High-Risk Subgroups Derive Kidney Protection from Rosuvastatin

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Rosuvastatin given shortly before angiography can help prevent contrast-induced acute kidney injury (CI-AKI) in high-risk patients, whether they have diabetes and chronic kidney disease or present with non-ST-segment elevation acute coronary syndromes (NSTE-ACS). The findings, from 2 randomized trials, were published online October 9, 2013, ahead of print in the Journal of the American College of Cardiology.

Diabetes Patients Benefit from Statin Therapy

For the larger of the 2 trials, Yaling Han, MD, PhD, of Shenyang Northern Hospital (Shenyang, China), and colleagues enrolled 2,998 patients with type 2 diabetes and concomitant chronic kidney disease undergoing coronary or peripheral arterial angiography with or without percutaneous intervention. Patients were randomized to rosuvastatin 10 mg/day for 5 days (2 days before and 3 days after the procedure; n = 1,498) or standard care (n = 1,500).

Hydration therapy was given at physician discretion to 44.9% of the rosuvastatin group and 42.8% of the control group. Slightly more than half of patients (58.4%) were statin naive, with the remainder (41.6%) having previously taken statins but not within the last 14 days.

Baseline levels of total cholesterol, LDL cholesterol, and high-sensitivity C-reactive protein were equivalent between the 2 treatment arms, but at follow-up, rosuvastatin patients had lower values for all 3 measurements compared with controls (P < 0.01, P < 0.01, and P = 0.01, respectively).

The incidence of CI-AKI (primary endpoint; increase in serum creatinine ≥ 0.5 mg/dL or ≥ 25% from baseline at 72 hours) was lower with rosuvastatin than with standard care both in the overall group and in the subgroup of patients with stage 2 chronic kidney disease. While there were no differences in all-cause death or dialysis/hemofiltration at 30 days, rosuvastatin did reduce the rate of worsening heart failure (table 1).

Table 1. Outcomes in Patients with Diabetes and Chronic Kidney Disease

 

Rosuvastatin
(n = 1,498)

Control
(n = 1,500)

P Value

CI-AKI
Overall
Stage 2 CKD

 
2.3%
1.5%

 
3.9%
3.3%

 
0.01
0.01

30-Day Outcomes
Death
Dialysis/Hemofiltration
Worsening HF

 0.2%
0
2.6%

 0.3%
0.1%
4.3%

 0.73
0.50
0.02

Abbreviations: CKD, chronic kidney disease; HF, heart failure.

On multivariable analysis, rosuvastatin use decreased the risk of developing CI-AKI (OR 0.60; 95% CI 0.39-0.94; P = 0.03) as did hemoglobin. Independent predictors of higher risk were baseline ACS, New York Heart Association functional class, and decreased eGFR.

Side effects related to muscle pain, liver function, GI disorders, edema, and rash occurred at similar rates in the rosuvastatin and control groups.

Renal Damage, Subsequent Adverse Events Less Likely in NSTE-ACS

The other study, PRATO-ACS, was previously presented at this year’s American College of Cardiology/i2 Scientific Session in San Francisco, CA. Researchers led by Anna Toso, MD, of Misericordia e Dolce Hospital (Prato, Italy), randomized 504 NSTE-ACS patients scheduled for PCI to standard preventive therapy with (n = 252) or without rosuvastatin (n = 252; 40 mg on admission plus 20 mg daily until discharge). Patients were statin naïve.

Development of CI-AKI (primary endpoint; defined as in the trial by Han et al) was less common in rosuvastatin patients compared with controls (6.7% vs. 15.1%; P = 0.003). After adjustment for sex, age, diabetes, and other potential confounders, statin treatment independently predicted reduced risk of CI-AKI (OR 0.38; 95% CI 0.20-0.71).

The number-needed-to-treat to prevent 1 case of CIN was 12, and rosuvastatin showed consistent benefits across other definitions of CI-AKI and all prespecified subgroups.

At 30 days, the risk of adverse cardiovascular and renal events (death, dialysis, MI, stroke, or persistent renal damage) was lower for patients randomized to rosuvastatin, driven by a lower rate of persistent renal damage. Rosuvastatin also showed a trend toward less death/nonfatal MI at 6 months (table 2).

