On-Treatment analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial.

Lead Investigator: J. David Spence, Western University, London, ON, Canada.
Title of Research Proposal:  On-Treatment analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Trial.
Vivli Data Request: 4118
Funding Source: None
Potential Conflicts of Interest: I have no relevant conflicts of interest. Unrelated disclosures: I am a consultant to Amgen and Orphan Technologies and an officer of Vascularis Inc.; I have received lecture fees from Pfizer and Bristol Myers Squibb

Summary of the Proposed Research:
There is a widespread belief that statins cause intracerebral hemorrhage (ICH). The result of this belief is that some patients who would benefit from statins to reduce their risk of stroke or other vascular events do not receive them, or low doses are used inappropriately. This is particularly the case in Asia, and in patients with a previous ICH. At a course in stroke prevention during the World Stroke Organization (WSO) conference in 2018, a leading expert from the UK, and chair of the WSO  education committee, cautioned against statins in Asians for this very reason, and another leading US expert presented a paper reviewing reasons why statins might cause intracerebral hemorrhage. Currently there is a randomized trial funded by NINDS in which patients with ICH are to be randomized to continue or stop statins. However, a number of large observational studies and at least two meta-analyses indicate that this statin do not cause ICH. Much of the mistaken belief that statins cause ICH originated with the intention-to-treat (ITT) analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial.

However, there were major problems with the ITT analysis, because many patients randomized to placebo crossed over to statin, and many patients stopped their statin.  Low levels of LDL-C do not cause ICH; this is now clear from the studies of PCSK9 antibodies, with LDL-C down to 0.2 mmol/L (~ 7.6 mg/dL).

It may be regarded as unethical to stop statins after stroke for the intended purpose of preventing intracerebral hemorrhages.

The lipid lowering trialists collaboration [1] estimated that the risk of ICH from statins is  ~ 50 times lower than the benefit than the benefit from taking statins. That estimate was predicated on a mistaken conclusion (based on a meta-analysis that was heavily weighted by the SPARCL trial) that statins slightly increase the risk of ICH; however, the totality of the evidence indicates that this relationship is not causal. This means that it is probably much more than 50 times higher risk to stop statins than continue them in stroke patients, who are at high risk of vascular events.

It is apparent that statins do not cause intracerebral hemorrhage; this is confirmed in two meta-analyses [2, 3] and several large cohort studies. [4-6] In patients who continued statin after intracerebral hemorrhage, there was a significant reduction of overall mortality, with no significant increase in ICH.

The main source of the controversy is an artefact resulting from the ITT analysis of SPARCL, in which ~ 25% of patients randomized to placebo crossed over to statin, and many patients randomized to atorvastatin discontinued statin.

The increase in ICH in patients randomized to statin in SPARCL could not have been due to statin, because the patients who had ICH did not have lower LDL-C. [7] It is not possible to not have a lower LDL-C when taking atorvastatin 80mg.  The participants who had ICH had higher blood pressures and were significantly more likely to have Stage 2 hypertension. The reason they had ICH was probably because when they had an adverse effect of statin on the study, they went off all their medication (as patients so often do), including their blood pressure medication.[8] When I called Michael Welch, the PI of SPARCL, about this at the time SPARCL was published, his response indicated that this hypothesis was probably correct.

Although intention-to-treat analysis is usually regarded as de rigeur, it is not perfect. [9, 10] There are good reasons to also perform analyses that show the potential of a treatment among persons able to take it. Hernan and Robins discussed this issue,[11] saying that ITT may not be directly relevant for guiding decisions in clinical settings with different adherence patterns. Sheiner[12]  made the distinction between “use effectiveness” (the result of prescribing a medication) and “method effectiveness” (the result of taking a medication). He pointed out that for the purpose of treating individual patients, method effectiveness was a more useful pharmacologic characteristic.

With regard to ITT vs. on-treatment (per protocol) analyses, Hernan and Robins [11] state the following: “An intention-to-treat analysis estimates the effect of treatment assignment in a particular trial, not the effect of treatment itself. Intention-to-treat effects are agnostic about postrandomization decisions, including treatment discontinuation and the use of concomitant therapies prohibited by the study protocol. For example, consider two pragmatic trials of a new active treatment versus standard of care. In the first trial, half the patients assigned to the active treatment actually received it and the other half did not. In the second trial, all the patients assigned to the active treatment received it. In neither study did any patient assigned to standard of care receive active treatment.” However, in SPARCL the situation was even worse, because ~ 25% of patients randomized to placebo crossed over to statins.

The primary objective of this proposal is to conduct an on-treatment/per protocol analysis of the SPARCL trial to assess the risk of ICH in patients who actually took statins vs. those who took placebo.

Requested Studies:

A Double-Blind, Randomized, Placebo- Controlled Study Of Atorvastatin As Prevention Of Cerebrovascular Events In Patients With A Previous Transient Ischemic Attack (TIA) Or Stroke. Pfizer Protocol Number: A2581138
Data Contributor: Pfizer Inc.
Study ID: NCT00147602

Update: This data request was withdrawn on 21 May 2021 by the researcher.