Statins, percutaneous coronary intervention and myocardial infarction

Abstract

Peri-procedural myocardial infarction occurs in up to 40% of otherwise successful percutaneous coronary intervention (PCI) procedures and such patients have a worse long term prognosis than those who do not have this complication. Statins administered at the time of PCI, particularly before the procedure, have been shown to reduce the risk of myocardial infarction during PCI, but the applicability of this treatment may be limited because of the widespread use of statins in patients with existing coronary artery disease, or in those at risk of developing the disease. The results of a study are reported in this issue of the journal in which a single dose of atorvastatin is given prior to PCI to patients already taking a statin, and shows a significant reduction in the risk of peri-procedural myocardial infarction. It may be that a single supplemental dose of a statin at PCI to all patients could confer clinical benefit.

Key words::

• Atorvastatin
• Cardiac troponin I
• Creatine kinase MB
• Myocardial infarction
• Percutaneous coronary intervention

Coronary revascularisation by percutaneous coronary intervention (PCI) is the treatment of choice in contemporary European and US guidelines for treatment of ST elevation myocardial infarction (STEMI), and PCI is used electively for the coronary revascularisation. In up to 40% of otherwise successful elective PCI procedures, there is a rise in the serum concentration of markers of cardiac necrosis1,2. This rise is sufficiently large in some cases to lead to a diagnosis of peri-procedural myocardial infarction and such patients have a worse long term prognosis than those in whom there is no rise in cardiac troponins or creatine kinase MB fraction3,4. Myocardial infarction is a thrombus-driven event. A number of pre- and peri-procedural therapeutic options are available to antagonise the pro-thrombotic environment seen in vaso-occlusive disease, and caused as a consequence of vessel trauma and embolisation in the revascularisation process5.

The second major pathological process in coronary artery disease is atherosclerosis, driven by the accumulation of low density lipoprotein (LDL) cholesterol in the arterial wall, which leads to plaque formation. Stable atherosclerotic plaques of sufficient size will lead to perfusion defects and angina, or if the plaque cap becomes unstable to thrombus formation and so to an acute coronary syndrome (ACS). Lowering plasma concentrations of LDL cholesterol with statins has been clearly shown to reduce the risk of all major vascular events, both in primary and secondary prevention, and this benefit is proportional to the extent to which LDL cholesterol is lowered6. It seems likely that this clinical benefit is related to a lack of progression, or indeed regression, of atherosclerotic plaques, and this being so the benefit would be seen only in medium to long term follow up.

The risk of recurrent ischaemic events is highest in patients early after suffering an ACS. In the MIRACL study7, 3086 patients with a non-STEMI or unstable angina were randomised to receive atorvastatin 80 mg/day or placebo with 96 hours of presentation, and they were then followed for 16 weeks. The relative risk of the composite endpoint of death, non-fatal myocardial infarction and symptomatic coronary ischaemia was 0.84 in those treated with atorvastatin. As would be expected in the atorvastatin group LDL cholesterol fell from an average of 3.2 to 1.9 mmol/L and although the authors did not discuss the reasons, it seems unlikely that this clinical benefit was related to an effect on LDL cholesterol driven atherosclerotic process in such a short time period. Statins inhibit an early rate limiting step in cholesterol biosynthesis, by competitively binding to hydroxy methyl glutaryl CoA reductase. This biochemical pathway is complex and a number of other important metabolites are produced as side branches from the cholesterol pathway. It has been speculated that non-LDL-cholesterol lowering effects of statins, the so called ‘pleiotropic’ effects8,9, may also be important in the clinical benefit seen with statin therapy. These effects relate to endothelial function, platelet aggregation, thrombus formation and vascular inflammation. It is possible that it was the effects of statins on such non-LDL factors which could explain the outcome of the MIRACL study.

