RESEARCHED DRUG INFORMATION QUESTION - WHILE AT THE UNIVERSITY AT BUFFALO, 2015
by Timothy Zablocki
From an Inpatient General Medicine Rotation
Date of Question: 03/02/15 Date of Response: 03/03/15
Question Source: Rounding Physician
Specific Question: Is long-term high-dose statin treatment, such as with 80mg of atorvastatin, associated with decreased kidney function or kidney-related adverse events in patients with renal insufficiency?
Data Sources:
Pub Med Search using the terms: “statin” AND “renal” AND “failure”
Filtered by article type: “Clinical Trial”
Response:
Background:
Atorvastatin is one of many HMG-CoA reductase inhibitors, more commonly known as “statins,” that are available for the treatment of hypercholesterolemia and for myocardial infarction or stroke prophylaxis. The enzyme HMG-CoA reductase is responsible for converting HMG-CoA to mevalonate, which is a precursor for cholesterol.(1) Treatment with statins inhibits HMG-CoA and prevents the conversion of mevalonate to cholesterol in the liver. Consequently, hepatic uptake of circulating LDL-cholesterol increases leading to a reduction of total cholesterol in the blood.
Renal insufficiency is listed as a precaution for use of statins such as atorvastatin, simvastatin and pravastatin.(1) Acute renal failure is a potential adverse event associated with atorvastatin and other statins and its occurrence is attributed to rhabdomyolysis and subsequent renal tubular obstruction.(1,2) Given that many patients prescribed statins may have kidney disease, it is important to take into consideration the frequency of actual kidney-related adverse events. A specific question that may be encountered in practice is whether there is risk in using a high-dose statin (such as 80mg atorvastatin), which in theory would be more likely to cause renal failure, in a patient that has renal insufficiency at baseline.
Literature Review:
In a pooled analysis that evaluated for renal-associated adverse events from 24 different placebo-controlled trials, a study found no differences in the rates of events within the first 120 days of statin use, after 120 days of use or in the rates of discontinuation of statins due to renal-associated adverse events as compared to placebo.(3) In two other trials discussed in the article that specifically compared outcomes of high dose statin use to low dose statin use, no differences were found for the same endpoints. In the “Treating to New Targets” (TNT) study, 80mg atorvastatin was compared to 10mg atorvastatin in 10,001 patients with coronary artery disease, of whom 3,107 had chronic kidney disease defined as an eGFR<60mL/min per 1.73m2.(4) Only 29 of those individuals, however, had stage 4 chronic kidney disease (eGFR 15 to 29mL/min per 1.73m2) and none had stage 5 disease (eGFR<15mL/min per 1.73m2), with most of the patients with CKD falling into stage 3 category. The median follow-up time in that study was 5.0 years. The “Incremental Decrease in End points through Aggressive Lipid lowering” (IDEAL) study compared treatment with 80mg atorvastatin to 20mg simvastatin in 8,888 patients following a myocardial infarction.(5) Although the median follow-up in this prospective randomized trial was also quite long at 4.8 years, no data on the baseline renal function of the subjects was presented by the authors in the original article.
An article by Sarma et al., looked at the risk of acute kidney injury in patients after an acute coronary syndrome across two randomized trials, one that compared individuals on 80mg atorvastatin to those on moderate-intensity 40mg pravastatin and another that compared individuals taking 40mg simvastatin for one month followed by 80mg thereafter to those that took placebo for 4 months followed by simvastatin 20mg afterward.(6) Follow-up was 24 months and data was collected at predetermined study visits every 4 months. Data collected specifically from patients with an eGFR<60mL/min per 1.73m2 at baseline showed that there was no significant difference in change from baseline SCr in those that received high dose atorvastatin compared to those that received moderate-intensity pravastatin at any of the follow-up visits. Similarly, no significant differences for baseline SCr changes were found between the high-dose simvastatin and placebo/simvastatin groups in patients with an eGFR<60mL/min per 1.73m2.
