Short-, mid-, and long-term benefits of peri-procedural high-intensity statin administration in patients undergoing percutaneous coronary intervention

Abstract

Administration of high intensity statins prior to percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) or stable coronary artery disease has been shown to reduce short-, mid-, and long-term cardiovascular disease (CVD) morbidity and mortality as well as overall mortality compared with lower intensity statins or no statin treatment. The mechanisms involved are probably related to the pleiotropic effects of statins. Improved endothelial function, reduced low grade inflammation and decreased thrombotic diathesis might reduce cardiac injury, diffuse cardiac necrosis, myocardial infarction and no-reflow phenomenon. A decreased risk of contrast-induced nephropathy (CIN) post-PCI might be an extracardiac mechanism that contributes to the reduction in all cause and CVD mortality. These results support the need for the administration of statins before PCI.

Key words::

• Chronic kidney disease
• Clinical events
• Contrast induced nephropathy
• High intensity statin treatment
• Percutaneous coronary intervention
• Survival

A recent ‘real world’ single center study presented data on the progression of cardiovascular disease (CVD) after percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS) in relation to the level of intensity of statin use prior to PCI1. This prospective study included 1528 consecutive patients undergoing PCI during an 8 year period; the primary endpoint was all-cause mortality1. From the 1528 patients, 926 (60.6%) received high-dose atorvastatin or rosuvastatin (high intensity) and 602 patients (39.4%) received low-dose statin therapy (low intensity) or were not on a statin at discharge1. The results showed that eight patients (0.9%) receiving high intensity statin therapy and 21 patients (3.5%) on low intensity statin or no statin at all died during the 3 month follow-up (hazard ratio [HR] 0.244, p = 0.001); after propensity score adjustment the results remained significant1. Thus, for ‘real-world’ patients undergoing PCI for ACS, a significant reduction in short-term all-cause mortality was observed in patients receiving high-intensity statin treatment compared with those on low-intensity treatment or no statins1.

This beneficial effect of statins was confirmed by a meta-analysis that included 8750 patients from 20 randomized controlled trials (RCTs)2. At 30 days, the rate of myocardial infarction (MI) was significantly lower in the high intensity statin group (p = 0.0007) with a trend toward reduced mortality (p = 0.06) and significant reductions in major adverse cardiac events (MACEs) or major adverse cardiac and cerebrovascular events (MACCEs) compared with no or low intensity statin treatment2. The 30 day incidence of MI was markedly lower when high intensity statins were administered before PCI (p < 0.0001) rather than after PCI (p = 0.28). By meta-regression, earlier statin administration correlated significantly with lower risk of MI, MACE, and MACCE at 30 days2, suggesting that the earlier the statin administration before PCI, the greater the benefits2. There were also mid- to long-term benefits of high-intensity statins before PCI vs no statin or low intensity statin (significant reductions in MACE after 30 days to up 4 years; p = 0.0002)2.

There are also data for very long-term clinical benefits of statin use prior to PCI. An older study included 243 patients on statins at PCI and 332 patients not on statins3. During an 11 year follow-up, 68 patients died; statin use was associated with lower all-cause mortality (8.2 vs 14.5%, p = 0.023) and cardiac mortality (2.5 vs 6.9%, p = 0.017)3. After adjusting for covariates, the results remained significant.

Nearly 5 years ago we wrote an editorial suggesting that administration of a statin at a high dose prior to PCI for an ACS may decrease MACEs, such as post-procedural myocardial necrosis, MI, or target and non-target vessels revascularization (TVR and non-TVR)4. The picture has become much wider now. This includes the effect of high intensity statin use on short-, mid-, and long-term mortality (all cause and cardiovascular) and not just morbidity1–3. Studies now include patients with ACS and stable angina pectoris5 and comparisons vs both placebo and lower intensity statin dose1. These beneficial effects of statin therapy on short- to long-term mortality seems to be related to the pleiotropic effects of statins4.

