Intolerance upon statin rechallenge: A systematic review and meta-analysis of randomized controlled trials

Classified as probably not a substantial claim.

A minimally clinically important difference was predefined as 10 or greater on a 100-point symptoms scale.

“We predefined a minimally clinically important difference as 10 or greater on a 100-point symptoms scale [9].”

• cites [9] AM Kelly, The minimum clinically significant difference in visual analogue scale pain score does not differ with severity of pain, Emerg Med J. 200 sourcePartly supported

  The Results report a minimum clinically significant difference of 12 mm on a 100 mm visual analogue pain scale, and Table 1 reports estimates of 10–14 mm across pain-severity groups. This supports a roughly 10-point benchmark for pain, but the paper does not establish a predefined threshold of 10 or greater for a general symptoms scale. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

The systematic review is reported according to PRISMA.

“This systematic review is reported according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [7].”

• cites [7] PRISMA Group, 2009, Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement, PLoS Med sourceSupported

May combine two claims.

Of 1,941 studies screened, 8 met inclusion criteria, with 8 to 491 participants from Asia, Europe, North America, and Oceana.

“Of 1,941 studies screened, 8 met our inclusion criteria (8 to 491 participants from Asia, Europe, North America, and Oceana).”

Classified as probably not a substantial claim. May combine two claims.

The systematic review screened 1,971 studies, reviewed 53 full texts, and included 8 trials meeting inclusion criteria.

“A total of 1,971 studies were screened for inclusion, with 53 undergoing full text review and 8 meeting our inclusion criteria (Fig 1).”

Probably not a substantial claim: may not pass S3 (load-bearing).

The median age of participants in the included trials was 65 years old (IQR 61 to 66).

“the median age was 65 years old, with an interquartile range of 61 to 66 years old.”

May combine two claims.

Only 1 of the 8 included trials had a parallel design; the others were n-of-1 (n=3) or crossover (n=4).

“Only 1 trial had a parallel design, with the others being n-of-1 (n = 3) or crossover (n = 4)”

Probably not a substantial claim: may not pass S3 (load-bearing).

Only two of the 8 included trials reported funding from the pharmaceutical industry.

“Only two trials reported funding from the pharmaceutical industry.”

May combine two claims.

Only one-third of those previously believed to be statin intolerant were unable to tolerate a statin on blinded rechallenge; one-quarter were intolerant of placebo.

“only one-third of those previously believed to be statin intolerant were unable to tolerate a statin on blinded rechallenge; one-quarter were intolerant of placebo.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The 8 included trials were published between 2008 and 2021.

“Overall, the 8 included trials were published between 2008–2021 and conducted in the United States (n = 2), United Kingdom (n = 2), Norway (n = 1), Canada (n = 1), and in multiple countries with a United States coordinating centre (n = 2).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The statins used in the included trials were atorvastatin (n=4), rosuvastatin (n=1), fluvastatin (n=1), simvastatin (n=1), and multiple statins (n=1).

“The statins used were atorvastatin (n = 4), rosuvastatin (n = 1), fluvastatin (n = 1), simvastatin (n = 1), and multiple statins (n = 1);”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The 8 included trials were conducted in the United States (n=2), United Kingdom (n=2), Norway (n=1), Canada (n=1), and multiple countries with a United States coordinating centre (n=2).

“Overall, the 8 included trials were published between 2008–2021 and conducted in the United States (n = 2), United Kingdom (n = 2), Norway (n = 1), Canada (n = 1), and in multiple countries with a United States coordinating centre (n = 2).”

May combine two claims.

In participants rechallenged with statin therapy, 36% experienced intolerance (325 events/906 total events), compared to 26% on placebo (233 events/911 total events) (RR 1.40, 95% CI 1.23 to 1.60, I2 = 0%, number needed to harm 10).

“In participants rechallenged with statin therapy, 36% experienced intolerance (325 events /906 total events), compared to 26% on placebo (233 events/911 total events) (RR 1.40, 95% CI, 1.23 to 1.60, I2 = 0%, number needed to harm 10).”

• Also stated in: § Discussion · plain

  “Only 36% of participants were intolerant of statins on rechallenge compared to 26% who were intolerant on placebo.”

