Discussion

Dr Matthew Dougherty (Philadelphia, Pa). There is no question, the statistics don’t lie, that there is a benefit, but I’m impressed with your data offered per thousand patients. If I read it correctly, there is about a 2% absolute reduction in peripheral vascular events over a 5-year period, even in the PAD group, which seems like a pretty small number. And I wonder whether you have done any cost–benefit analysis to achieve that 0.4% per year reduction?

Dr Richard Bulbulia. Considering major vascular events, an economic analysis of HPS has shown that, at 2001 prices, 40 mg simvastatin is cost effective for all study participants. And, with patent expiry, the price of simvastatin is falling and it should be cost-saving for all HPS participants, particularly for those with PAD who actually derived the largest absolute benefits from statin therapy, with an absolute reduction in MVE of around 6%.

Dr Michael Conte (Boston, Mass). Congratulations to you and your coauthors for another outstanding contribution. For those who are not familiar with it, the original report from the Heart Protection Study was published a couple of years ago in The Lancet. This is an important follow-up to that study focused on our peripheral vascular patients, and I have a couple of questions. First, can you tell us if the presence or absence of diabetes affected the outcome in relation to statins? Was the apparent benefit of statins more or less enriched in the diabetic population?

Second, can you tell us a little bit more about the timing of the events in the PAD patients? Did you observe a uniform distribution of risk reduction over time, or was the effect seen mostly within the first year or two after randomization?

Finally, what can you tell us about antiplatelet therapy in the trial?

Dr Bulbulia. The beneficial effect of simvastatin was not influenced by the presence or absence of diabetes at baseline. A reduction in major vascular events was seen after around 1 year of treatment; however, in the recent Cholesterol Treatment Trialists Meta-analysis of over 91,000 participants, benefits emerge within the first year. Finally, the benefits seen with statin therapy were additional to, and therefore independent of, any other treatments, including antiplatelet agents.

Dr Eric Wahlberg (Stockholm, Sweden). Did you have a chance to look at the patients with PAD without cardiac disease at all? Could you also enlighten me if this paper differs anything from your previous publication from the HPS study, besides the analysis of the peripheral vascular events?

Dr Bulbulia. Around 2700 patients with PAD had no pre-existing coronary artery disease at baseline, and they achieved similar proportional benefits as those with CAD and PAD. This presentation provides more detailed analyses of the PAD subgroup in HPS and emphasizes that all such patients should be on a statin. Observational studies suggest that less than one third of our patients are currently receiving appropriate lipid-lowering therapy. In addition, we have shown a reduction in peripheral vascular events with statin allocation, which has not been reported in any previous study.

Dr Thomas Lindsay (Toronto, Ontario, Canada). I would applaud this as probably the first study that demonstrates the benefit of statin therapy in a predominantly PAD group, so I think it’s very important data. I have a couple of questions. First, what was the number needed to treat in order to prevent an event in the PAD subgroup vs the non-PAD subgroup?

Secondly, you said that the overall reduction in cholesterol was 1 mmol/L. Is there a better benefit with greater reductions in cholesterol level? Was there a dose-response in terms of the patients’ benefit?

Third, many of these patients also have elevated triglycerides, which are in fact, much more difficult to treat. Was the effect of statin therapy dependent or independent of elevated triglyceride levels?

Dr Bulbulia. The number needed to treat to prevent a first major vascular event was 16 in the PAD subgroup and 20 in those without PAD. The effects of statin therapy were independent of baseline lipid profiles, including triglycerides. Finally, there is a trend towards using higher doses of statins in high-risk patients. Indeed the recent CTT meta-analysis suggests that an increased reduction in LDL cholesterol may result in increased benefits.

Dr Lindsay. What would you say is an appropriate LDL target level? As vascular surgeons take hold of risk reduction in our patient population, we really need to have some target to treat to. Your first slide implied the lower the better. We see the cardiologists going from what used to be levels of 3 mmol/L down to 2 for LDL to now less than 2. Based on this data, what threshold would you recommend for trying to get a patient’s LDL cholesterol to?

Dr Bulbulia. There should be no threshold for initiation of statin therapy. HPS was not a target-finding study, but results from some “more vs less” statin trials suggest that higher doses of statin therapy will reduce cardiac and noncardiac vascular events further. However, the question is whether the risks of side effects associated with statins, which are dose-dependent, justify this approach.

Dr Jacob Lustgarten (Chevy Chase, Md). Did you notice any morbidity and mortality benefits in patients who underwent surgery? Statins are increasingly associated with a plaque stabilization effect and a lower perioperative rate of adverse cardiac events, and even a lower stroke risk after carotid surgery. It seems almost like these patients should be on statins much the way β-blockers are used. You followed a large number of randomized patients. Did you look for this effect?

Dr Bulbulia. We have not performed such an analysis, but I am aware of the results of observational and smaller interventional studies suggesting improved outcomes with statin therapy in the perioperative period. However, our results clearly demonstrate that all these patients should be on a statin before, during, and after their operation.