐in period 6‐week before and after trial
Participants	64 men and women with hypercholesterolaemia age 36‐63 years old 16 participants received fluvastatin mean values were as followed: TC = 6.86 mmol/L (265 mg/dL) HDL‐C = 1.24 mmol/L (48 mg/dL) TG = 1.13 mmol/L (100 mg/dL) BMI = 24.7 no participant was taking hypolipidaemic, antiplatelet, anticoagulant or pro fibrinolytic drugs all females were not receiving hormone therapy exclusion criteria: cardiovascular events in the clinical history and hypertension, diabetes,liver renal thyroid, infectious, immunological or malignant disease 16 participants received each of the drugs Fluvastatin 40 mg/day baseline TC : 6.86 mmol/L (265 mg/dL)  Fluvastatin 40 mg/day baseline LDL‐C : 5.13 mmol/L (198 mg/dL)  Fluvastatin 40 mg/day baseline HDL‐C : 1.26 mmol/L (49 mg/dL) Fluvastatin 40 mg/day baseline triglycerides: 1.14 mmol/L (101 mg/dL)
Interventions	atorvastatin 10 mg/day simvastatin 20 mg/day fluvastatin 40 mg/day pravastatin 40 mg/day
Outcomes	per cent change from baseline at 3‐6 weeks of serum TC, LDL‐C, HDL‐C, and triglycerides
Source of Funding	unknown
Notes	simvastatin 20 mg/day fluvastatin 40 mg/day pravastatin 40 mg/day groups were not included in the efficacy analysis SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before and after design
Allocation concealment (selection bias)	High risk	Controlled before and after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAEs	High risk	No comparison possible
Incomplete outcome data (attrition bias)   All outcomes	Low risk	all participants were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding was not reported

Methods	no washout required because no participants was receiving lipid‐altering substances within 8 weeks of the study 12‐week before and after trial
Participants	48 men and women of Czech nationality with hypercholesterolaemia exclusion criteria:diabetes mellitus, liver disease, metabolic disease, previous treatment with fluvastatin, concomitant therapy with strong CYP2C9 inducers or inhibitors, history of stomach or gut surgery, cancer,immunosuppressant therapy, pregnancy , lactation, alcoholism Fluvastatin 80 mg/day baseline TC : 6.56 mmol/L (254 mg/dL)  Fluvastatin 80 mg/day baseline LDL‐C : 3.86 mmol/L (149 mg/dL) Fluvastatin 80 mg/day baseline triglycerides: 2.34 mmol/L (207 mg/dL)
Interventions	Fluvastatin 80 mg/day
Outcomes	per cent change from baseline at 12 weeks of plasma TC, LDL‐C, and triglycerides
Source of Funding	Charles University (PRVOUK)
Notes	SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before and after design
Allocation concealment (selection bias)	High risk	Controlled before and after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAEs	High risk	No comparison possible
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All participants were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Low risk	Research program of the Charles University (PRVOUK)

Methods	4‐week low‐fat dietary washout period 42‐84 days before and after trial
Participants	men and women 18 years or older with confirmed primary hypercholesterolaemia and TG levels ≤ 400 mg/dL (4.52 mmol/L) TC levels ≥ 300 mg/dL (7.76 mmol/L) LDL‐cholesterol level ≥ 130 mg/dL (3.36 mmol/L) exclusion criteria:pregnant women, child bearing potential,active liver disease, severe renal insufficiency
Interventions	42‐day fluvastatin 20 mg/day 42‐84 day fluvastatin 20‐40 mg/day
Outcomes	per cent change from baseline at 48 days of serum LDL‐C, HDL‐C, and triglycerides
Source of Funding	unknown
Notes	42‐84 day time period was not analysed because some patients remained on 20 mg/day while others had their dose raised to 40 mg/day Total cholesterol data were not included in the efficacy analysis because the calculated value was different by more than 10% from the given value SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before and after design
Allocation concealment (selection bias)	High risk	Controlled before and after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAEs	High risk	No comparison possible
Incomplete outcome data (attrition bias)   All outcomes	High risk	16.3% participants were not included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding was not provided

