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COMPARING HIGH INTENSITY WITH LOW INTENSITY STATINS IN ACHIEVING OPTIMAL LDL GOALS AMONG CORONARY ARTERY DISEASE PATIENTS IN SUBURBAN POPULATION IN SOUTH INDIA.

BACKGROUND

Unstable plaque in epicardial coronary arteries leads to acute coronary syndrome (ACS) and this in turn, results in clinical conditions extending from unstable angina to sudden cardiac death. [1] Statins are known as the agents with pleotropic effects and maximum lipid-lowering efficacy in patients with proven coronary artery disease. [2] Low-density lipoprotein cholesterol (LDL-C) in various studies have shown to be the chief risk determinant for coronary events and has a positive interrelation even for values within the normal range. [3] Evidence collated over the years demonstrates that statins can decrease the long-term cardiovascular risk by reducing the elevated LDL-C, small-dense LDL-C, and C-reactive protein. [2] For very high risk patients, the present ESC/EAS guidelines (2016) for the treatment of dyslipidaemias advocates the LDL-C levels of <70 mg/dl (target goal). [4] In ACS patients, a meta-analysis validated the advantages of early intensive statin use in reducing the recurrent myocardial ischemia. [5] However, as a result of the safety concerns, intensive statin therapies not employed frequently. [6] Both atorvastatin and rosuvastatin are potent statins with varying pharmacologic characteristics. Evidence conveys that rosuvastatin produces greater decline in LDL-C and has a higher rate of accomplishing the therapeutic goals compared to other statins. [7]

Although there is abundant data analysing the efficacy of atorvastatin and rosuvastatin at different doses, in general, there is no analytical comparison of their lipid depleting effects in ACS patients. [8-12]

It has been demonstrated in numerous studies that many high risk patients do not attain desired LDL-C control in spite of being treated with intensive statin therapy. [13,14] Thus, the aim of the present study was to analyse the control of LDL-C and high-density lipoprotein (HDL-C) levels after 12 weeks of statin therapy at different doses, in patients who had ACS and those who underwent revascularization with or without a prior episode of ACS.

MATERIALS AND METHODS

This was a 12 week, a prospective cohort Study. It was designed to analyse the efficacy of atorvastatin and rosuvastatin at different doses in patients with ACS or those who had undergone coronary intervention with or without prior ACS. The pre-requisite at the time of enrolment was that patients should have an LDL-C level >70 mg/dl.

The study was performed at a hospital over a period of 24 weeks (From October 2016 to March 2017). Patients more than 18 years of age were enrolled in the study only after obtaining the approval of the Institutional Ethics Committee. Patients were explained about the study and written informed consent was obtained from them in their native language. A detailed history was taken, and clinical examination was performed. Blood samples were obtained for estimation of serum total cholesterol (TC) and HDL-C after fasting for 12 hours using Beckman Coulter AU5800 chemistry auto-analyser. Friedewald equation was used for calculation of LDL-C (LDL-C = total cholesterol - (HDL-C+ triglyceride/5). These biochemical parameters were estimated again at the end of 12 weeks.

A total of 100 consecutives cases were initiated on either atorvastatin (ATV) (10 mg to 80 mg) or rosuvastatin (RSV) (5 mg to 20 mg), according to initial LDL values, at an index point of contact. Comparison of each class of patients, according to their respective dose of statin and the percentage change in LDL-C after 12 weeks of treatment was done. Patients were excluded, if they had moderate or severe congestive heart failure, new-onset atrial fibrillation with an uncontrolled ventricular rate (100 beats/min), pulmonary oedema, complete heart block, sepsis, stroke or acute pericarditis within the preceding 4 weeks; women who were pregnant or breastfeeding; malignancy; active liver disease; malnutrition; hypothyroidism; and those taking oral contraceptives within the previous 3 months.

Statistical Analysis

Statistical analysis was done using the software SPSS version 21. Mean of Pre-test scores and Post-test scores for all the parameters were compared using Paired samples t-test. Cognitive gain was calculated as Post-test score minus Pretest score. For all statistical evaluations, probability of value <0.05 was considered significant.

RESULTS

A total of 136 consecutive patients were screened, of which 100 patients were included and completed the study. Demographics and baseline biochemical parameters are described in Table 1. Overall, most patients were male (80 %). This points to higher incidence of dyslipidaemia in male patients. Distribution of patients in each group is described in Table 2. Doubling the doses of both the agents resulted in anticipated additional gain in terms of change in LDL-C, TC and HDL-C.

