DALLAS—A pooled analysis of two large randomized clinical trials found no increased risk of kidney injury with the use of high-potency statins compared with moderate-potency statins in patients with acute coronary syndromes (ACS). The analysis was presented by Amy A. Sarma, MD, at the American Heart Association’s Scientific Sessions 2013.
Earlier this year, caution was urged in prescribing high-potency statins when examination of a large administrative database found that newly treated patients who were prescribed high-potency statins—defined as 10 mg or more of rosuvastatin, 20 mg or more of atorvastatin, or 40 mg or more of simvastatin—was associated with an increased rate of hospital admission for acute kidney injury compared with lower potency statins. The increased risk of admission occurred early, within 120 days after statin treatment and remained elevated for at least two years.
Two large double-blind trials in which patients with ACS were randomized to high- or moderate-potency statins were examined: PROVE IT-TIMI 22 and A to Z. In PROVE-IT TIMI, 4,162 patients were randomized to receive either pravastatin 40 mg/day or atorvastatin 80 mg/day. In the “Z” phase of the A to Z trial, 4,497 ACS patients were randomly assigned to simvastatin 20 mg/day or 40 mg/day for one month, followed by simvastatin 80 mg/day (intensive strategy) or placebo for four months followed by simvastatin 20 mg/day (conservative strategy). Patients with baseline serum creatinine levels of 2.0 mg/dL or higher in either trial were excluded from the pooled analysis.
Baseline characteristics were similar in the two studies, including levels of serum creatinine (1.03 mg/dL in PROVE IT-TIMI 22 vs. 1.14 mg/dL in A to Z). The mean follow-up in both trials was two years.
Kidney injury was defined by the Kidney Disease: Improving Global Outcomes (KDIGO) classification with serum creatinine as the referent. Kidney function was assessed at 1, 4, 8, and 12 months in each trial.
The odds of a 1.5-fold or greater increase and a twofold or greater increase in serum creatinine levels were not significantly different between the high-potency regimens and the moderate-potency regimens in either study, said Dr. Sarma, a resident physician in internal medicine at Brigham and Women’s Hospital in Boston.
Compared with moderate-potency statins, high-potency statins were associated with a non-significant 16% increased odds of a 1.5-fold or greater increase in serum creatinine in PROVE-IT TIMI and a non-significant 9% decreased odds in A to Z. Compared with moderate-potency statins, high-potency statins were associated with a non-significant twofold or greater increase in serum creatinine in PROVE-IT TIMI and a non-significant 25% increased odds in A to Z.
When the trials were pooled, the risk of kidney injury-related adverse events was not significantly different between the moderate- and high-potency regimens, both within the first four months and later trial periods.
During the first four months of treatment, when previous studies showed that kidney injury from statin therapy was most likely, there was no difference in the change in creatinine level between the high-potency and moderate-potency regimens. This was also the case over the long term.
The rates of kidney injury were also not significantly different between the two groups in the subgroup of patients with baseline estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73m2.
Tara I. Chang, MD, MS, an instructor of medicine at Stanford University in Palo Alto, Calif., said the results of the pooled analysis may have been affected by patient demographics. Those enrolled in PROVE IT-TIMI 22 and A to Z were younger than the general population with myocardial infarction, were less often female, and fewer had diabetes. “Age, sex, and diabetes are strong risk factors for subsequent kidney injury,” she said. In addition, the percentage with an eGFR below 60 was only 14% in PROVE IT-TIM 22 and 60% in A to A.
She also questioned the ability of the pooled analysis to detect a safety signal, with only about 8,600 participants combined in the two trials, whereas recent observational studies finding a link between high-dose statins and kidney injury included more than four million. In fact, the point estimates for acute kidney injury and kidney injury over the long term in the pooled analysis were consistent with those of the observational studies, but because the pooled analysis had fewer enrollees and fewer events, the confidence intervals were wide and crossed 1.0.
Finally, the definition of “high potency” varied between studies, which could have affected outcomes, Dr. Chang said.