High Dose Statins

In 2003, Law and others (1) reported the remarkable effects of low dose statins on both LDL cholesterol and ischemic heart disease reduction in an impressive study reported in BMJ.

One would have thought this comprehensive meta-analysis would have shaken the very foundation of the medical community with respect to dosing strategy of the statin drugs, yet all that was heard was an inaudible "ho-hum" as if nothing had registered.

The authors of this impressive, to me, study reported that reductions in LDL cholesterol (in the 164 trials observed) were 2.8 mmol/l (60%) with Crestor 80 mg/day, compared with 1.8 mmol/l (40%) with Crestor 5 mg/day, compared with pretreatment LDL cholesterol concentrations of 4.8 mmol/l. The cholesterol reductions from low dose therapy I consider irrelevant but what really impressed was the risk reduction.

In the 58 trials where the effect of statins on ischemic heart disease was studied, Law reported that Crestor 80 mg/day showed dramatic reduction of IHD events over a three-year period but 61% of this reduction was gained just from the use of Crestor 5 mg/day. His results from the same 58 trials, corroborated by results from the nine cohort studies, showed that Crestor 5mg/day reduced stroke risks by 17% over the study period, compared with 28% reduction for Crestor 80mg/day.

Although the rest of the medical community may have "ho-hummed" Law's BMJ paper, the results astounded me. I am very impressed that Crestor 5 mg/day, one sixteenth the size of the 80 mg dose, (and much less the cost) can give 61% of the ischemic heart disease reduction of an 80 mg/day dose and similar reduction in stroke risk.

Support for this approach comes from the following report. In March 2005, a new study in the New England Journal of Medicine made headlines that high-dose Lipitor reduced cardiovascular incidents (such as heart attacks or strokes) better than low-dose Lipitor. In this study, which was funded by Lipitor's manufacturer, Pfizer, 5,000 people with coronary heart disease received the maximum 80-mg dose of Lipitor daily, and another 5,000 received 10 mg of Lipitor daily.(2)

Over the 5-years of the study, 8.7% (434) in the 80-mg group experienced another cardiovascular incident (such as heart attack or stroke) vs. 10.9% (548 patients) in the 10-mg group. This was an improvement of 2.2%, which meant 104 fewer incidents with high-dose Lipitor. High-dose Lipitor also reduced the number of deaths from cardiovascular causes: 126 with 80-mg Lipitor vs. 155 with 10-mg Lipitor. Twenty-nine fewer cardiovascular deaths was also a very positive result, but it was completely offset when 31 more people died from other causes while taking high-dose Lipitor.

As with the Law study above approximately 60% of the benefit of 80mg dose on heart attacks and deaths was achieved with the 10mg dose. This becomes of special importance when one compares the side effects profiles.

Side effects occurred more commonly with high-dose Lipitor: 406 people (8.1%) on high-dose Lipitor got side effects vs. 289 (5.8%) on lower-dose Lipitor. More people discontinued treatment (7.2%) because of side effects with high-dose Lipitor than with lower-dose Lipitor (5.3%). The number of people developing liver enzyme elevations, which indicates liver irritation, increased more than 500%: Sixty people developed liver enzyme elevations with high-dose Lipitor vs. nine with lower-dose Lipitor.

I can think of no stronger support for the consideration of low dose statins by primary care physicians than these two reports. To obtain maximum effectiveness with the minimum of side effects should be their over-riding goal in administering medication.

1. Law MR and others. Quantifying effect of Statins on low density lipoprotein cholesterol, ischemic heart disease, and stroke: systematic review and meta-analysis. BMJ 326:1423, 2006

2. LaRosa, JC, Grundy, SM, Waters, DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. New England Journal of Medicine 352(14):1425-1435. 2005

Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor

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