Methods	at least a 4‐week dietary washout period 12‐week before and after trial
Participants	18 men and women are broken into 2 groups: 8 participants have heterozygous familial hypercholesterolaemia and 10 participants have familial combined hyperlipidaemia age is 34‐55 years exclusion criteria: none reported Fluvastatin 20 mg/day baseline TC : 7.95 mmol/L (307 mg/dL)  Fluvastatin 20 mg/day baseline LDL‐C : 5.5 mmol/L (213 mg/dL)  Fluvastatin 20 mg/day baseline HDL‐C : 1.25 mmol/L (48 mg/dL) Fluvastatin 20 mg/day baseline triglycerides: 2.4 mmol/L (213 mg/dL)
Interventions	Fluvastatin 20 mg/day for 0‐6 weeks Fluvastatin 40 mg/day for 6‐12 weeks
Outcomes	per cent change from baseline at 6 weeks of serum TC, LDL‐C, HDL‐C, and triglycerides
Source of Funding	government grant IGA MZ CR 2351
Notes	Fluvastatin 40 mg/day for 6‐12 weeks group was not included in the efficacy analysis SDs were imputed by the method of Furukawa 2006
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before and after design
Allocation concealment (selection bias)	High risk	Controlled before and after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAEs	High risk	No comparison possible
Incomplete outcome data (attrition bias)   All outcomes	Low risk	All participants were included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Low risk	Work was supported by grant IGA MZ CR 2351

Methods	6‐week dietary run‐in period 8‐week before and after trial
Participants	Men and women 18‐80 years old with hypercholesterolaemia 25 participants received fluvastatin plasma LDL cholesterol ≥ 160 mg/dL ( ≥ 4.14 mmol/L) plasma triglycerides ≤ 400 mg/dL (4.5 mmol/L) exclusion criteria:primary hypothyroidism, nephrotic syndrome, type 1 or uncontrolled type 2 diabetes, hepatic dysfunction, BMI > 32 uncontrolled hypertension; MI, coronary angioplasty, coronary bypass graft, severe or unstable angina pectoris within 3 months, statin hypersensitivities significant abnormalities that could affect the study Fluvastatin 20 mg/day baseline TC : 8.3 mmol/L (321 mg/dL)  Fluvastatin 20 mg/day baseline LDL‐C : 6.1 mmol/L (236 mg/dL)  Fluvastatin 20 mg/day baseline HDL‐C : 1.3 mmol/L (50 mg/dL) Fluvastatin 20 mg/day baseline triglycerides: 2.1 mmol/L (186 mg/dL) Fluvastatin 40 mg/day baseline TC : 7.1 mmol/L (275 mg/dL)  Fluvastatin 40 mg/day baseline LDL‐C : 5.0 mmol/L (193 mg/dL)  Fluvastatin 40 mg/day baseline HDL‐C : 1.3 mmol/L (50 mg/dL) Fluvastatin 40 mg/day baseline triglycerides: 2.0 mmol/L (177 mg/dL)
Interventions	atorvastatin 10, 20, 40 and 80 mg/day simvastatin 10, 20, and 40 mg/day pravastatin 10, 20, and 40 mg/day lovastatin 20, 40 mg/day and 40 mg twice daily fluvastatin 20 mg/day fluvastatin 40 mg/day
Outcomes	per cent change from baseline at 8 weeks of serum TC, LDL‐C, HDL‐C, and triglycerides
Source of Funding	unknown
Notes	atorvastatin 10, 20, 40 and 80 mg/day simvastatin 10, 20, and 40 mg/day pravastatin 10, 20, and 40 mg/day lovastatin 20, 40 mg/day and 40 mg twice daily groups were not analysed
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Controlled before and after design
Allocation concealment (selection bias)	High risk	Controlled before and after design
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Lipid parameter measurements unlikely influenced by lack of blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	Lipid parameters were measured in a remote laboratory
Blinding of outcome assessment (detection bias)   WDAEs	High risk	No comparison possible
Incomplete outcome data (attrition bias)   All outcomes	Low risk	4% participants were not included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	source of funding was not provided