In a randomized controlled trial, the effect of 80mg atorvastatin on estimated glomerular filtration rate was compared to placebo in 4,719 patients with chronic kidney disease (eGFR<60mL/min per 1.73m2) and without CKD (eGFR>60mL/min per 1.73m2).(7) Both groups of patients, with and without CKD, on high-dose atorvastatin had significantly higher increases in their eGFR as compared to those that were given placebo as measured at each follow-up study visit every 12 months for up to 5 years. The mean increase in eGFR in the CKD group treated with high-dose atorvastatin at 60 months was 4.24 ± 0.60mL/min per 1.73m2. In comparison, the mean increase in eGFR in the CKD group treated with placebo was 2.53 ± 0.60mL/min per 1.73m2. The study was limited to patients with a prior stroke or TIA and similarly had a small proportion of subjects that had stage 4 or 5 CKD, but showed that high-dose statins may actually be nephro-protective in patients with CKD.
Another study that looked specifically at atorvastatin use at strengths ranging from 10mg to 80mg per day in Greek patients with coronary heart disease (CHD) had similar findings.(8) Statin use was associated with a greater increase in CrCl over a period of 48 months in patients that had a lower eGFR at baseline compared to those with a higher eGFR at the start of therapy. Additionally, patients on higher doses of atorvastatin (40-80mg/day) showed a significantly (p = 0.001) greater increase in CrCl than those on lower doses of atorvastatin (10-20mg/day). The authors concluded that high-dose statins prevent decline in renal function in patients with CHD.
In contrast, the authors of a large population-based case-control study that looked at individuals in a region of Italy and collected and analyzed data from a healthcare utilization database found that high-potency statin use was associated with a significantly higher risk of hospitalization related to acute kidney injury.(9) In this retrospective study, however, a large number of confounding factors were present, which the authors acknowledged and attempted to correct for. The authors added that because this adverse event is so rare and that data in support of statin use is so overwhelming they did not believe that prescribing patterns needed to change based specifically on their findings.
Summary:
Studies suggesting that statin use may be associated with renal failure have largely been observational or retrospective in nature.(2,9) Data from numerous clinical trials suggests that renal function is not affected significantly by high-dose statin use in patients that have chronic kidney disease and that it may actually be improved. In a specific situation where an 80mg per day regimen of atorvastatin is prescribed to a patient with renal insufficiency, the treatment is likely to have little risk associated with it and may have additional benefit. However, there are some considerations that should be taken into account before advocating the safety of high-dose statin use in this type of patient. First, the majority of the studies found and discussed here looked at the use of high-dose atorvastatin specifically rather than any of the other available alternatives. Second, many of the studies included relatively few patients that had stage 4 or 5 CKD or that were on dialysis. Finally, as always, the presence of other factors, such as drug interactions or comorbidities, need to be assessed in each patient before making a similar recommendation.
References:
1. Clinical Pharmacology. Elsevier/Gold Standard. http://www.clinicalpharmacology-ip.com/default.aspx. Accessed March 3, 2015.
2. Ram R, Swarnalatha G, Ramesh V, Rao KN, Dakshinamurty KV. Rhabdomyolysis induced acute renal failure secondary to statins. Indian journal of nephrology. 2013;23(3):211-213.
3. Bangalore S, Fayyad R, Hovingh GK, et al. Statin and the risk of renal-related serious adverse events: Analysis from the IDEAL, TNT, CARDS, ASPEN, SPARCL, and other placebo-controlled trials. The American journal of cardiology. 2014;113(12):2018-2020.
4. Shepherd J, Kastelein JJ, Bittner V, et al. Intensive lipid lowering with atorvastatin in patients with coronary heart disease and chronic kidney disease: the TNT (Treating to New Targets) study. Journal of the American College of Cardiology. 2008;51(15):1448-1454.
5. Pedersen TR, Faergeman O, Kastelein JJ, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. Jama. 2005;294(19):2437-2445.
6. Sarma A, Cannon CP, de Lemos J, et al. The incidence of kidney injury for patients treated with a high-potency versus moderate-potency statin regimen after an acute coronary syndrome. Journal of the American Heart Association. 2014;3(3):e000784.
7. Amarenco P, Callahan A, 3rd, Campese VM, et al. Effect of high-dose atorvastatin on renal function in subjects with stroke or transient ischemic attack in the SPARCL trial. Stroke; a journal of cerebral circulation. 2014;45(10):2974-2982.
8. Athyros VG, Mikhailidis DP, Papageorgiou AA, et al. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study. Journal of clinical pathology. 2004;57(7):728-734.
9. Corrao G, Soranna D, Casula M, Merlino L, Porcellini MG, Catapano AL. High-potency statins increase the risk of acute kidney injury: evidence from a large population-based study. Atherosclerosis. 2014;234(1):224-229.