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Kidney-injury analysis "reassuring" for high-potency statins in PROVE-IT, A to Z
  June 21, 2013
"High-potency" statins linked to acute kidney injury
[Lipid/Metabolic > Lipid/Metabolic; Mar 19, 2013]
Boston, MA - A new analysis of the PROVE IT-TIMI 22 and A to Z (Z phase) studies "provides reassurance" that intensive statin therapy does not increase serum creatinine or the risk of kidney injury, investigators say [1].


Dr Amy Sarma
Dr Amy Sarma (Brigham and Women's Hospital, Boston, MA) presented the analysis Wednesday as part of the American Heart Association's Emerging Science series, a live online broadcast.
Concerns about kidney injury with high-potency statins have gathered steam in the wake of several large observational studies. One recent study, in particular-a large administrative database of more than two million newly prescribed statin takers in Canada, the US, and the UK-found that >10-mg rosuvastatin (Crestor, AstraZeneca), >20-mg atorvastatin, or >40-mg simvastatin were all significantly worse than lower-dose statin therapy for the end point of acute kidney injury hospitalization.
Insights from randomized data
For their new analysis, Sarma and colleagues looked at the PROVE IT-TIMI 22 and A to Z (Z phase) trials, excluding any patients with baseline elevations in serum creatinine of >2.0 mg/dL. They then compared the incidence of adverse events relating to kidney injury between the low- and high-potency statin groups in these studies.
In PROVE-IT, the high-potency group received atorvastatin 80 mg, while the standard-therapy group received pravastatin 40 mg. The A to Z compared 20-mg simvastatin with a 40-mg and 80-mg dose of the same drug.
Over long-term follow-up in both studies, incidence of creatinine elevations was no different between high- and low-potency statin groups. When Sarma et al looked only at the first four months of treatment-identified as a critical period for kidney injury in the earlier studies-they still saw no differences in creatinine elevation between lower- and higher-dose statin groups.
When the trials were combined, risk of kidney-injury-related adverse events was the same for the low- and high-potency groups, both within the early (first four months) and later trial period (continued-access database).
"These findings provide important reassurance to clinicians that the use of high-potency statins is safe for patients after ACS," Sarma concluded.


Timing of kidney effects
Creatinine was only centrally assessed at prespecified time points in both trials; "therefore, we cannot exclude the possibility that a transient rise in serum creatinine could have been missed," she noted. However, reassuringly, the lack of a signal of acute kidney injury was also consistent with the results seen for creatinine elevation.
This may be one explanation for why these findings from two large randomized clinical trials differed from the community-based studies. "In the administrative database trials they were relying on ICD codes and other codes [as surrogates for kidney injury] that are subject to interpretational issues," Sarma said.
In the panel discussion following Sarma's presentation, Dr Neil J Stone (Feinberg School of Medicine, Northwestern University, Chicago, IL) asked about higher-risk patient groups, pointing out that younger and older patients may not be represented in the PROVE-IT and A to Z trial populations.
Sarma responded that she and her colleagues had conducted separate analyses looking both at patients with higher and lower levels of estimated glomerular filtration rate (eGFR) at baseline, as well as at patients with and without diabetes, and found no differences between groups. Of note, however, the trials included a limited number of patients with eGFR <30 mL/min/1.73 m2 at baseline. Other studies are exploring the impact of high-potency statins in vulnerable populations, including those at younger and older ages, she added.
Another panel member, Dr Vasan Ramachandran (Framingham Heart Study, Boston, MA), pointed out that rare adverse events can be missed in randomized trials yet nevertheless prove important in the population at large. It bears remembering that this is a post hoc analysis and therefore only hypothesis-generating, he observed.
Sarma disclosed having no conflicts of interest. Disclosures for coauthors are listed in the abstract provided on the AHA Emerging Science website.
1. Sarma A, Cannon CP, Wiviott SD, et al. The incidence of kidney injury for patients treated with intensive versus less potent statin therapy after an acute coronary syndrome. Circulation 2013; DOI: 10.1161/CIR.0b013e31829ecc16.

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