Probably not a substantial claim: may not pass S3 (load-bearing).

In 3 trials, ≥75% of participants tried at least 2 statins before the trial.

“In 3 trials, ≥75% of participants tried at least 2 statins before the trial;”

Probably not a substantial claim: may not pass S3 (load-bearing).

Our findings were consistent with subgroup and sensitivity analysis.

“our findings were consistent with subgroup and sensitivity analysis”

Probably not a substantial claim: may not pass S3 (load-bearing).

In 2 trials, 25% to 50% of participants tried at least 2 statins before the trial.

“in 2 trials, 25% to 50% tried at least 2 statins;”

Probably not a substantial claim: may not pass S3 (load-bearing).

The remainder of the trials did not provide information on the number of statins tried before the trial.

“and the remainder of the trials did not provide this information.”

May combine two claims.

Overall, statin recipients were more symptomatic than placebo recipients, but this was not statistically significant: symptom scores were a mean 1.08 points higher out of 100 (95% CI -1.51 to 3.67, I2 = 0%).

“Overall, statin recipients were more symptomatic than placebo recipients, but this was not statistically significant: symptom scores were a mean 1.08 points higher out of 100 (95% CI, -1.51 to 3.67, I2 = 0%).”

• Also stated in: § Discussion · plain

  “no significant difference in mean myalgia or global symptom scores was found between statins and placebo.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Participants were recruited from a variety of sites including primary care clinics, specialty clinics, hospitals, and a veteran affairs primary care centre.

“Participants were recruited from a variety of sites including primary care clinics, specialty clinics, hospitals, and a veteran affairs primary care centre.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Among the 6 trials that reported ethnicity, all participants were ≥90% Caucasian except for Kennedy with 68% Caucasian, 18% African American, and 6% Hispanic.

“Among the 6 trials that reported ethnicity, all participants were ≥ 90% Caucasian except for Kennedy with 68% Caucasian, 18% African American, and 6% Hispanic.”

Probably not a substantial claim: may not pass S3 (load-bearing).

In the Howard trial, 30/60 (50%) remained on statins at 6 months.

“This included Howard, where 30/60 (50%) remained on statins at 6 months”

Probably not a substantial claim: may not pass S3 (load-bearing).

In the Joy trial, 5/8 (62.5%) remained on statins at 10 months.

“and Joy, where 5/8 (62.5%) remained on statins at 10 months.”

May combine two claims.

Seven trials provided data related to intolerance including patient-reported intolerable myalgia (n=1); predefined change in VAS score (n=1); stops and withdrawals (n=4); and withdrawals (n=1).

“Seven trials provided data related to intolerance including patient-reported intolerable myalgia (n = 1); predefined change in VAS score (n = 1); stops and withdrawals (n = 4); and withdrawals (n = 1).”

May combine two claims.

Five trials provided data for the myalgia or global symptom score analysis, four reporting myalgia and one reporting global symptoms.

“Five trials provided data for this analysis, four reporting myalgia and one reporting global symptoms.”

Classified as probably not a substantial claim.

Eligible trials with unblinded participants or comparators of usual care and no intervention were excluded from data synthesis to avoid the potential nocebo effect.

“To ensure intolerance was not impacted by the potential nocebo effect, any eligible trials with unblinded participants or comparators of usual care and no intervention were not included in data synthesis.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The small number of trials is a limitation.

“the small number of trials”

Probably not a substantial claim: may not pass S3 (load-bearing).

The review protocol was published on PROSPERO prior to data extraction.

“the protocol was published on the Prospero database (CRD42023437648) prior to data extraction.”

Classified as probably not a substantial claim.

Statin intolerance has no consensus definition.

“Given that statin intolerance has no consensus definition [8]”

• cites [8] BS Wiggins, 2022, Statin-associated muscle symptoms-A review: Individualizing the approach to optimize care, Pharmacotherapy sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

There is potential for carryover effects in crossover/n-of-1 trial designs.

“the potential for carryover effects in crossover/n-of-1 trial designs.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The search was carried out on May 1, 2023, with no restrictions on date or language.