There is also published evidence relating to the beneficial effects of statins initiated peri-procedurally at the time of elective PCI. Statins initiated during PCI have been evaluated in clinical trials mainly to assess if this therapy reduces subsequent restenosis. Mood et al.10, however, conducted a meta-analysis of six studies on the effect of statin therapy on outcomes other than restenosis. These trials were Prevention of Restenosis by Elisor After Transluminal Coronary Angioplasty [PREDICT]11, Fluvastatin Angioplasty Restenosis [FLARE]12, the Lescol Intervention Prevention Study [LIPS]13, German Atorvastatin Intravascular Ultrasound [GAIN]14, Atorvastatin for Reduction of Myocardial Damage During Angioplasty [ARMYDA]15, and a study by Briguori et al.16. In total these trials randomised 1967 patients to statins and 1974 to placebo, with a follow up of up to 45 months. The incidence of myocardial infarction was 3.0% in the statin group and 5.2% in the placebo group (odds ratio 0.57); the incidence of all-cause mortality was 2.3% versus 3.0% (odds ratio 0.74) and of cardiovascular mortality was 0.71% versus 1.2% (odds ratio 0.58). The reduction in the risk of myocardial infarction appeared very early after PCI and it seemed that initiation before PCI, in the ARMYDA and Briguori studies at least three days before, was preferable to starting treatment after PCI. Two further meta-analyses17,18 came to a similar conclusion. In a further study by Briguori et al.19, the Novel Approaches for Preventing or Limiting Events (Naples) II Trial, just one 80 mg dose of atorvastatin, or placebo, was given to 668 statin naïve patients within the 24 hour period before elective PCI. The incidence of peri-procedural myocardial infarction in those given atorvastatin was 9.5% compared to 15.8% in those given a placebo, an odds ratio of 0.56. It appears therefore that there is good evidence that administering a statin before PCI is beneficial but on the basis of the Naples II trial elective PCI need not be delayed by more than 24 hours to attain that benefit, and a single loading dose may be sufficient in those who have never been prescribed statins previously.

The clear evidence of benefit for statin therapy in patients with known coronary disease and in those with a high projected future risk of such disease means that patients coming to elective PCI are likely to have been given statins before the procedure, and so the desirability of initiating statins in those who are naïve to these drugs may be relevant only in a minority. In this issue of the journal however Nafasi et al.20 report the outcome of a trial in which 190 patients who were all taking a statin were randomised to receive a single, additional 80 mg dose of atorvastatin, or placebo, 24 hours before elective PCI. Troponin I (TnI) and highly sensitive C reactive protein (hs-CRP), as an index of inflammation, were measured at baseline, and six and twelve hours after PCI. A peri-procedural myocardial infarction was defined as a TnI elevation of five-fold or more in those with normal baseline TnI concentrations, or a change in concentration of 20% or more in those with an elevated baseline TnI concentrations. Peri-procedural myocardial infarction occurred in 3.1% of the atorvastatin group and 10.5% of the placebo group, a statistically significant difference. At 12 hours post PCI serum hs-CRP concentrations were significantly lower in the atorvastatin group than the placebo group suggesting a beneficial effect of the single atorvastatin tablet on inflammation.

This finding raises the possibility that a single dose of atorvastatin given even to patients who are already prescribed statins could confer clinical benefit in PCI procedures. However, it should be noted though that the mean LDL cholesterol concentrations in the atorvastatin and placebo groups were 80.4 mg/dL (2.09 mmol/L) and 85.9 mg/dL (2.23 mmol/L), and so were not below the commonly accepted therapeutic LDL target of 2.0 mmol/L in patients with known coronary disease. In addition the 95% distribution range for LDL concentrations in this study can be calculated to be 0.84 to 3.25 mmol/L and 1.04 to 3.44 mmol/L in the atorvastatin and placebo groups respectively. Hence a significant number of patients in this trial might be considered to have less than optimally controlled LDL concentrations and so less than optimal statin treatment. Irrespective of whether or not the benefit of pre-PCI statin therapy is related to effects on LDL cholesterol or other ‘pleiotropic’ effects, and the latter seems more likely, it is not unreasonable to hypothesise that LDL concentration can be taken as a surrogate for the quantitative ‘pleiotropic’ effects of the statin. Given that a significant number of the patients in the Nafasi et al. study had LDLs above target it might be presumed that there was an opportunity for benefit from the single additional dose of statin which might not be seen in patients on more effective statin regimes. Nafasi et al. do not describe the particular statins or doses used in their patients, nor have they been able to determine whether the benefit they describe is related to the baseline LDL cholesterol concentration. Nevertheless this is an intriguing observation, but it will need to be replicated in a larger group, with the post-PCI outcomes analysed in relation to the preceding statin dosages and biochemical efficacy of prior statin treatment.

Transparency

Declaration of funding

This paper was not funded.

Declaration of financial/other relationships

A.J. has disclosed that he has no significant relationships with or financial interests in any commercial companies related to this study or article.