Skip to main content
Download PDF
Download ePub

Prompt impact of first prospective statin mega-trials on postoperative lipid management of CABG patients: a 20-year follow-up in a single hospital

Lipids in Health and Disease volume 15, Article number: 124 (2016) Cite this article

Abstract

Background

The long-term success of coronary artery bypass grafting (CABG) depends on secondary prevention. Vast evidence provided by the results of cholesterol mega-trials over two decades has shown that effective reduction of LDL cholesterol improves the prognosis of patients with coronary heart disease. However, the implementation of these results into the clinical practice has turned out to be challenging. We analysed how the information derived from clinical statin trials and international recommendations affected the local treatment practices of dyslipidaemia of CABG patients during a 20-year time period.

Methods

The cohort includes all CABG patients (n = 953) treated in Kanta-Häme Central Hospital during the time period 1990–2009. At the postoperative visits in the cardiology outpatient clinic, each patient’s statin prescription was recorded, and blood lipids were determined.

Results

During 1990–1994, 12.0 % of patients were on statins and during the following 5-year time periods the proportion was 57.2, 82.2 and 96.8 %, respectively. During the 20-year observation period (1990–2009), the effective statin dose increased progressively during these 5-year periods up to 36-fold, while the mean concentration of LDL cholesterol decreased from 3.7 to 2.1 mmol/l and that of apolipoprotein B from 1.3 to 0.8 g/l. In the very last year of follow-up, the mean concentrations of LDL-C and apoB were 1.83 mmol/l and 0.78 g/l, respectively. The most prominent increase in statin use and dosage took place during 1994–1996 and 2003–2005, respectively.

Conclusions

Among CABG patients the lipid-lowering efficacy of statin therapy improved dramatically since 1994. This progress was accompanied by significant and favourable changes of lipid and apolipoprotein-B values. This study shows that it is possible to effectively improve lipid treatment policy once the results of relevant trials are available, and that this may happen even before international or national guidelines have been updated.

Background

Coronary artery bypass grafting (CABG) efficiently alleviates coronary heart disease (CHD) symptoms. However, without an effective secondary prevention, it does not offer permanent improvement of cardiac symptoms or prognosis [1, 2].

The primary target of the secondary prevention of coronary heart disease is effective reduction of low-density lipoprotein cholesterol (LDL-C), which diminishes cardiovascular and total mortality [3–6]. The lipid-lowering therapy is based on two approaches, i.e. change in lifestyle and pharmacological therapy [7]. In acute coronary syndrome patients it is desirable to start an effective statin therapy immediately after the event, i.e. already during the hospital stay [8].

According to early mega-trials, the turning points in secondary prevention of coronary heart disease were the years 1994, 1996 and 1997 when the first statin mega-trials 4S and CARE as well as the Post-CABG trial were published, and showed that effective therapy with statins improves the prognosis of patients with CHD [2–4]. The next key observations with a major influence on statin therapy occurred in 2004–2005, when the beneficial effects of intensive statin therapy, as compared with moderate statin therapy, were published [6, 8].

Two lipid-lowering recommendations, one in the U.S. and the other in Europe, were published just before the first statin mega-trials, i.e. in 1994 [9, 10]. They pointed out the central importance of increased cholesterol concentrations in determining the CHD risk; yet, due to the lack of evidence, the recommendations were conservative in their drug therapy guidelines [9, 10].

In 1998, the European targets for total cholesterol (T-C) and LDL-C were set below 5.0 mmol/l and 3.0 mmol/l, respectively [11]. One year later in the USA, the target for LDL-C in CABG patients was set below 100 mg/dL (2.6 mmol/l) [12]. Further in 2001 and 2003 LDL-C targets were set below 2.6 mmol/l and 2.5 mmol/l in the USA and Europe, respectively [13, 14]. Even though the goals were more demanding, the major emphasis was still on therapeutic lifestyle changes. Eventually, in 2004 the American guidelines and in 2007 the European guidelines for cardiovascular disease prevention recommended that in patients with established coronary heart disease LDL-C should be lowered below 2.5 mmol/l, or below 1.8/2.0 mmol/l, “if achievable” [15, 16].

The evidence indicates that the combined use of different apolipoprotein (apo) measures might improve the risk assessment of cardiovascular disease [17, 18]. Regarding the atherogenicity of the lipoproteins, the apolipoprotein B (apoB)-containing lipoproteins are of primary importance. Since one apoB molecule is present in each very-low-density lipoprotein (VLDL), intermediate-low-density lipoprotein (IDL) and LDL particle [19, 20], the plasma concentration of apoB indicates the total number of circulating atherogenic apoB-containing lipoprotein particles. ApoB concentration as a complementary measure was included first in recommendations in 2008 [7], and in the highest risk patients, the treatment goal was set to 0.80 g/l. To achieve this goal, effective lipid-lowering drug therapy is needed [21].