The influence of ascending doses of each statin on LDL-C levels is described in Table 3. The absence of additional benefit noticed at the highest dose of rosuvastatin was basically due to lower baseline LDL-C levels and probably indicates the higher possibility that they would acquire their target levels. Significant decline in LDL-C was observed with ATV20 (p = 0.028) and ATV40 (p = 0.0001) at the end of 12 weeks. The decline in LDL-C with ATV80 did not acquire the significance, but there was a tendency towards statistical significance (p = 0.068). At the end of treatment period, LDL-C decreased in all the groups except ATV10 and RSV5 (Table 4). After controlling for statin dose and baseline LDL-C level, multivariate analysis revealed increasing age (p = 0.038) as a predictor of accomplishing LDL-C goal of <70 mg/dl.

The influence of ascending dose of each statin on HDL-C levels is described in Table 3. Mean change in HDL-C over 12 weeks demonstrated that HDL-C increased to a significant extent with ATV40 (p = 0.024) (Table 3). At the end of treatment period, HDL-C was raised in all the groups except ATV10 (Table 4). The chance of reaching a HDL-C level > 40 mg/dl was more inpatients with lower baseline levels or those on higher doses of statin (Table 4).

The influence of ascending dose of each statin on TC levels is described in Table 3. Significant decline in TC was noticed with ATV10 (p = 0.039), ATV20 (p = 0.026) and ATV40 (p = 0.0001) at the end of 12 weeks. The decline in TC with ATV80 did not acquire the significance, but, there was a tendency towards statistical significance (p = 0.068). At the end of treatment period, TC cholesterol decreased in all the groups (Table 4).

On analysis, only 69% of the patients received high dose of statin. More than 80% of the patients using high dose statins i.e., ATV40 and ATV80 and RSV20 achieved optimal LDL-C control. In patients, taking lower dose of statin > 50% people did not attain optimal LDL-C control. Reduction in LDL-C in RSV20 is not significant as baseline LDL-C was near optimal level and these patients were already on statins.

DISCUSSION

The present study analysed the relative efficacy of atorvastatin and rosuvastatin over the dose range in Indian patients and thus, presented an opportunity to distinguish the percentage change in lipid levels determined by doubling the dose of statins. The conclusion that the greatest gain is derived at the highest dose of statins is uniform with the observation that the greatest impact on clinical events [15,16] and on the advancement of atherosclerosis [17, 18]is observed at these doses. Overall, high dose ATV (20-80 mg) and RSV (20 mg) were effective in decreasing LDL-C levels after 12 weeks of treatment. Various studies have established that in real-world scenario, only 67% of dyslipidemic patients reach their desired LDL-C level goals. [19] These studies highlight the distinction of practicing high intensity statins therapy in very high-risk patients to warrant them to acquire the target LDL-C level.

With respect to other components of the lipid profile, overall decline in TC was greater with ATV as compared to RSV, while rise in HDL-C was relatively equal (maximum with ATV80) across all the treatment groups, except ATV10.

Thapa R et al. [12] compared RSV5 with ATV10 and demonstrated significant change in LDL-C, TC, and HDL-C with both at the end of 3rd and 6th months. Similarly, percentage change in LDL-C, TC, and HDL-C with RSV5 was--48.69%, -35.01%, and +25.56% respectively, while that with ATV10 was--43.85%, -34.94%, and +8.71% respectively. All these observations are contradictory to our findings, except significant decline in TC with ATV10.

Park JS et al. [8] Demonstrated significant change in LDL-C and TC on treatment with both RSV10 and ATV10 for a period of 6 weeks. Moreover, ATV10 demonstrated significant change in HDL-C. Percentage change in LDL-C, TC and HDL-C with RSV10 was--48%, -35% and -1%, respectively, while that with ATV10 was--40%, -30% and 4% respectively. Only significant decline in TC and percentage decrease in HDL-C levels with ATV10 is in accordance with our study.

Lee CW et al. [9] compared RSV10 and ATV20 in 350 cases and reported significant change in LDL-C, HDL-C and TC with both at the end of treatment period. Percentage change in LDL-C, TC and HDL-C with RSV10 was--49%, -1% and +20%, respectively, while that with ATV20 was--47%, -29% and +19% respectively. However, the present study demonstrated similar trend with respect to percentage change in biochemical parameters in both the groups, but the intensity of percentage change was relatively less.