Table 2. PRATO-ACS: Clinical Outcomes

 

Rosuvastatin
(n = 252)

Control
(n = 252)

P Value

30-Day Adverse Events
Death
Dialysis
MI
Stroke
Persistent Renal Damage

3.6%
0.8%

0.8%

2%

7.9%
1.2%
0.8%
2%

4.8%

0.036
> 0.90
0.50
0.45

0.15

6-Month Death/Nonfatal MI

3.6%

7.2%

0.07


‘Provocative Link’ Apparent

Hitinder S. Gurm, MD, of the University of Michigan (Ann Arbor, MI), told TCTMD in an e-mail communication that while using statins to prevent CI-AKI “is still not standard of care,” most experts now “recognize the provocative link” between statins and AKI reduction based on positive results of multiple small studies. Moreover, short-term statin therapy is safe and has no known downsides, Dr. Gurm reported.

In a telephone interview with TCTMD, Peter A. McCullough, MD, MPH, of St. John Providence Health System (Warren, MI), pointed out that a large Blue Cross Blue Shield study of more than 30,000 patients some years ago found an association between preprocedural statin therapy and reduced AKI risk (Khanal S, et al. Am J Med. 2005;118:843-849).

“It was always thought that maybe [the finding was] due to selection, [in that] better patients take statins or more careful doctors prescribe more statins. A couple of randomized trials were mixed on whether statins have any effect,” but the large size of the study by Dr. Han and colleagues provides convincing evidence that the benefit is real, Dr. McCullough said.

“Statins work to inhibit a major pumping function of the proximal tubular cells” in the kidneys, he explained. Typically, these cells absorb small amounts of contrast media in the process of removing impurities and producing urine. “Maybe the reason why statins are protective is that they’re allowing the contrast to get out through the urine and not be reabsorbed,” Dr. McCullough said.

Many Unanswered Questions

The current studies enrolled patients who either were statin naive or had not been taking the drugs for some time, raising the question as to whether patients already on statins might benefit. Dr. Gurm predicted that the effects would likely be seen across the board but added, “It needs to be established if we should be reloading patients who are already on high-dose statins.”

Additionally, it is still unknown whether the results seen here represent a class effect, or if rosuvastatin is somehow unique. Dr. Gurm noted that similar benefits have been seen with other statins such as atorvastatin, and Dr. McCullough agreed that they probably “all have an effect.”

An accompanying editorial by Martin A. Alpert, MD, of the University of Missouri Health Sciences Center (Columbia, MO), does not rule out the possibility that rosuvastatin may be uniquely protective. “Head-to-head comparison of commercially available hydrophilic and lipophilic statins at both high and low doses would help to determine if differences exist in their ability to reduce CI-AKI risk and whether dose matters,” he advises, adding that other research might look into whether the severity of baseline chronic kidney disease affects benefit.

For patients undergoing emergent procedures, Dr. McCullough sees no reason not to try preventative statins. “It takes a few days for [statins] to have a biological effect, but we have a lot of acute coronary syndrome data showing they probably have an acute effect as well,” he said.

Note: Roxana Mehran, MD, of Mount Sinai Medical Center (New York, NY), who coauthored the paper by Han et al, is a faculty member of the Cardiovascular Research Foundation, which owns and operates TCTMD.

 


Sources:
1. Han Y, Zhu G, Han L, et al. Short-term rosuvastatin therapy for prevention of contrast-induced acute kidney injury in patients with diabetes and chronic kidney disease. J Am Coll Cardiol. 2013;Epub ahead of print.

2. Leoncini M, Toso A, Maioli M, et al. Early high-dose rosuvastatin for contrast-induced nephropathy prevention in acute coronary syndrome: Results from Protective effect of Rosuvastatin and Antiplatelet Therapy On contrast-induced acute kidney injury and myocardial damage in patients with Acute Coronary Syndrome (PRATO-ACS study). J Am Coll Cardiol. 2013;Epub ahead of print.

3. Alpert MA. Do statins reduce the risk of contrast-induced acute kidney injury in patients undergoing coronary angiography or percutaneous coronary interventions [editorial]? J Am Coll Cardiol. 2013;Epub ahead of print.

 

 

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Disclosures
  • Drs. Han, Toso, Alpert, Gurm, and McCullough report no relevant conflicts of interest.

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