The aim of our study was to assess whether statin mega-trials and the recommendations based on their results influenced the local treatment practice regarding statin-dependent control of lipid levels in CABG patients over the critical 20-year period (1990–2009) which encompassed milestone publications regarding LDL-C lowering-based pharmacotherapy in preventive cardiology. We also attempted to learn whether the evolving changes in the LDL-C targets were reflected in the concentrations of different lipid classes and apolipoproteins in the patient cohort.

Methods

Patients

We studied all annual cohorts of CABG patients treated in Kanta-Häme Central Hospital (K-HCH) during the years 1990–2009. The primary catchment population of the hospital is 175 000 inhabitants living in Southern Finland. CABG was performed in Tampere University Hospital for 953 patients and, after the operation, they were transferred to K-HCH for further recovery.

After discharge the patients were followed according to hospital policy. Of the patients, 946 (99.3 %) had at least one visit in the outpatient clinic of cardiology during the first three postoperative months.

Material analysis

Results of all patients who visited the outpatient clinic were analysed. Patients who had laboratory values on the first postoperative visit, but not on the 3-month visit, were also included; that is, a “last observation—carry forward” principle was adopted. Accordingly, data derived from the final postoperative outpatient visit are presented, 19 and 81 % of them being derived from the 1 to 3-month visits, respectively.

The year of CABG, postoperative lipid values, medication, and absence/presence of various CHD risk factors including smoking, hypertension, diabetes, and obesity (body mass index, BMI) were collected from the patient records. Patients’ data were coded, and data analysis was carried out with the coded material only. The study was approved by the Ethics Committee of Kanta-Häme Hospital District (Dnro E511/08).

The influence of the statin trials and recommendations on treatment goals were examined by comparing CABG patients’ postoperative lipid values taken at various time points over a time span of 20 years. The study period was divided into four consecutive 5-year time periods, namely 1990–1994, 1995–1999, 2000–2004, and 2005–2009. During this 20-year time period several new statins with different efficacies received their marketing authorisation. Accordingly, the daily dose and the dose-dependent LDL-C lowering effect of each individual statin had to be taken into account. This enabled us to compare the lipid-lowering efficacy of the statin therapy during the entire period.

A daily dose of 20 mg simvastatin or equipotent dose of another statin is the smallest statin dose used in most prospective trials, and this dose was defined as “daily statin dose index (DSDI) 1”. In the Tables and Graphs, in which the effective doses of various statins are presented, the DSDI 1 corresponds to a daily dose of 80 mg fluvastatin, 40 mg lovastatin or pravastatin, 20 mg simvastatin, 10 mg atorvastatin or 5 mg rosuvastatin. The lipid-lowering efficacy of each statin was assumed to be linearly correlated with the dose; i.e. the DSDI of 80 mg simvastatin, 40 mg atorvastatin or 20 mg rosuvastatin was 4 [22–25].

Lipid analysis

Total and high-density lipoprotein cholesterol (HDL-C) concentrations were determined from plasma samples by using Hitachi 911 analyser with Boehringer-Mannheim reagents in 1990–1996. Roche Diagnostics enzymatic methods were used since 1996, which also applied to direct LDL-C analysis from 2000 onwards. All chemical analyses were carried out in the Laboratory of Kanta-Häme Central Hospital. Lipid analyses have been under the Nordic quality control during the entire study period.

For the calculation of LDL-C with the classical Friedewald formula (FW) data on T-C, HDL-C and triglycerides (TG) are required. Since FW is valid provided serum TG ≤ 4.5 mmol/l, we also applied a novel extended Friedewald (eFW) approach, which is more tolerant on elevated triglycerides [26, 27]. The eFW is based on artificial neural network regression algorithms which utilize data on classical FW inputs [26]. This method allowed us to calculate LDL-C, IDL cholesterol (IDL-C), HDL2 cholesterol (HDL2-C) and VLDL triglyceride (VLDL-TG) concentrations. It also computationally yields estimates of the apoB and apolipoprotein A-1 (apoA1) concentrations. To estimate HDL3 cholesterol (HDL3-C), the HDL2-C value obtained with eFW was subtracted from the measured HDL-C [26].