Khurana S et al. [n]compared RSV20 and ATV40 in 100 patients and demonstrated significant change in LDL-C, HDL-C and TC with both at the end of 4 weeks. Percentage change in LDL-C, TC and HDL-C with RSV20 was--39.16%, -28.36% and -0.68% respectively, while that with ATV40 was --37.06%, -26.40% and -0.78% respectively. Percentage change in LDL-C and TC with both the treatments demonstrated similar trend but percentage change in HDL-C was opposite to that of our findings.

Pitt Bet al. [10] Reported significant change in LDL-C, HDL-C and TC on treatment with both RSV20 and ATV80 for a period of 12 weeks. Percentage change in LDL-C, TC and HDL-C with RSV20 was--42%, -28.6% and +9.7%, respectively, while that with ATV80 was--42.7%, -30.9% and +5.6% respectively. With ATV80, percentage change in LDL-C and TC were similar, while in HDL-C was more in the present study. RSV20 demonstrated trend which was similar to our study, although magnitude of change was relatively large.

It was an observational study and thus, has its own limitations. Limitations of the study includes small sample size, significant difference in the baseline biochemical parameters among different groups, rosuvastatin 40 mg was not compared, and using low-dose statins in very high-risk patients.

Unwillingness to use the higher doses of statin may be correlated by some to the perception of a relatively small additional decline in LDL-C levels. It is apparent from this study that the use of high-dose statin leads to greatest proportion of patients acquiring treatment goals of all components of lipid profile. he significance of attaining target goals has evolved as a basic component of guidelines for management of dyslipidaemia, thus additionally emphasizing the distinction of the present findings.

CONCLUSION

This study demonstrates that over all, patients on high dose atorvastatin and rosuvastatin achieve optimal levels of LDLC and TC. Moreover, it was observed that atorvastatin raised the HDL-C to a greater extent as compared to rosuvastatin. Additional studies analysing statins across different doses in Indian patients, not acquiring their treatment goals with low-dose statins, are needed.

REFERENCES

[1] Braunwald E. Unstable angina and non-ST elevation myocardial infarction. Am J Respir Crit Care Med 2012;185(9):924-32.

[2] Ostadal P. Statins as first-line therapy for acute coronary syndrome? Exp Clin Cardiol 2012;17(4):227-36.

[3] O'Keefe Jr JH, Cordain L, Harris WH, et al. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. Journal of the American College of Cardiology 2004;43(11):2142-6.

[4] Catapano AL, Graham I, De Backer G, et al. 2016 ESC/ EAS guidelines for the management of dyslipidaemias. European Heart Journal 2016;37(39):2999-3058.

[5] Hulten E, Jackson JL, Douglas K, et al. The effect of early, intensive statin therapy on acute coronary syndrome: a meta-analysis of randomized controlled trials. Arch Intern Med 2006;166(17):1814-21.

[6] Armitage J. The safety of statins in clinical practice. Lancet 2007;370(9601):1781-90.

[7] Kurabayashi M, Yamazaki T, SUBARU Study Group. Superior benefit of aggressive lipid-lowering therapy for high-risk patients using statins: the SUBARU study--more hypercholesterolemic patients achieve Japan atherosclerosis society LDL-C goals with rosuvastatin therapy than with atorvastatin therapy. Journal of Atherosclerosis and Trombosis 2008;15(6):314-23.

[8] Park JS, Kim YJ, Choi JY, et al. Comparative study of low doses of rosuvastatin and atorvastatin on lipid and glycemic control in patients with metabolic syndrome and hypercholesterolemia. Korean J Intern Med 2010;25(1):27-35.

[9] Lee CW, Kang SJ, Ahn JM, et al. Comparison of effects of Atorvastatin (20 mg) versus Rosuvastatin(10 mg) therapy on mild coronary atherosclerotic plaques (from the ARTMAP Trial). Am J Cardiol 2012;109(12):1700-4.

[10] Pitt B, Loscalzo J, Monyak J, et al. Comparison of lipid-modifying efficacy of rosuvastatin versus atorvastatin in patients with acute coronary syndrome (from the LUNAR Study). Am J Cardiol 2012;109(9):1239-46.