“The search was carried out on May 1, 2023, with no restrictions on date or language.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Two data extractors assessed all included trials for potential bias using the Cochrane Collaboration's risk-of-bias tool 1.

“Two data extractors (FW and EM) assessed all included trials for potential bias using the Cochrane Collaboration’s risk-of-bias tool 1 [10].”

• cites [10] JPT Higgins, 2017Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S1 (asserted).

Trials with high attrition bias (stopping and withdrawal exceeding 10% in all groups at all time points) were excluded.

“If stopping and withdrawal exceeded 10% at all time points in any group, that trial was excluded.”

• AssumptionRests on an assumption: Individuals who are more symptomatic are more likely to stop the study drug or withdraw from the trial, making groups appear more similar than reality.

Probably not a substantial claim: may not pass S3 (load-bearing).

All participants in the included trials were blinded.

“All participants were blinded.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Two authors independently extracted data, with differences resolved by consensus or a third person.

“Two authors (FW and EM) independently extracted data using Google spreadsheet. Differences were resolved by consensus or by involving a third person (RK).”

Classified as probably not a substantial claim.

When data was available from multiple time points, the furthest time point with negligible attrition bias was chosen.

“When data was available from multiple time points, we chose the furthest time point in the trial where attrition bias appeared negligible (defined as stopping and withdrawal being less than 10% in all groups).”

Probably not a substantial claim: may not pass S3 (load-bearing).

A definition of statin intolerance was provided for only 2 of the included trials.

“A definition of statin intolerance was provided for only 2 trials.”

Probably not a substantial claim: may not pass S3 (load-bearing).

A health sciences librarian developed the search strategy and adapted it for Medline, Embase, CINAHL Plus, Scopus, and the Cochrane CENTRAL trial registry.

“A health sciences librarian (LD) developed a search strategy and adapted it for Medline, Embase, CINAHL Plus, Scopus, and the Cochrane CENTRAL trial registry (S1 Text).”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

There is a possibility of attrition bias.

“the possibility of attrition bias”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Two authors independently screened titles and abstracts and examined full texts to determine eligibility, with conflicts resolved by consensus or a third reviewer.

“Two authors (FW and EM) independently screened titles and abstracts and examined full texts to determine eligibility. Any conflicts were resolved by consensus or by a third reviewer (RK) if needed.”

May combine two claims.

Although attrition bias is possible, it is doubtful that it would cause a clinically meaningful difference to myalgia or global symptom score, given that trials either adjusted the scores for attrition, had minimal attrition, or had similar attrition between statin and placebo periods.

“There is a possibility of attrition bias, but doubtful this would cause a clinically meaningful difference to myalgia or global symptom score given that either trials adjusted the scores for attrition, had minimal attrition, or had similar attrition between statin and placebo periods.”

May combine two claims.

Generalizability is further improved with the wide variety of statins used; the variety of countries in which the trials took place (although most were Caucasian and in their 60s); the wide variety of preventive settings out of which participants were recruited; and the number of times participants attempted to take a statin prior to being enrolled in a trial.

“Generalizability is further improved with the wide variety of statins used; the variety of countries in which the trials took place (although most were Caucasian and in their 60s); the wide variety of preventive settings out of which participants were recruited; and the number of times participants attempted to take a statin prior to being enrolled in a trial.”

Probably not a substantial claim: may not pass S2 (checkable).

These findings appear robust.

“These findings appear robust”

Classified as probably not a substantial claim.

The half-life of statin medication ranges between 5 and 30 hours.

“Although the half-life of statin medication ranges between 5 and 30 hours [23]”

• cites [23] S Bellosta, 2012, Statin drug interactions and related adverse reactions, Expert Opin Drug Saf sourceNot checked — no full text of the source

May combine two claims.

The potential for missing intolerant participants is mitigated by the high weighting of the trial asking about intolerable symptoms, the lack of heterogeneity between trials, and sensitivity analysis that found little difference between groups.

“Mitigating against this is the high weighting of the trial asking about intolerable symptoms, the lack of heterogeneity between trials, and sensitivity analysis that found little difference between groups.”