Statistical analysis

Evolution of postoperative statin therapy and lipid values over 20 years was studied using ANOVA test in the 5-year groups. With dichotomal variables, the 5-year groups were compared using extended χ 2 test [28]. D’Agostino’s test was used to determine normality and scedasticity. Percentage or mean and standard deviation of demographic characteristics and lipid variables are presented. Multiple linear regression analysis was used when comparing lipid values with each other, and also when LDL-C values obtained by enzymatic methods were compared with those obtained by the classical Friedewald equation or by the extended Friedewald approach.

Results

Together 400 to 650 CABG patients were operated yearly in Tampere University Hospital during 1990–2009. On average, 50 patients of them were postoperatively treated annually in K-HCH. Patient records of altogether 946 subjects who attended postoperative cardiac outpatient clinic were analysed over a period of 20 years divided into four consecutive 5-year time periods, each consisting on average of 237 patients (ranging from 219 to 256 patients). The proportion of male patients ranged from 72 to 80 %. The changes in patients’ demographics followed both national and international trends, and the demographic characteristics are presented in Table 1.

Table 1 Demographics of patients undergone CABG during 1990–2009, divided into 4 consecutive 5-year periods
Full size table

Lipid treatment practice

Altogether 803 patients had their lipid values measured, 81.3 % of them at the 3-month visit. During the first 5-year period, 63.6 % of the patients and during the subsequent 5-year periods 85.6, 94.2 and 96.8 %, respectively, had their lipids analysed. Thus, there was an initial strong and statistically significant (p < 0.01) increase in the proportion of patients having their lipids determined.

During the 20-year observation period, the use of statins increased markedly, the most prominent increase having taken place during 1995–1999 (Additional file 1: Table S1B). Within the last years of the follow-up, practically all CABG patients were on statin therapy (Fig. 1a).

Fig. 1
figure 1

a LDL-C ± 1 SD calculated by Friedewald formula (mmol/l, black line ± 1 SD blue shadowing) and the amount of statin users (%, red line) at postoperative visits. b Plasma correlation of apoB ± 1 SD (g/l, black line ± 1 SD blue shadowing) and daily statin dose index (DSDI, black line ± 1 SD red shadowing) (see Methods) at postoperative visits. Red arrows indicate the publication of landmark studies from left to right: 4S3, CARE4, LIPID5, REVERSAL6 and PROVE IT8. Blue arrows refer to the publication of lipid lowering recommendations from left to right: Second European Task Force11, NCEP ATP III12, Third European Task force13, NCEP ATP III (Implication of recent clinical trials)14, and Fourth European Task Force15. Black arrows indicate the years, when the two most effective statins entered the Finnish market, i.e. atorvastatin in 1997 and rosuvastatin in 2003. LDL-C was calculated by Friedewald formula and apoB was obtained using extended Friedewald approach (see Methods)

Full size image

The DSDIs were small during the initial years, and effective statin doses increased progressively during the last years of follow-up. Thus, the average DSDIs of all patients, even when those without statin therapy were included, increased during four consecutive 5-year time periods from 0.07 (±0.23) to 0.46 (±0.53), 1.25 (±1.19) and 2.52 (±1.52) (p for trend < 0.001) (Fig. 1b, Table 2). The DSDI 2.86 (±0.41) during the very last year of observation corresponds to a mean simvastatin dose of 57 (±8) mg/day.

Table 2 Postoperative plasma lipid and lipoprotein levels in consecutive 5-year periods in statin-treated patients undergone CABG
Full size table

Plasma lipid and apolipoprotein levels

The mean concentrations of LDL-C were 3.7 and 2.1 mmol/l, and those of apoB 1.3 and 0.8 g/l, during the initial (1990–1994) and final (2005–2009) 5-year time periods, respectively (Fig. 1, Table 2). During the last single year of follow-up (2009), the mean concentrations of LDL-C and apoB were 1.83 mmol/l and 0.78 g/l, respectively.

The decrease in apoB concentration was progressive during the 20-year time span. It reflects not only the decrease in LDL-C concentration, but also in the concentrations of other apoB-containing lipoproteins, as seen in decreases of VLDL-TG and IDL-C, which were reduced proportionately (Fig. 2a). HDL-C increased from 1.02 (±0.29) to 1.22 (±0.34) particularly due to an increase in the concentration of HDL2-C, while the concentration of HDL3-C remained at a constant level of 0.45 mmol/l (Fig. 2b). The multiple linear correlations of different lipoproteins are presented in Additional file 2: Table S2B.

