Preventive Medicine 69 (2014) 314–316
Contents lists available at ScienceDirect
Preventive Medicine journal homepage: www.elsevier.com/locate/ypmed
Commentary
New cholesterol guidelines and the secondary prevention of cardiovascular disease — A commentary on epistemic aspects José Pedro L. Nunes ⁎ Faculdade de Medicina da Universidade do Porto, Department of Medicine, Alameda Prof. Hernani Monteiro, 4200 Porto, Portugal
a r t i c l e
i n f o
Available online 13 August 2014 Keywords: Cholesterol Guidelines Statins
a b s t r a c t The recommendations contained in the 2013 cholesterol guidelines may be described as either with or without a direct empirical clinical trial basis. Recommendations without a direct empirical clinical trial basis tend to be controversial. Recommendations with and without a direct empirical clinical trial basis are mixed in the same text — while at the same time (rightfully) rejecting previous recommendations, also without a direct empirical clinical trial basis. © 2014 Elsevier Inc. All rights reserved.
New cholesterol guidelines have been issued in November 2013 (Stone et al., 2014). The development of these guidelines was a meritorious effort, but it is up to the clinical and scientific community to examine the text and feed-back the comments that may seem appropriate for a global discussion on the topic. The text departs from the previous guidelines in several aspects, and may be considered a significant step in the right direction (Ridker and Cook, 2013). Two aspects appear as prominent improvements, at least from the perspective of a better fit between the guidelines and the clinical trial evidence: 1) the focus on statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) as the major type of drugs to be used; and 2) the focus on the use of statins in conditions similar to clinical trials, rather than on the use of arbitrary targets of LDL-C (low density lipoprotein cholesterol). However, a detailed analysis of the text shows that the philosophy chosen which led to the relevant changes outlined above does not appear to have been followed in an entirely complete way, leading to what would seem to be epistemic inconsistencies. In what concerns secondary prevention, the following recommendation is issued: “High-intensity statin therapy should be initiated or continued as first-line therapy in women and men ≤ 75 years of age who have clinical ASCVD, unless contraindicated” (“ASCVD” stands for atherosclerotic cardiovascular disease) (Stone et al., 2014). Highintensity statin therapy is presented as a daily dose that lowers LDL-C on average, by approximately ≥50%. According to the text, atorvastatin 40–80 mg and rosuvastatin 20–40 mg are the drugs and dosages to be chosen in order to produce such an effect. As shown in Table 1, three major clinical trials have compared either simvastatin or pravastatin to placebo in cardiac secondary prevention
⁎ Fax: +351 22 551 3601. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.ypmed.2014.06.035 0091-7435/© 2014 Elsevier Inc. All rights reserved.
(Group, 1994; Group, 1998; Sacks et al., 1996), whereas five further major clinical trials, carried out circa a decade later, compared highdose to a lower dose of statins (Armitage et al., 2010; Cannon et al., 2004; de Lemos et al., 2004; LaRosa et al., 2005; Murphy et al., 2009; Pedersen et al., 2005). Simvastatin and atorvastatin were the two drugs used as high dose statin therapy in the five trials. Since high dose (80 mg daily) simvastatin is no longer recommended due to increased incidence of myopathy (FDA, 2011), we are left with a single drug to be used as high dose in secondary prevention, with the support of at least one major clinical trial carried out in this context — atorvastatin. The indication, in the 2013 cholesterol guidelines, of high dose rosuvastatin to be used in cardiovascular secondary prevention, essentially lacks direct clinical trial supporting evidence, and constitutes a prominent epistemic inconsistency — it does not make sense to “get rid” of nonstatin drugs and insist in keeping drugs in indications with no direct supporting evidence. The same reasoning applies to pitavastatin, a drug for which no major clinical outcome trial was presented in the text, but that is nevertheless recommended, in this case for “low-intensity” and “moderate-intensity statin therapy” — a recommendation with no solid direct empirical basis. The recommendation, mentioned above, to use high dose statin therapy in cardiovascular secondary prevention would seem to be itself debatable. Although it is clear that high dose statins decrease cardiovascular events (Armitage et al., 2010; Cannon et al., 2004; de Lemos et al., 2004; LaRosa et al., 2005; Murphy et al., 2009; Pedersen et al., 2005), this type of therapy does not appear to alter the major parameter to be taken into consideration in this context — total mortality (Cannon et al., 2006). As shown in Fig. 1, it is striking that high dose statin therapy does not decrease the mortality rate, when compared to drugs used in low/standard dose. The same phenomenon was seen in a trial comparing high dose atorvastatin to placebo in stroke/transient ischemic attack
J.P.L. Nunes / Preventive Medicine 69 (2014) 314–316
315
Table 1 Inclusion criteria and drug dosages used in major cardiovascular secondary prevention clinical trials using statins. Study
Inclusion criteria
Drug therapy
4S (1994) (Group, 1994)
- Angina pectoris or previous myocardial infarction - Total cholesterol 5.5–8 mmol/L and triglyceride ≤ 2.5 mmol/L
CARE (1996) (Sacks et al., 1996)
- Myocardial infarction - Total cholesterol b 240 mg/dL, LDL-C of 115–174 mg/dL and triglyceride b 350 mg/dL - Myocardial infarction or unstable angina - Total cholesterol of 155–271 mg/dL and triglyceride b 445 mg/dL - Acute coronary syndrome - Total cholesterol ≤ 240 mg/dL or ≤200 mg/dL if already on lipid-lowering therapy - Acute coronary syndrome (either with or without ST segment elevation) - Total cholesterol level ≤ 250 mg/dL
LIPID (1998) (Group, 1998) PROVE IT TIMI 22 (2004) (Cannon et al., 2004) A TO Z (2004) (de Lemos et al., 2004)
TNT (2005) (LaRosa et al., 2005)
IDEAL (2005) (Pedersen et al., 2005)
SEARCH (2010) (Armitage et al., 2010)
- Stable coronary heart disease - LDL-C 130–250 mg/dL and triglyceride ≤ 600 mg/dL; LDL-C b 130 mg/dL after 8 week run-in period with atorvastatin 10 mg. - History of definite myocardial infarction
- History of myocardial infarction - Total cholesterol of at least 3.5 mmol/L if already on a statin or 4.5 mmol/L if not.
