In older hypertensive patients with moderate dyslipidemia, pravastatin was not superior to usual care in preventing clinical kidney disease outcomes. This was consistent across the strata of baseline eGFR. There was a trend for a higher eGFR in the pravastatin group which was not statistically significant.
Previous studies that have examined the effect of statin therapy on progression of kidney disease have yielded inconsistent results, perhaps due to their heterogeneity with regard to patient population studied, baseline kidney function and proteinuria, the criteria used to measure kidney function, and the type of statin used.17
Several studies have shown no benefit of statin therapy on slowing decline in GFR,9;10;18–24
particularly in patients with high levels of proteinuria28
have shown that statin therapy is associated with slower decline in GFR. In the Cholesterol and Recurrent Events trial (CARE), decline in GFR in the pravastatin group was slower than that in the placebo group only in those with GFR <40 ml mL/min per 1.73 m2
(0.67 mL/s/1.73 m2
In the Pravastatin Pooling Project, using data obtained from three large trials (West of Scotland Coronary Prevention Study, Cholesterol and Recurrent Events, and Long-term Intervention with Pravastatin in Ischemic Disease), there was a modestly (0.2 ml/min/year) slower decline in GFR in patients with an eGFR <60 mL/min per 1.73 m2
(<1.00 mL/s/1.73 m2
) who were treated with pravastatin compared to the control group, but there was no significant reduction in the frequency of a 25% decline in GFR.30
In a meta-analysis of 27 randomized trials, statin therapy had an overall modest beneficial effect on change in GFR (1.22 ml/min/1.73 m2
/year [0.02 mL/s/1.73 m2
]); however, there was substantial variability across the studies.31
Specifically, in the hypertensive and diabetic cohorts, likely the ones most similar to ALLHAT-LLT, there was no beneficial effect of statin therapy on decline in GFR. Finally, a recent meta-analysis of 11 trials by Strippoli and colleagues also showed no benefit of statin therapy on decline in kidney function. 32
Our study makes an important contribution to this literature. In the ALLHAT-LLT, there was no consistent benefit of pravastatin therapy compared to usual care with regard to a variety of kidney disease outcomes. This is consistent with the findings in the CARE study, the Strippoli meta-analyses, and diabetic and hypertensive cohorts in the Sandhu meta-analyses.29;31;32
While there was a trend for eGFR to be higher in the pravastatin group at some points in time, this finding was not consistent, and has to be interpreted with caution due to the multiple comparisons involved.
Several factors may have a bearing on the interpretation of our findings. First, the rate of decline in GFR in patients with a eGFR<60 mL/min per 1.73 m2
(<1.00 mL/s/1.73 m2
) was very slow in both pravastatin and the usual care groups. While this may relate to overall excellent levels of blood pressure control in ALLHAT, the slow rate of progression decreases the ability to detect a difference between the two randomized groups. In addition, the mean eGFR at baseline in patients in the moderate-severe group (50 mL/min per 1.73 m2
[0.83 mL/s/1.73 m2
) was higher than in studies that have shown a beneficial effect of statin therapy (most marked in the <40 mL/min per 1.73 m2
[0.67 mL/s/1.73 m2
] group in CARE). However, results in the smaller subset of participants with eGFR<45 ml/min/1.73 m2
(0.75 mL/s/1.73 m2
) did not suggest improved outcomes with pravastatin. Secondly, while proteinuria measurements were not obtained, we speculate that based on the inclusion criteria, the ALLHAT patient population profile is associated with relatively low levels of proteinuria. In addition, patients were excluded if they had a specific indication for ACE inhibitor therapy, such as proteinuria. The LLT results are consistent with studies that show no beneficial effects of statin therapy in patients with minimal proteinuria, compared to a marked benefit in those with high grade proteinuria. Finally, due to the significant drop-in during the course of the study, the difference in the total and LDL-cholesterol between the randomized groups was modest when compared to traditional lipid lowering trials, and did not achieve the 30–40% reduction in LDL-C recommended in current lipid guidelines.33
The achieved LDL-cholesterol in the patients in the moderate to severe reduction in eGFR group in the ALLHAT-LLT (102 mg/dL [2.64 mmol/L] at year 2) was similar to the achieved LDL-cholesterol in a similar population in the Pravastatin Pooling Project (103.9 mg/dL [2.69 mmol/L] at year 1).34
However, the usual care group also had a decrement in LDL-cholesterol in the ALLHAT –LLT with a net difference of 30 mg/dL (0.78 mmol/L) at year 2, compared to a difference between pravastatin and placebo of 47 mg/dL (1.22 mmol/L) at year 1 in the Pravastatin Pooling Project. The smaller difference in LDL-cholesterol may contribute to the lack of statistically significant benefit seen with statin therapy in our study. It is also possible that level of LDL- and total cholesterol achieved in the ALLHAT-LLT are still too high for CKD patients; whether more aggressive lipid lowering will result in improved outcomes in these patients remains to be seen. The lack of a statistically significant difference between the two groups may be due lack of power given the relatively low event rate; based on the observed event rates, we estimate that the study was adequately powered (80%) to estimate rate reductions of 41.8% for ESRD or 25.2% for a combined end point of ESRD and 50% decline in eGFR. However, the study did have adequate power to detect a 10% difference in the composite end point of ESRD and 25% decline in eGFR.