Fig. 2
figure 2

a Apolipoprotein B (ApoB, g/l), VLDL-triglycerides (mmol/l) and IDL-cholesterol (mmol/l) at postoperative visits. b Apolipoprotein A-1 (ApoA1, g/l), HDL-cholesterol (mmol/l), HDL2-cholesterol (mmol/l) and HDL3-cholesterol (mmol/l) at postoperative visits are shown both as curves and as linear representations. All parameters except HDL-C were obtained using extended Friedewald approach

Full size image

Discussion

Our main findings indicate that during a 20-year follow-up (1990–2009) of CABG patients the following beneficial changes in lipid and lipoprotein measurements and in lipid treatment efficacies occurred in sequence. First, the percentage of patients with measured cholesterol levels increased, and thereafter, the share of patients on statin therapy and the efficacy of the therapy increased consecutively. Moreover, the concentrations of LDL-C and of apoB, the latter reflecting the number of atherogenic apoB-containing lipoprotein particles, decreased by 45 and 40 %, respectively.

Importantly, the primary changes took place immediately after the first statin mega-trial had been published, i.e. before their results had been integrated into the updated formulations of the relevant international guidelines [3, 4]. The mean dosage of statin increased rapidly after 2002, when the most effective statin, rosuvastatin, had become available in the market. In 2002 and 2005 DSDI-values were 1.08 and 2.56, respectively, see Fig. 1b). Although during the 20-year follow-up period, the levels of total cholesterol in the Finnish population steadily decreased [29], the decrease in our patients was 3- to 4-fold when compared with that of the general population. This finding accords with the notion that, at least the majority of the excess decrease in LDL-C among the CABG patients must have been due to statin treatment. Thus our results comply with the observed significant decreases in LDL-C found in mega-trials in which decreased cardiovascular morbidity and mortality with intensified statin therapy could also be achieved [3–6, 8].

The efficiency of secondary prevention of CHD in Europe has been evaluated in the Euroaspire studies I and II. In the Euroaspire II study (1999–2000) consisting of coronary patients (including also CABG patients) from 15 European countries, 42 % had their T-C < 5.0 mmol/l and 61 % were on lipid-lowering medication [30]. At the same time the corresponding numbers in our patient population were 68 and 76 %, respectively. In an international cross-sectional study by Gitt et al. [31], the prevalence of lipid abnormalities were assessed in 2008–2009 in more than 22 000 European and Canadian patients on statin treatment. In this study, 58 % of patients having a cardiovascular high-risk had their LDL-C < 2.5 mmol/l. Their mean DSDI was 1.85, corresponding to a simvastatin dose of 37 mg [31]. In another study carried out 2009–2010, out of 151 patients undergone CABG, 83.4 % had lipid profile measured during the first postoperative year [32]. In this group, the mean LDL-C level was 1.86 mmol/l, i.e. at the same level as it was during the last years of our study. It has recently been indicated, that physicians’ lipid-lowering treatment choices are usually more conservative than guideline recommendations [33]. However, our results reveal that, in a proactive clinic, it is feasible to react without delay to the inflowing relevant information describing results of new well-conducted lipid-lowering trials published in peer-reviewed high-impact journals.

The concentrations of HDL-C and phospholipids, as well as the HDL2/HDL3-ratio, increased in the CABG patients during the 20-year observational period. Regarding the potential clinical significance of these observations, following points need to be considered. The apparently beneficial changes must have been partly due to statin treatment and partly to life style changes. Inasmuch as beneficial life style changes are accompanied by beneficial changes in various cardiometabolic measures, quantitation of the role of changes in Apolipoprotein A-I containing lipoproteins or their components is not feasible. Similarly, the clinical relevance of the minor statin induced increases in various parameters of HDL particles and their constituents remains uncertain. Interestingly, the moderate increase in HDL-C levels with statins correlates with regression of coronary atherosclerosis [34]. With respect to the size of the HDL particles, the larger HDL2 particles have been associated with greater CHD protection than the smaller HDL3 particles [35, 36]. However in recent meta-analysis of 80 published investigations, no differences in cardioprotective properties between these two HDL subclasses were discerned [37, 38]. Importantly, regarding the cardioprotective functions of HDL, the scientific interest is shifting largely to unravelling the biologic activity of HDL [38]. Thus, assigning any presumed clinical significance to the modest increases in the various metrics of Apo A-I containing lipoprotein fractions is not possible at present.

