Cholesterol Management.

Cholesterol management, what to do?

New guidelines on managing cholesterol were published in Circulation this month by the ACC/AHA task force. As we spend much of our time in CKD clinic managing cardiovascular risk factors such as blood pressure, diabetes, lifestyle factors and cholesterol I think it is important we are up to date on the latest guidelines.

The task force based their recommendations based on randomized controlled trials based on fixed doses of statins in those at risk for atherosclerotic cardiovascular disease. The authors also emphasize the continuing importance of lifestyle modification for the reduction of ASCVD.

Those who benefit from statins are (Task Force Summary):

1. Individuals with clinical ASCVD

2. Individuals with primary elevations of LDL–C ≥190 mg/dL

3. Individuals 40 to 75 years of age with diabetes and LDL–C 70 to189 mg/dL without clinical ASCVD

4. Individuals without clinical ASCVD or diabetes who are 40 to 75 years of age with LDL–C 70 to 189 mg/dL and have an estimated 10-year ASCVD risk of 7.5% or higher.

Risk calculator

The Caveats; no evidence for statin therapy in these groups:

Primary prevention in over 75s unless clinically evident ASCVD present

Those with NYHA HF class II – IV

Those on hemodialysis

Significant changes to note:

No specific LDL-C and non-HDL-C targets recommended once on statin therapy

The de-emphasis of surrogate markers such as CRP and calcium scores.

Cautious use and clinical judgment in those over 75 years without clinical ASCVD

What about renal patients?

The Task Force Authors looked at the TNT trial and the subgroup analysis from Shepard et al. The guidelines do not explicitly recommend the use of statins in CKD patients but they do highlight the beneficial findings of high dose (80mg) atorvastatin.

Shepard et al did a subgroup analysis of the TNT trial looking at secondary prevention of major cardiovascular events in patients with an MDRD eGFR less than 60. In the original TNT study patients were age 35 to 75 and patients on long-term immunosuppression or with nephrotic syndrome were excluded. At baseline patients already had an LDL-C of less than 130mg/dl. Shepard showed that 80mg of atorvastatin reduced the RR of a major CV by 32% compared with 10mg of atorvastatin.

My impression is that we should use statins in our CKD patients but remain cautious with respect to drug interactions and side effects.

Cholesterol RCTs in renal patients (a refresher on the evidence ).

4D - Die Deutsche Diabetes Dialyse Studie.

N Engl J Med, 353 (2005), pp. 238–248

This German trial looked at 18 to 80 year olds with type 2 DM on hemodialysis for less than 2 years. Patients with LDL-C outside the 80 to 190 range were excluded as were failed kidney transplant patients. After a 4 week lipid-med free wash out patients were assigned to atorvastatin 20mg or placebo. The primary outcome was a composite of cardiovascular death. About 1200 patients were enrolled for a mean of nearly 4 years. In this trial statin did reduce LDL-C levels but there was no significant difference in the primary or secondary outcomes.

AURORA.

N Engl J Med. 2009 Apr 2;360(14):1395-407

Were the 4D study focused on the high risk diabetic population on HD this trial investigated the efficacy of statin therapy in the general dialysis population. Patients were 50 to 80 years and on regular hemodialysis or filtration for 3 months. Expected transplantation within the next year or statin therapy within the last 6 months excluded patients. Randomization was to rosuvastatin 10mg or placebo and the primary endpoint was cardiovascular death or non-fatal stroke or MI. Again, statin therapy reduced cholesterol levels significantly but there was no difference in primary or secondary outcomes. Further more, there was no correlation between primary outcome and baseline LDL-C or 3 month LDL-C.

SHARP.

Lancet. 2011 Jun 25;377(9784):2181-92.

This trial attempted to look at the effects of simvastatin 20mg + ezetimibe 10mg versus placebo on major atherosclerotic events in patients with CKD with no previous MI or revascularization3. About 3000 of the 9000 patients were on dialysis. The authors concluded that combination therapy produced a relative risk reduction of 17% for major ASCVD outcomes. This trial came in for a lot of criticism mainly because the authors appeared to extrapolate their results by assuming all patients actually took their assigned meds. 2700 patients were enrolled for a mean trial length of over 3 years.

ALERT (Assessment of LEscol in Renal Transplantation)

Lancet, 361 (2003), pp. 2024–2031

This study assessed the use of statin therapy on transplant patients. Enrolled patients were between 30 and 75 and had a kidney or KP transplant for more than 6 months with stable renal function. All patients were on ciclosporin and had total cholesterol levels between 4 and 8 mmol/l. Patients were excluded if they had rejection in the last 3 months or were already on statin therapy. 2100 patients were enrolled and followed for a mean of 5 years. Randomization was to fluvastatin 40mg or placebo. The primary end point was cardiac death, non-fatal MI or coronary revascularization. Fluvastatin lowered LDL-C by 32% but there was no significant difference in the primary endpoints. Interestingly in this study only about 13% in each group had diabetic nephropathy and about 5% had ‘hypertensive nephrosclerosis’ as a cause of their primary renal failure. This study was conducted in Canada and Europe.