Lowering of low-density lipoprotein cholesterol (LDL-cholesterol) with statins has become part of the standard treatment regimen in patients with established coronary heart disease. The Scandinavian Simvastatin Survival Study (4 S) which was published in 1994 was the first large endpoint study showing clear beneficial effects on cardiovascular morbidity/mortality with simvastatin treatment 
. Effect on cardiovascular morbidity/mortality has been demonstrated in patients without known coronary heart disease 
, in patients with various degrees of hypercholesterolemia and coronary artery disease, and in diabetics [19–21]
. In one recently published study aggressive treatment with a statin to patients with a stroke/TIA demonstrated a significant decrease in fatal and non-fatal strokes over an observation period of five years 
When dietary measures are not sufficient to control hyperlipidemia, pharmacological treatment may be considered. In Sweden, simvastatin is used as first-line treatment in most patients who are considered to be suitable for drug treatment 
. Since current guidelines recommend that treatment in the secondary preventive setting and in diabetics should be intensive, large populations of patients, especially elderly patients, are treated with statins.
It has been suggested that the magnitude of the lipid-lowering effect is of importance for the progression of atherosclerosis and a more pronounced reduction of LDL-cholesterol has been shown to reduce the atheroma burden by more than a modest decrease 
. Furthermore a more aggressive reduction in LDL-cholesterol has been demonstrated to reduce the incidence of major cardiovascular events 
. It is not known if there is a linear relationship between LDL-cholesterol reduction and cardiovascular prevention. Based on results from large studies, it could be questioned whether there may be a threshold for the beneficial effect on cardiovascular morbidity/mortality. Thus, a small reduction in LDL-cholesterol may not result in any benefit at all. In the large ALLHAT-LLT study, pravastatin was compared with usual care in a subset of patients with hypercholesterolemia. The mean difference in LDL-cholesterol levels between active treatment and control at study end was only 0.5
mmol/L. No significant benefit was demonstrated in this large study, in which more than 10
000 patients were included 
. In another large trial, the ASCOT-LLA study, hypertensive patients with other risk factors and non-fasting total cholesterol below 6.5
mmol/L were treated with either atorvastatin or placebo for 3
years. The difference in LDL-cholesterol between groups at the end of follow-up was 0.95
mmol/L. In this study a clear benefit regarding cardiovascular morbidity was found 
. The discrepancy in outcome between ALLHAT-LLT and ASCOT-LLA may partly be explained by the effects accomplished on LDL-cholesterol. Thus, a more modest reduction in LDL-cholesterol (0.5
mmol/L) may not be sufficient to reduce atherosclerosis and prevent cardiovascular events. On the other hand a reduction in LDL-cholesterol in a magnitude of 1
mmol/L has been shown to have a preventive effect on cardiovascular events in many large studies. The dose of atorvastatin in the ASCOT-LLA study was 10 mg and this dose caused a reduction in LDL-cholesterol in a magnitude of 1
mmol/L. The lipid-lowering potency of different statins at different doses has been compared in the CURVES study 
. The conclusions from this study are that 10
mg of atorvastatin has an effect on LDL-cholesterol comparable to that of 20–40
mg of simvastatin.
The patients in our trial had a mean simvastatin dose of 20.8
mg. We do not know the actual absolute reduction in our patients, since they were on stable chronic medication and we did not change their simvastatin treatment. From the results given in major studies, as mentioned earlier, it could, however, be assumed that the absolute reduction achieved for our patient population would be slightly lower than 1
mmol/L but greater than 0.5
The main finding in our study was that the commercially available St John's Wort product (Movina®) at a recommended dose given for one month together with simvastatin reduced the effect of simvastatin in a clinically significant way. Thus, mean total cholesterol was increased by 0.52
mmol/L and LDL-cholesterol was increased by 0.42
mmol/L. No change in HDL-cholesterol was observed, while triglycerides were slightly but significantly increased by 0.24
It could be concluded that about half of the effect of simvastatin on LDL-cholesterol was lost in our patients, when they were on concomitant treatment with the St John's Wort-containing product at a recommended dose for one month. It seems quite clear from large controlled studies that the magnitude of LDL-reduction is of importance for the cardiovascular preventive effects observed with simvastatin and other statins. Whether there is a threshold for the preventive effect of LDL-lowering therapy around 0.5
mmol/L is not known, but if this were to be the case, then the total effect on cardiovascular prevention with simvastatin would be abolished by concomitant treatment with a St John's Wort-containing product.
Our study has limitations since it was not double-blind. Bias from expectations may have occurred and carry-over effects may be present in crossover studies. The treatment periods in our study were each 4 weeks and it would seem unlikely that any clinically important carry-over effect would be present for a short-acting product such as Movina®. Furthermore, there is no reason to believe that patients or doctors would have mismanaged the diet or lipid-lowering medication during Movina® treatment in order to achieve a less satisfactory result after active treatment. The study was randomized and the assessments of lipids were performed by a central laboratory, which was blinded to treatment regimen. Furthermore, the results as regards total cholesterol and LDL-cholesterol were robust and occurred in both males and females. The results are in line with what could be expected from a product interfering with a central metabolizing enzyme of importance for simvastatin pharmacokinetics. Simvastatin lowers the levels of triglycerides and this effect was also partly inhibited by active treatment. These results were less robust compared with the effect on cholesterol. The effect was statistically significant in the total patient cohort. When the results were analysed according to gender, only females had a statistically significant increase in triglycerides. The clinical importance of this finding is unclear. Since this was a short and small study, we cannot draw any conclusions about long-term effects on cardiovascular morbidity/mortality. Such effects could only be demonstrated in a larger prospective controlled long-term trial. If simvastatin is given together with a St John's Wort-containing product, the efficacy, as measured by LDL- and total cholesterol concentration, is diminished. This will result in difficulties in reaching recommended therapeutic goals. It could therefore be concluded that these products should not be given together.