Although LDL is considered the main atherogenic cholesterol-rich particle, also other apoB-containing lipoproteins contribute to intimal cholesterol deposition, i.e. they also are atherogenic [20]. Importantly, the recent increase in the incidence of metabolic syndrome and diabetes has re-emphasized the requirement for obtaining additional data on triglyceride rich lipoproteins like VLDL and IDL. For example, IDL particles and their cholesterol are contributing to the progression of coronary and carotid artery atherosclerosis [39]. Besides the number of apoB-containing lipoproteins, also the size of these particles is considered a key determinant in atherosclerosis [40]. The small dense LDL particles, when being present in high numbers, particularly increase the risk of ischemic heart disease [41]. While the large chylomicrons fail to penetrate the arterial wall, triglyceride rich chylomicron remnants and VLDL remnants (IDL) with smaller particle sizes, enter the arterial wall and so drive atherogenesis [20, 42, 43]. To the best of our knowledge, an observation of diminished IDL-C during intensified statin treatment with lipid values taken and analysed 1–3 months postoperatively over a time span of 20 years, has not been reported earlier.

A limitation associated with this study is its retrospective nature. Therefore we lack knowledge of possible statin intolerance, which is nowadays considered a notable problem in statin treatment. Although in observational studies even 10–15 % of patients have reported muscle symptoms, most of them might be successfully treated with careful management [44, 45]. During the last years of our study only about 2 % of patients were not on statins. That might represent the maximal percentage of patients suffering from clinically relevant statin intolerance in this well-motivated patient population. A possible explanation for the success in statin therapy might be the highly individualized care of the cardiovascular patients in our hospital.

Due to the retrospective nature of this study, the investigators had to rely on medical records with all their imperfections. For example, information concerning laboratory values and medications was occasionally incomplete. Nevertheless, for 85 % of the patients all relevant data were available. Moreover, during the last four decades our hospital has had a fairly stable catchment population without any significant national or international migration. Thus the genetic and racial backgrounds, two factors of potential importance considering the limited size of our study sample, have remained stable.

Conclusions

To conclude, prominent increase of statin use in patients undergone CABG took place immediately after the first statin mega-trial was published. Further, over a 20-year period (1990–2009) the efficacy of statin treatment gradually increased and the concentration of LDL-C, measured 1–3 months postoperatively, gradually decreased. Also the decreases of apoB, IDL-C and VLDL-TG were favourable. Our results show that, based on the outcomes of relevant mega-trials, it is possible in a single centre to optimise clinical practice without delay even before they have led to reformulations of international guidelines.

References

  1. Coronary artery surgery study (CASS). A randomized trial of coronary artery bypass surgery. Quality of life in patients randomly assigned to treatment groups. Circulation. 1983;68:951–60.

    Article  Google Scholar 

  2. Post Coronary Artery Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein cholesterol levels and low-dose anticoagulation on obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med. 1997;336:153–62.

    Article  Google Scholar 

  3. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–9.

  4. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC,Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001–9.

  5. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349–57.

    Article  Google Scholar 

  6. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, Crowe T, Howard G, Cooper CJ, Brodie B, Grines CL, DeMaria AN. REVERSAL investigators effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071–80.

  7. Brunzell JD, Davidson M, Furber CD, Goldberg RB, Howard BV, Stein JH, Witztum JL. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American diabetes association and the American college of cardiology foundation. J Am Coll Cardiol. 2008;51:1512–24.

  8. Ray KK, Cannon CP, McCabe CH, Cairns R, Tonkin AM, Sacks FM, Jackson G, Braunwald E, for the PROVE IT-TIMI 22 Investigators. Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes. Results from the PROVE iT-TIMI 22 trial. J Am Coll Cardiol. 2005;46:1405–10.

  9. National Cholesterol Education Program. Second report of the expert panel on detection, evaluation and treatment of high blood cholesterol in adults (adult treatment panel II). Circulation. 1994;89:1333–445.

    Article  Google Scholar 

  10. Pyörälä K, De Backer G, Graham I, Poole-Wilson P, Wood D. Prevention of coronary heart disease in clinical practise. Recommendations of the task force of the European society of cardiology, European atherosclerosis society and European society of hypertension. Eur Heart J. 1994;15:1300–31.

    PubMed  Google Scholar 

  11. Wood D, De Backer G, Faergeman O, Graham I, Mancia G, Pyörälä K, together with members of the task force. Prevention of coronary heart disease in clinical practice. Recommendations of the second task force of European and other societies on coronary prevention. Eur Heart J. 1998;19:1434–503.