[11] Khurana S, Gupta S, Bhalla H, et al. Comparison of anti-inflammatory effect of atorvastatin with rosuvastatin in patients of acute coronary syndrome. J Pharmacol Pharmacother 2015;6(3):130-5.

[12] Thapa R, Rai P, Mahara L, et al. A comparative study of atorvastatin and rosuvastatin in dyslipidemia. Int J Basic & Clin Pharmacol 2017;6(11):2551-5.

[13] Leibovitz E, Harats D, Gavish D. Efficacy of atorvastatin in treating high risk patients to reach low density lipoprotein-cholesterol goals: the Treat to Target (TTT-Israel) Study. Isr Med Assoc J 2002;4(6):407-10.

[14] Yood MU, McCarthy BD, Kempf J, et al. Racial differences in reaching target low-density lipoprotein goal among individuals treated with prescription statin therapy. Am Heart J 2006;152(4):777-84.

[15] LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352(14):1425-35.

[16] Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350(15):1495-504.

[17] Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295(13):1556-65.

[18] Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA 2004;291(9):1071-80.

[19] Davidson MH. Differences between clinical trial efficacy and real-world effectiveness. Am J Manag Care 2006;12(Suppl 15):S405-S11.

Vinodkumar Balakrishnan (1), Ramesh Sankaran (2), Thanikachalam S (3), Muralidharan T. R (4), Nagendra Boopathy Senguttuvan (5), Dasarath Boppana (6)

(1) Assistant Professor, Department of Cardiology, Sriramachandra Institute of Higher Education and Research (Deemed to be University), Chennai, Tamilnadu, India.

(2) Associate Professor, Department of Cardiology, Sriramachandra Institute of Higher Education and Research (Deemed to be University), Chennai, Tamilnadu, India.

(3) Professor, Department of Cardiology, Sriramachandra Institute of Higher Education and Research (Deemed to be University), Chennai, Tamilnadu, India.

(4) Professor, Department of Cardiology, Sriramachandra Institute of Higher Education and Research (Deemed to be University), Chennai, Tamilnadu, India.

(5) Assistant Professor, Department of Cardiology, Sriramachandra Institute of Higher Education and Research (Deemed to be University), Chennai, Tamilnadu, India.

(6) Resident, Department of Cardiology, Sriramachandra Institute of Higher Education and Research (Deemed to be University), Chennai, Tamilnadu, India.

'Financial or Other Competing Interest': None.

Submission 30-11-2018, Peer Review 25-01-2019, Acceptance 01-02-2019, Published 11-02-2019.

Corresponding Author: Ramesh Sankaran, Associate Professor, Department of Cardiology, Sriramachandra Institute of Higher Education and Research (Deemed to be University), Chennai, Tamilnadu, India.

E-mail: sankaran_ramesh2000@yahoo.co.in

DOI: 10.14260/jemds/2019/80
Table 1. Demographics and Baseline Biochemical
Parameters

Sr. No.             Parameters                 Cohort (n = 100)

1                 Mean Age (yrs)             58.41 [+ or -] 10.57

2                 Male Gender (%)                    80 %

3         Total Cholesterol (TC) (mg/dl)    161.95 [+ or -] 40.84

4             Low Density Lipoprotein
            Cholesterol (LDL-C) (mg/dl)     125.46 [+ or -] 112.29
             High Density Lipoprotein

5           cholesterol (HDL-C) (mg/dl)      38.60 [+ or -] 10.87

Data is expressed as mean [+ or -]SD or as percentages

Table 2. Distribution of Patients (N = 100) In Each
Treatment Group

Statin      Gender       Total (n = 100)

         Male   Female

ATV10     11      2            13
ATV20     12      4            16
ATV40     37      12           49
ATV80     4       0             4
RSV5      3       0             3
RSV10     8       1             9
RSV20     5       1             6

Data expressed as absolute numbers

Table 3. Within Group Analysis of Different Treatment
Groups at The End of Treatment

                     Statins
                       and
Sr.                   their
No.    Parameters     Doses       Baseline (mg/dl)

1        Total        ATV10    173.92 [+ or -] 58.45
      Cholesterol     ATV20    156.50 [+ or -] 45.67
          (TC)        ATV40    159.27 [+ or -] 36.90
                      ATV80    195.50 [+ or -] 12.77
                      RSV5     145.33 [+ or -] 19.63
                      RSV10    176.67 [+ or -] 38.24
                      RSV20    136.83 [+ or -] 12.07