The effect of statin therapy on kidney function may depend on the population studied. In the Sandhu meta-analyses, statin therapy was associated with improved kidney function in patients with cardiovascular disease, but not in diabetic or hypertensive patients. It can be speculated that reduction in cardiovascular events in high risk patients with statins results in fewer catheterization/interventional procedures with lower burden of contrast exposure, and atheroemboli. This effect would not be marked in patients at lower risk for cardiovascular disease.
Our study has several strengths. With more than 1500 patients with moderately reduced eGFR, this is one of the largest individual studies to address the issue of statins in kidney disease. In addition, the mean duration of follow up of 4.8 years is longer than many published studies in this area. Measurement of creatinine in a single central lab minimizes issues of variability of creatinine measurement. The methodologic rigor of the study with careful event ascertainment and minimal loss to follow up enhances the credibility of the study. The results are generalizable to patients with early stage 3 CKD (mean eGFR 50 mL/min per 1.73 m2 [0.83 mL/s/1.73 m2] in the moderate-severe reduction stratum); though the results were consistent in the subgroup with eGFR < 45 mL/min per 1.73 m2 (0.75 mL/s/1.73 m2) whether similar results are seen in more advanced CKD needs additional study.
There are important limitations to our analyses. Several studies have shown beneficial effects of statin therapy on proteinuria;35
however, others have shown increase in tubular proteinuria.36
Since proteinuria data are not available in ALLHAT participants, we cannot study the effects of pravastatin therapy on proteinuria or assess the role of proteinuria level as a predictor of response to statin therapy. In addition, these are post hoc analyses; therefore, these can be hypothesis generating, and will await confirmation in other clinical trials. The validity of the MDRD study equation in predicting change in eGFRs in the normal range (>90 mL/min per 1.73 m2
[1.50 mL/s/1.73 m2
]) has not been confirmed. Therefore, the relatively rapid decline seen in this group may represent hyperfiltration, or simply a regression to the mean. The substantial drop-in rate in the usual care group (23% at year 6) coupled with some drop-out in the pravastatin group (13% at year 6) may limit the power of the study to detect a difference between the two groups. Decreasing sample size over time is another possible limitation. Such a decrease happens in all trials for a number of reasons, including deaths, end-of-study censoring, and losses to follow-up, and participants who remain in the study but who are missing laboratory analyses. The average follow-up time in the ALLHAT lipid-lowering trial was 4.8 years, and the minimum potential follow-up time was less than 4 years. Therefore, the 4-year data to some extent, and especially the 6-year data, were particularly prone to be missing. Finally, it remains to be seen whether other statins that have greater potency in lipid lowering than pravastatin have a greater impact on clinical outcomes in this population.
Our findings support statin use in accordance with published guidelines and reinforces the importance of achieving target LDL- and total cholesterol reduction with statin therapy.33
The ALLHAT-LLT, in the context of the inconsistent findings in the literature, does not provide a compelling rationale for routine use of statin therapy specifically to improve GFR in hypertensive patients with CKD. This important question is best resolved by prospective clinical trials specifically designed to address the issue; the results of the ongoing Study of Heart and Renal Protection (SHARP) study will be eagerly awaited to guide clinical practice in this area.37
In summary, this post-hoc analysis of the ALLHAT-LLT demonstrates that in hypertensive patients with moderate dyslipidemia, pravastatin was not superior to usual care in preventing kidney disease outcomes. This was consistent across the strata of baseline eGFR level. However, potential benefit from statin therapy may depend of degree of reduction achieved in total and LDL-cholesterol.