  12. Eagle KA, Guyton RA, Davidoff R, Ewy GA, Fonger J, Gardner TJ, Gott JP, Herrmann HC, Marlow RA, Nugent WC, O'Connor GT, Orszulak TA, Rieselbach RE, Winters WL, Yusuf S, Gibbons RJ, Alpert JS, Eagle KA, Garson A Jr, Gregoratos G, Russell RO, Smith SC Jr. 1991 guidelines for coronary artery bypass graft surgery). American college of cardiology/American heart association. J Am Coll Cardiol. 1999;4:1262–347.

  13. Executive Summary of the Third Report of The National Cholesterol Education Program (NCEP). Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA. 2001;285:2486–97.

    Article  Google Scholar 

  14. European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J. 2003;24:1601–10.

  15. Grundy SM, Cleeman JI, Merz CN, Brewer Jr HM, Clark LT, Hunninghake DB, Pasternack RC, Smith SC Jr, Stone NJ, for the Coordinating Committee of the National Cholesterol Education Program. Implications of resent clinical trials for the national cholesterol education program adult treatment panel III guidelines. J Am Coll Cardiol. 2004;44:720–32.

  16. Graham I, Atar D, Borch-Johnsen K, Boysen G, Burell G, Cifkova R, Dallongeville J, De Backer G, Ebrahim S, Gjelsvik B, Herrmann-Lingen C, Hoes A, Humphries S, Knapton M, Perk J, Priori SG, Pyorala K, Reiner Z, Ruilope L, Sans-Menendez S, Op Reimer WS, Weissberg P, Wood D, Yarnell J, Zamorano JL. European guidelines on cardiovascular disease prevention in clinical practice: executive summary. ESC Committee for Practice Guidelines Atherosclerosis. 2007;194:1–45.

  17. Carmena R, Duriez P, Fruchart JC. Atherogenic lipoprotein particles in atherosclerosis. Circulation. 2004;109:2–7.

    Article  Google Scholar 

  18. Mudd JO, Borlaug BA, Johnston PV, Kral BG, Rouf R, Blumenthal RS, et al. Beyond low-density lipoprotein cholesterol. J Am Coll Cardiol. 2007;50:1735–41.

    Article  CAS  PubMed  Google Scholar 

  19. Mcqueen MJ, Hawken S, Wang X, Ounpuu S, Sniderman A, Probstfield J, Steyn K, Sanderson JE, Hasani M, Volkova E, Kazmi K, Yusuf S. Lipids, lipoproteins, and apolipoproteins as risk markers of myocardial infarction in 52 countries (the INTERHEART study): a case-control study. Lancet. 2008;372:224–33.

  20. Chapman MJ, Ginsberg HN, Amarenco P, Andreotti F, Borén J, Catapano AL, Descamps OS, Fisher E, Kovanen PT, Kuivenhoven JA, Lesnik P, Masana L, Nordestgaard BG, Ray KK, Reiner Z, Taskinen MR, Tokgözoglu L, Tybjærg-Hansen A, Watts GF. European atherosclerosis society consensus panel. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J. 2011;32:1345–61.

  21. Constance C, Ben-Yehuda O, Wenger NK, Zieve F, Lin J, Hanson ME, Lowe RS, Tershakovec AM. Atorvastatin 10 mg plus ezetimibe versus titration to atorvastatin 40 mg: attainment of European and Canadian guideline lipid targets in high-risk subjects ≥65 years. Lipids Health Dis. 2014;13:13.

  22. Jones PH, Davidson MH, Stein EA, Bays HE, Mckenney JM, Miller E, Cain VA, Blasetto JW, STELLAR Study Group. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR trial). Am J Cardiol. 2003;92:152–60.

  23. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. Br Med J. 2003;326:1423–7.

    Article  CAS  Google Scholar 

  24. Edwards JE, Moore RA. Statins in hypercholesterolaemia: a dose-specific meta-analysis of lipid changes in randomised, double blind trials. BMC Fam Pract. 2003;4:18.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Naci H, Brugts JJ, Fleurence R, Ades AE. Dose-comparative effects of different statins on serum lipid levels: a network meta-analysis of 256,827 individuals in 181 randomized controlled trials. Eur J Prev Cardiol. 2013;20:658–70.

    Article  PubMed  Google Scholar 

  26. Niemi J, Mäkinen VP, Heikkonen J, Tenkanen L, Hiltunen Y, Hannuksela ML, Jauhiainen M, Forsblom C, Taskinen MR, Kesäniemi YA; Savolainen MJ, Kaski K, Groop PH, Kovanen PT, Ala-Korpela M. Estimation of VLDL, IDL, LDL, HDL2, apoA-I, and apoB from the friedewald inputs—apoB and IDL, but not LDL, are associated with mortality in type 1 diabetes. Ann Med. 2009;41:451–61.