In the Atorvastatin for Reduction of Myocardial Damage During Angioplasty (ARMYDA) (for patients with stable angina pectoris undergoing elective PCI)6 and ARMYDA ACS (undergoing early PCI for unstable angina)7 studies, the benefit of high-dose atorvastatin prior to PCI was essentially driven by a significant reduction in procedural myocardial injury and necrosis as well as procedural MI6^,7. In stable patients6 post-procedural peak levels of cardiac enzymes were significantly lower in the statin than in the placebo group (creatine kinase-MB [CK-MB, p = 0.007], troponin I [p = 0.0008] and myoglobin [p = 0.0002])6. MI by CK-MB determination was detected after PCI in 5% of patients in the statin group and in 18% of those in the placebo group (p = 0.025)6. In ACS patients7 post-procedural elevation of CK-MB and troponin I was also significantly lower in the atorvastatin group compared with the placebo group (7 vs 27%, p = 0.001 and 41 vs 58%, p = 0.039, respectively)7. Multivariable analysis showed that pre-treatment with 80 mg/day of atorvastatin conferred an 88% risk reduction of 30 day MACE (odds ratio [OR] 0.12, 95% confidence interval [CI] 0.05–0.50; p = 0.004)7. Another possible mechanism of benefit associated with high dose high intensity statin PCI pre-treatment is the attenuation of endothelial activation, as represented by a post-interventional significant decrease in E-selectin and cell adhesion molecules (CAMs). Also, attenuating the inflammatory response post-PCI, as suggested by a substantial reduction in the recruitment of inflammatory cells locally, may result in improved cardiac vessel function8. Furthermore, the ARMYDA-RECAPTURE trial9 showed an 82% relative risk reduction (RRR; p = 0.027) in patients already on average statin treatment when a high intensity statin was administered prior to PCI9. This suggests that routine reload with a high-dose statin before intervention is highly beneficial even in patients already on average statin therapy9.

The ARMYDA trials were multicenter studies that included a relatively low number of patients6–9. They compared atorvastatin 80 mg/day with no statin therapy and their results were confined to 30 day morbidity rates6–9. The Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial recruited 4162 patients with ACS10. These were randomized to high intensity statin (atorvastatin 80 mg) or standard statin therapy (pravastatin 40 mg); the composite endpoint was death, MI or rehospitalization for recurrent ACS at 30 days, 6 months and 2 years10. PROVE IT-TIMI 22 showed that high intensity statin therapy early after ACS leads to a reduction in clinical events at 30 days (related to early pleiotropic effects), 6 months and 2 years, compared with standard statin treatment10. Of 4162 patients of PROVE IT TIMI-22, 2868 underwent PCI for ACS11. Treatment with 80 mg atorvastatin reduced the incidence of the composite endpoint (death, MI, or rehospitalization, p = 0.002) and lowered the incidence of both TVR (p = 0.001) and non-TVR (p = 0.017) compared with 40 mg pravastatin11. Thus, intensive statin treatment may exert short-, mid-, and long-term beneficial effects both on morbidity and mortality compared with low-intensity statin therapy11. However, the clinical benefits of PROVE IT-TIMI 22 were not confirmed by the results from the Aggrastat to Zocor (A to Z) trial where a stepwise increase in statin therapy (simvastatin 40 mg for 1 month vs placebo and then 80 vs 20 mg for 2 years in nearly 4500 ACS patients) showed no significant difference in efficacy at the fourth treatment month and during the entire study (2 years)12. The fall in high sensitivity C-reactive protein (hsCRP) (17% in A to Z by high dose simvastatin vs a 38% fall by atorvastatin in PROVE IT) may be relevant13. Decreased low density lipoprotein cholesterol (LDL-C) levels are a useful marker of benefit in statin-treated patients, but it seems that the pleiotropic effects (as in this case with the reduction of low-grade inflammation as suggested by the lower hsCRP levels) are necessary for the early benefits of high intensity statin therapy13. However, during long-term follow-up (from 4 to 24 months) subjects on a high dose of simvastatin in the A to Z trial had a significant reduction in the primary endpoint (by 27%, p = 0.02) compared with the 20 mg group; lower LDL-C levels in the high-dose group might account for this longer-term benefit12.