2     Low-Density     ATV10    106.23 [+ or -] 42.88
      Lipoprotein     ATV20    109.50 [+ or -] 34.51
      Cholesterol     ATV40    137.08 [+ or -] 155.38
        (LDL-C)       ATV80    177.25 [+ or -] 16.19
                      RSV5     111.33 [+ or -] 27.15
                      RSV10    125.11 [+ or -] 36.34
                      RSV20     87.83 [+ or -] 17.21

3     High-Density    ATV10     41.46 [+ or -] 12.25
      Lipoprotein     ATV20     38.13 [+ or -] 12.24
      Cholesterol     ATV40     38.04 [+ or -] 11.17
        (HDL-C)       ATV80     33.50 [+ or -] 9.00
                      RSV5      37.00 [+ or -] 3.46
                      RSV10     41.56 [+ or -] 10.67
                      RSV20     38.00 [+ or -] 5.79

                     Statins
                       and
Sr.                   their
No.    Parameters     Doses      12 Weeks (mg/dl)      p value

1        Total        ATV10    152.69 [+ or -] 34.89    <0.05
      Cholesterol     ATV20    139.94 [+ or -] 37.88    <0.05
          (TC)        ATV40    125.06 [+ or -] 26.87    <0.05
                      ATV80    133.25 [+ or -] 11.64    >0.05
                      RSV5     136.67 [+ or -] 31.01    >0.05
                      RSV10    162.44 [+ or -] 30.15    >0.05
                      RSV20    123.33 [+ or -] 22.26    >0.05

2     Low-Density     ATV10    109.46 [+ or -] 34.06    >0.05
      Lipoprotein     ATV20    98.88 [+ or -] 26.37     <0.05
      Cholesterol     ATV40    93.04 [+ or -] 20.37     <0.05
        (LDL-C)       ATV80     96.00 [+ or -] 2.83     >0.05
                      RSV5     114.00 [+ or -] 26.46    >0.05
                      RSV10    118.89 [+ or -] 30.63    >0.05
                      RSV20     84.17 [+ or -] 8.99     >0.05

3     High-Density    ATV10     41.00 [+ or -] 8.45     >0.05
      Lipoprotein     ATV20     39.81 [+ or -] 7.37     >0.05
      Cholesterol     ATV40     39.53 [+ or -] 7.78     <0.05
        (HDL-C)       ATV80    37.00 [+ or -] 12.06     >0.05
                      RSV5      38.00 [+ or -] 6.96     >0.05
                      RSV10     42.00 [+ or -] 7.81     >0.05
                      RSV20     38.50 [+ or -] 6.25     >0.05

Values expressed as mean [+ or -] SD; within group analysis done
by One-way ANOVA; p < 0.05 is considered as statistically
significant; ATV--Atorvastatin; RSV--Rosuvastatin

Table 4. Mean and Percentage Change in
Biochemical Parameters at The End Of 12 Weeks

                         Mean Change     %
Parameters     Statins     (mg/dl)     Change

Total           ATV10       -21.2      -12.13
Cholesterol     ATV20       -16.6      -10.61
(TC)            ATV40       -34.2      -21.47
                ATV80       -62.2      -31.82
                RSV5        -8.6       -5.92
                RSV10       -14.3      -8.09
                RSV20       -13.5      -9.87

Low-Density     ATV10        3.3        3.11
Lipoprotein
Cholesterol
(LDL-C)

High-Density    ATV20       -10.6      -9.68
Lipoprotein     ATV40       -44.1      -32.17
Cholesterol     ATV80       -81.3      -45.85
(HDL-C)         RSV5         2.7        2.43
                RSV10       -6.2       -4.96
                RSV20       -3.6        -4.1
                ATV10       -0.5        -1.2
                ATV20        1.7        4.46
                ATV40        1.5        3.95
                ATV80        3.5       10.45
                RSV5          1         2.70
                RSV10        0.4        0.96
                RSV20        0.5        1.32

Data expressed as mean or percentage; ATV--Atorvastatin;
RSV--Rosuvastatin
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Title Annotation:Original Research Article
Author:Balakrishnan, Vinodkumar; Sankaran, Ramesh; Thanikachalam, S.; Muralidharan, T.R.; Senguttuvan, Nage
Publication:Journal of Evolution of Medical and Dental Sciences
Article Type:Report
Geographic Code:9INDI
Date:Feb 11, 2019
Words:3270
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