  27. Raitakari OT, Mäkinen VP, Mcqueen MJ, Niemi J, Juonala M, Jauhiainen M, Salomaa V, Hannuksela ML, Savolainen MJ, Kesäniemi YA, Kovanen PT, Sundvall J, Solakivi T, Loo BM, Marniemi J, Hernesniemi J, Lehtimäki T, Kähönen M, Peltonen M, Leiviskä J, Jula A, Anand SS, Miller R, Yusuf S, Viikari JS. Computationally estimated apolipoproteins B and A1 in predicting cardiovascular risk. Atherosclerosis. 2013;226:245–51.

  28. Siegel S, Castellan Jr NJ. The case of k independent samples. In: Siegel S, editor. Nonparametric statistics for behavioral sciences. 2nd ed. New York: McGraw-Hill Inc; 1988. p. 174–9.

    Google Scholar 

  29. Valsta LM, Tapanainen H, Sundvall J, Laatikainen T, Männistö S, Pietinen P, Vartiainen E. Explaining the 25-year decline of serum cholesterol by dietary changes and use of lipid-lowering medication in Finland. Public Health Nutr. 2010;13:932–8.

  30. Euroaspire II, study Group. Lifestyle, risk factor management and use of drug therapies in coronary patients from 15 countries. Principal results from EUROASPIRE II. Euro heart survey programme. Eur Heart J. 2001;22:554–72.

    Article  Google Scholar 

  31. Gitt AK, Drexel H, Feely J, Ferrières J, Gonzalez-Juanatey JR, Thomsen KK, Leiter LA, Lundman P, da Silva PM, Pedersen T, Wood D, Jünger C, Dellea PS, Sazonov V, Chazelle F, Kastelein JJ. Persistent lipid abnormalities in statin-treated patients and predictors of LDL-cholesterol goal achievement in clinical practice in Europe and Canada. Eur J Prev Cardiol. 2012;19:221–30.

  32. Barry AR, Koshman SL, Norris CM, Ross DB, Pearson GJ. Evaluation of preventive cardiovascular pharmacotherapy after coronary artery bypass graft surgery. Pharmacotherapy. 2014;34:464–72.

    Article  PubMed  Google Scholar 

  33. Krempf M, Simpson Jr RJ, Ramey DR, Brudi P, Giezek H, Tomassini JE, Lee R, Farnier M. Patient and physician factors influence decision-making in hypercholesterolemia: a questionnaire-based survey. Lipids Health Dis. 2015;14:45.

  34. Nicholls SJ, Nissen SE. New targets of high-density lipoprotein therapy. Curr Opin Lipidol. 2007;18:421–6.

    Article  CAS  PubMed  Google Scholar 

  35. Morgan J, Carey C, Lincoff A, Capuzzi D. High-density lipoprotein subfractions and risk of coronary artery disease. Curr Atheroscler Rep. 2004;6:359–65.

    Article  PubMed  Google Scholar 

  36. Williams PT, Feldman DE. Prospective study of coronary heart disease vs. HDL2, HDL3, and other lipoproteins in Gofman’s Livermore cohort. Atherosclerosis. 2011;214:196–202.

    Article  CAS  PubMed  Google Scholar 

  37. Superko HR, Pendyala L, Williams PT, Momary KM, King 3rd SB, Garrett BC. High-density lipoprotein subclasses and their relationship to cardiovascular disease. J Clin Lipidol. 2012;6:496–523.

    Article  PubMed  Google Scholar 

  38. Hovingh GK, Rader DJ, Hegele RA. HDL re-examined. Curr Opin Lipidol. 2015;26:127–32.

    Article  CAS  PubMed  Google Scholar 

  39. Hodis HN, Mack WJ, Dunn M, Liu C, Selzer RH, et al. Intermediate-density lipoproteins and progression of carotid arterialwall intima-media thickness. Circulation. 1997;95:2022–6.

    Article  CAS  PubMed  Google Scholar 

  40. Kovanen PT, Jauhiainen M. Coronary heart disease prediction: Apolipoprotein B shows its might again—but still in vain? Eur J Prev Cardiol. 2015;22:1317-20.