Another possible mechanism of benefit in pre-PCI high intensity statin therapy is the attenuation of the myocardial no-reflow phenomenon14. This is associated with myocardial damage, worse contractile function and adverse effects on left ventricular remodelling14. The exact mechanism of the no-reflow phenomenon is not entirely clear; endothelial dysfunction and ischemia-induced microvascular dysfunction may be involved14. Both these factors seem to be improved by high intensity statin treatment8. Indeed a meta-analysis that included seven studies with 3086 patients showed that intensive statin therapy before PCI significantly reduces the risk of post-procedural no-reflow phenomenon14. This was mainly observed in the populations receiving early intensive statin therapy (RR 0.43, 95% CI 0.26 to 0.71, p = 0.001)14.

Besides local cardiac effects, other factors might account for the benefit of intensive statin administration pre-PCI. One of these might be kidney function. Contrast-induced nephropathy (CIN – an increase in serum creatinine of ≥ 25% or 0.5 mg/dl from baseline within 1 week of contrast medium exposure), is a common complication of administration of iodinated radiographic contrast medium that may increase the risk of adverse events and death15. Even small to moderate decreases in glomerular filtration rate (GFR) can be associated with worse clinical outcomes, increasing short- and long-term mortality15. Data from the Ibaraki Cardiovascular Assessment Study (ICAS), a multicenter trial, suggest that after multivariate logistic regression analysis, statin pre-treatment remained an independent and significant predictor of decreased risk of CIN (OR: 0.31, 95% CI: 0.18–0.53, p < 0.001)16. Furthermore, the Protective Effect of Rosuvastatin and Antiplatelet Therapy On Contrast-Induced Acute Kidney Injury and Myocardial Damage in Patients With Acute Coronary Syndrome (PRATO-ACS) study included 504 patients with ACS; 252 on 40 mg of rosuvastatin and 252 not on a statin treatment (control group)17. In PRATO the incidence of CIN was significantly lower in the high intensity statin group than in controls (6.7 vs 15.1%; adjusted OR 0.38; 95% CI 0.20 to 0.71; p = 0.003). At the same time, the 30 day incidence of adverse CVD and renal events (death, dialysis, MI, stroke, or persistent renal damage) was significantly lower in the statin group (3.6 vs 7.9%, respectively; p = 0.036)17. Moreover, high intensity statin administration on admission was associated with a trend for a lower rate of death or non-fatal MI at 6 month follow-up (3.6 vs 7.2%; p = 0.07)17. The benefits were similar in the Rosuvastatin (adjusted dose of 10 mg/day) Prevent Contrast Induced Acute Kidney Injury in Patients With Diabetes (TRACK-D) study in 2998 patients with type 2 diabetes mellitus (DM) and related chronic kidney disease (CKD)18. There was a significantly reduced risk of CIN in patients with DM and CKD undergoing arterial contrast medium injection, despite the fact that CKD is an independent predictor of CIN18. An earlier study, the Novel Approaches for Preventing or Limiting Events (NAPLES) II trial, investigated the rates of CIN in 202 patients after administration of a single dose of atorvastatin (80 mg) within 24 h before contrast media exposure19^,20. In the atorvastatin group 9/202 (4.5%) patients and in the control group 37/208 (17.8%) patients (p = 0.005; OR = 0.22; 95% CI, 0.07–0.69) developed CIN19^,20. The CIN rate remained lower in the atorvastatin group when patients with and without DM and those with moderate CKD (stage 3, estimated GFR [eGFR] 31–60 ml/min/1.73 m²) were taken into consideration20. Finally, data from the ARMYDA Group21 showed that 5% of patients on atorvastatin developed CIN vs 13.2% of those on placebo (OR 0.34, 95% CI 0.12–0.97, p = 0.046). Anti-inflammatory effects of high intensity statin may be involved in this renal protection21. Multivariable analysis showed that pre-treatment with atorvastatin was also independently related to a shorter hospital stay (p = 0.007)21.