Methods	lipid‐lowering treatment was discontinued for 10 weeks (1 year for probucol) prior to the study start 6‐week dietary placebo run‐in period 6‐week randomised placebo‐controlled double‐blind trial
Participants	429 men and women LDL‐C > 160 mg/dL (4.14 mmol/L) and premature CHD and/or two associated risk factors LDL‐C > 190 mg/dL (4.91 mmol/L) and no CHD, plus triglycerides < 300 mg/dL (3.39 mmol/L) Placebo baseline LDL‐C : 6.53 mmol/dL (253 mg/dL) Fluvastatin 2.5 mg/day baseline LDL‐C : 6.74 mmol/L (261 mg/dL) Fluvastatin 5 mg/day baseline LDL‐C : 6.76 mmol/L (261 mg/dL) Fluvastatin 10 mg/day baseline LDL‐C : 6.24 mmol/L (241 mg/dL) Fluvastatin 20 mg/day baseline LDL‐C : 6.24 mmol/L (241 mg/dL)
Interventions	Placebo for 6 weeks Fluvastatin 2.5 mg/day for 6 weeks Fluvastatin 5 mg/day for 6 weeks Fluvastatin 10 mg/day for 6 weeks Fluvastatin 20 mg/day for 6 weeks
Outcomes	per cent change from baseline at 6 weeks of LDL‐C
Source of Funding	unknown
Notes	TC, HDL‐C, triglycerides and WDAEs were not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Random sequence generation method not reported
Allocation concealment (selection bias)	Unclear risk	Allocation concealment not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind Lipid parameter measurements unlikely influenced by lack of proper blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	LDL‐C was determined by the Pasteur Institute Central Laboratory
Blinding of outcome assessment (detection bias)   WDAEs	High risk	WDAEs were not reported
Incomplete outcome data (attrition bias)   All outcomes	Low risk	0.2% participants were not included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding was not reported

Methods	6‐week diet plus placebo run‐in period 6‐week double‐blind placebo‐controlled trial
Participants	423 men and women with hypercholesterolaemia LDL‐Cholesterol > 160 mg/dL (4.14 mmol/L) and premature CAD and/or two associated risk factors; LDL‐Cholesterol > 190 mg/dL (4.91 mmol/L) and no CAD triglycerides < 300 mg/dL (3.39 mmol/L) Placebo baseline TC : 8.4 mmol/L (325 mg/dL)  Placebo baseline LDL‐C : 6.3 mmol/L (244 mg/dL)  Placebo baseline HDL‐C : 1.3 mmol/L (50 mg/dL) Placebo baseline triglycerides: 1.6 mmol/L (142 mg/dL) Fluvastatin 20 mg/day baseline TC : 8.3 mmol/L (321 mg/dL)  Fluvastatin 20 mg/day baseline LDL‐C : 6.2 mmol/L (240 mg/dL)  Fluvastatin 20 mg/day baseline HDL‐C : 1.4 mmol/L (54 mg/dL) Fluvastatin 20 mg/day baseline triglycerides: 1.6 mmol/L (142 mg/dL) Fluvastatin 40 mg/day baseline TC : 8.0 mmol/L (309 mg/dL)  Fluvastatin 40 mg/day baseline LDL‐C : 6.0 mmol/L (232 mg/dL)  Fluvastatin 40 mg/day baseline HDL‐C : 1.3 mmol/L (50 mg/dL) Fluvastatin 40 mg/day baseline triglycerides: 1.6 mmol/L (142 mg/dL)
Interventions	Placebo for 6 weeks Fluvastatin 20 mg/day for 6 weeks Fluvastatin 40 mg/day for 6 weeks
Outcomes	per cent change from baseline at 6 weeks of serum TC and LDL‐C for the 20 mg/day data set per cent change from baseline at 6 weeks of serum TC, LDL‐C and triglycerides for the 40 mg/day data set
Source of Funding	unknown
Notes	HDL‐C and triglycerides were not included in the efficacy analysis of the 20 mg/day data set because the calculated data were different by more than 10% from the given data HDL‐C was not included in the efficacy analysis of the 40 mg/day data set because the calculated value was different by more than 10% from the given value WDAEs were not reported
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of random sequence generation was not reported
Allocation concealment (selection bias)	Unclear risk	Allocation concealment was not reported
Blinding of participants and personnel (performance bias)   All outcomes	Low risk	Double‐blind placebo and fluvastatin capsule appearances were not reported as appearing identical Lipid parameter measurements unlikely influenced by lack of proper blinding
Blinding of outcome assessment (detection bias)   LDL‐cholesterol	Low risk	LDL‐C was determined by the Pasteur Institute Central Laboratory
Blinding of outcome assessment (detection bias)   WDAEs	High risk	No WDAES were reported
Incomplete outcome data (attrition bias)   All outcomes	Low risk	2.6% participants were not included in the efficacy analysis
Selective reporting (reporting bias)	Low risk	LDL‐C outcome was reported
Other bias	Unclear risk	Source of funding was not reported