  41. Sniderman AD, St-Pierre AC, Cantin B, Dagenais GR, Després JP, Lamarche B. Concordance/discordance between plasma apolipoprotein B levels and the cholesterol indexes of atherosclerotic risk. Am J Cardiol. 2003;91:1173–7.

    Article  CAS  PubMed  Google Scholar 

  42. Alaupovic P, Mack WJ, Knight-Gibson C, Hodis HN. The role of triglyceride-rich lipoprotein families in the progression of atherosclerotic lesions as determined by sequential coronary angiography from a controlled clinical trial. Arterioscler Thromb Vasc Biol. 1997;17:715–22.

    Article  CAS  PubMed  Google Scholar 

  43. Chan DC, Watts GF. Dyslipidemia in the metabolic syndrome and type 2 diabetes: pathogenesis, priorities, pharmacotherapies. Expert Opin Pharmacother. 2011;12:13–30.

    Article  CAS  PubMed  Google Scholar 

  44. Banach M, Rizzo M, Toth PP, Farnier M, Davidson MH, Al-Rasadi K, Aronow WS, Athyros V, Djuric DM, Ezhov MV, Greenfield RS, Hovingh GK, Kostner K, Serban C, Lighezan D, Fras Z, Moriarty PM, Muntner P, Goudev A, Ceska R, Nicholls SJ, Broncel M, Nikolic D, Pella D, Puri R, Rysz J, Wong ND, Bajnok L, Jones SR, Ray KK, Mikhailidis DP.. Statin intolerance—an attempt at a unified definition. Position paper from an international lipid expert panel. Expert Opin Drug Saf. 2015;6:935–55.

  45. Nissen SE, Stroes E, Dent-Acosta RE, Rosenson RS, Lehman SJ, Sattar N, E, Češka R, Lepor N, Ballantyne CM, Gouni-Berthold J, Elliott M, Brennan DM, Wasserman SM, Somaratne R, Scott R, Stein EA, for the GAUSS-3 Investigators. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance. The GAUSS-3 randomized clinical trial. JAMA. 2016;315:1580–90.

Download references

Acknowledgements

We acknowledge the professional technical help received from Timo Lukkarinen M.D. and Annika Palomäki M.Sc. (Admin.).

Funding

The study was supported by grants from Häme Regional Funds under the auspices of the Finnish Cultural Foundation, the Ministry of Health and Social Welfare in Finland through the Medical Research Fund of Kanta-Häme Central Hospital, and Wihuri Research Institute maintained by the Jenny and Antti Wihuri Foundation.

Availability of data and materials

The datasets analysed during the current study are available from the corresponding author on reasonable request.

Authors’ contributions

AP and VH designed the study and acquired the data. AP, VH and PTK drafted the manuscript. MA-K and KM carried out data maintenance and statistics and gave valuable contribution to the manuscript. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

The study was approved by the Ethics Committee of Kanta-Häme Hospital District (Dnro E511/08).

Author information

Authors and Affiliations

  1. Department of Emergency Medicine, Kanta-Häme Central Hospital, FIN-13530, Hämeenlinna, Finland

    A. Palomäki & V. Hällberg

  2. Medical School, University of Tampere, Tampere, Finland

    A. Palomäki, V. Hällberg & K. Malminiemi

  3. University of Oulu, Institute of Health Sciences, Computational Medicine and Oulu University Hospital, Oulu, Finland

    M. Ala-Korpela

  4. School of Social and Community Medicine and Medical Research Council Integrative Epidemiology Unit, Computational Medicine, University of Bristol, Bristol, UK

    M. Ala-Korpela

  5. Wihuri Research Institute, Helsinki, Finland

    P. T. Kovanen

  6. Department of Emergency Medicine, Tampere University Hospital, Tampere, Finland

    K. Malminiemi

Authors
  1. A. Palomäki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. V. Hällberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Ala-Korpela
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P. T. Kovanen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K. Malminiemi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to V. Hällberg.

Additional files

Additional file 1: Table S1B.

Percentages in consecutive 5-year periods of patients having statin therapy after the CABG during 1990–2009. (DOCX 14 kb)

Additional file 2: Table S2B.

Multiple linear regression analysis between lipid values obtained with different methods. (DOCX 16 kb)

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Palomäki, A., Hällberg, V., Ala-Korpela, M. et al. Prompt impact of first prospective statin mega-trials on postoperative lipid management of CABG patients: a 20-year follow-up in a single hospital. Lipids Health Dis 15, 124 (2016). https://doi.org/10.1186/s12944-016-0292-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12944-016-0292-6

Keywords

Lipids in Health and Disease

ISSN: 1476-511X