However, last year the results of a retrospective observational analysis of administrative databases suggested that high potency statins are associated with an increased risk of acute kidney injury (AKI) compared with low potency statins22. This kind of study design has substantial inherent problems and it is difficult to prove causality, which was exactly what this paper tried to do but instead raised what seems to be a false alarm. Indeed, two analyses of RCTs that included patients with ACS did not support these findings23^,24. The combined analysis of the PROVE IT-TIMI 22 (n = 4162) and A to Z trials (n = 4497) showed that the use of high-intensity statins did not increase the risk of AKI23. Also, a meta-analysis of the IDEAL, TNT, CARDS, ASPEN, SPARCL and 19 other RCTs (149,882 patient-years of follow-up) failed to show an increase in AKI by high intensity statin administration compared with lower intensity statins or placebo24.

The Greek Atorvastatin and Coronary heart disease Evaluation (GREACE) and the Treating to New Targets (TNT) trials showed a significant increase in eGFR in coronary heart disease patients with and without CKD with atorvastatin used to achieve LDL-C goals (2.6 mmol/l; 100 mg/dl) vs usual care or higher (80 mg) vs lower dose (10 mg) atorvastatin, respectively25^,26. Moreover, there was an independent greater reduction in CVD events in patients with CKD compared with those with normal renal function in both trials25^,27. In addition, data from GREACE and TNT support the concept that improving GFR reduces morbidity related to heart failure28. Finally, a recent study showed that high intensity statin treatment was associated with reduced all-cause mortality in patients with CKD and CAD after PCI29. In another study, 434 consecutive patients underwent PCI and were followed up for 4 years30. During follow-up, patients that received high intensity statins before PCI had a significant decrease in CIN; this early protective effect was translated into a better long-term event-free survival30.

Another interesting issue is that high intensity statins, mainly lipophilic, such as atorvastatin, have an ‘upstream’ property and may be more effective in preventing the recurrence of paroxysmal atrial fibrillation (AF), not rare after PCI, and its conversion to permanent AF than pravastatin, a low intensity statin31.

ACS patients also benefit from early statin administration32. Furthermore, abrupt cessation of statin administration in high risk patients is associated with an increased risk of vascular events33.

In conclusion, high intensity statins early before PCI is associated with substantially reduced short-, mid-, and long-term CVD morbidity and mortality as well as all-cause mortality when compared with lower intensity statins or no statin therapy. Probably the pleiotropic effects of statins on the heart and coronary macro- and micro-circulation are involved. The protection of renal function (e.g. decreased risk of CIN) may contribute to these benefits.

Transparency

Declaration of funding

This editorial was written independently. The authors did not receive financial or professional help with the preparation of the manuscript.

Declaration of financial/other relationships

The authors have given talks, attended conferences and participated in advisory boards and trials sponsored by various pharmaceutical companies. V.G.A. has nothing to declare. N.K. has disclosed that she has attended conferences and participated in trials sponsored by Novartis, Pfizer, MSD and WinMedica. A.K. has disclosed that he has given talks and attended conferences sponsored by Pfizer, Astra-Zeneca, Menarini and Novartis. D.P.M. has disclosed that he has given talks and attended conferences sponsored by Merck, Sharp & Dohme and Genzyme. D.P.M. has disclosed that he is Editor-in-Chief of CMRO; V.G.A. has disclosed that he is on CMRO’s International Advisory Board. N.K. and A.K. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article.

The CMRO peer reviewer on this manuscript has no relevant financial or other relationships to disclose.