patients — decrease in ischemic events with no decrease in mortality (in this case, hemorrhagic stroke was noted to increase in patients treated with atorvastatin) (Investigators, 2006). Clearly, there is more in the human body than the coronary arteries, and effects on the coronary arteries (Nicholls et al., 2011) must be regarded as a surrogate marker in this context. It is the whole set of effects of statins on humans that must be taken into consideration, including cardiovascular and noncardiovascular effects — raising doubts on the decision to write the guidelines focusing on preventing the occurrence of cardiovascular endpoints. The recommendations contained in the 2013 cholesterol guidelines (Stone et al., 2014) may be described as either with or without a direct empirical clinical trial basis (Table 2). Recommendations without a direct empirical clinical trial basis tend to be controversial (Abramson and Redberg, 2013). Epistemic inconsistencies stem from the fact that recommendations with and without a direct empirical clinical trial
- Simvastatin, 20 mg daily, versus placebo. - 37% of patients changed to simvastatin 40 mg, 2 patients changed to 10 mg (goal being of a total cholesterol of 3.0–5–2 mmol/L) - 40 mg pravastatin versus placebo - Dietary counseling and cholestyramine 8–16 g used if LDL-C ≥ 175 mg/dL - 40 mg pravastatin versus placebo - 40 mg pravastatin versus 80 mg atorvastatin - 8% of patients under pravastatin had the dose increased to 80 mg, due to LDL-C N 125 mg/dL - Early intensive statin treatment (simvastatin, 40 mg for 30 days, followed by simvastatin, 80 mg) versus delayed less intensive regimen (placebo four months, followed by simvastatin 20 mg) - Atorvastatin 80 mg versus atorvastatin 10 mg
- Atorvastatin 80 mg versus simvastatin 20 mg - 23% of patients under simvastatin increased dose to 40 mg due to total cholesterol N 190 mg/dL and 13% of patients under atorvastatin decreased dose to 40 mg due to adverse events - Simvastatin 80 mg versus simvastatin 20 mg
basis are mixed in the same text — while at the same time (rightfully) rejecting previous recommendations, also without a direct empirical clinical trial basis. The risk score presented in the 2013 cholesterol guidelines (Stone et al., 2014) has been commented and criticized (Abramson and Redberg, 2013; Ridker and Cook, 2013). Regarding the risk score, its application must obey, at least in part, to a deductive line of reasoning, since it has not been directly applied in clinical trials. From a strict empiricist viewpoint (Nunes, 2013), inductive reasoning, based on clinical trial data, would be a preferable way to guide medical therapeutics. Significant limitations have been shown to exist when attempts are made to use syllogistic-like reasoning in medical therapeutics (Nunes, 2013). Conflict of interest None to declare.
Fig. 1. Meta-analysis of mortality data in five major trials comparing high dose statins to low/standard dose. High — high dose statin. Low/standard — low/standard dose statin. Meta-analysis was carried out by using the Comprehensive Meta-analysis software, version 2.0 (Biostat, NJ, USA), and odds ratios and 95% confidence intervals are presented. Randomeffects analysis was carried out, given the considerable heterogeneity of the data. Data from the original publications (Armitage et al., 2010; de Lemos et al., 2004; LaRosa et al., 2005; Pedersen et al., 2005) were used, except in the case of the PROVE IT-TIMI 22 trial (Cannon et al., 2004), which reported no mortality data in the main report, and the corresponding data were obtained from a later publication (Murphy et al., 2009).
316
J.P.L. Nunes / Preventive Medicine 69 (2014) 314–316
Table 2 Classification of recommendations according to empirical evidence. Recommendations with a direct empirical clinical trial basis
Recommendations without a direct empirical clinical trial basis
Use of simvastatin, pravastatin or atorvastatin in secondary cardiovascular prevention. Drug doses chosen according to clinical trial data. Statins as preferred drugs.
Use of rosuvastatin in secondary prevention, based on effects on surrogate markers and on theoretical models. Use of pitavastatin in the absence of major clinical trial data on “hard” outcomes. Use of a risk score derived from clinical trials but not directly tested in clinical trials.
Funding None. References Abramson, J., Redberg, R., 2013. Don't Give More Patients Statins. The New York Times, New York. Armitage, J., Bowman, L., Wallendszus, K., et al., 2010. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet 376, 1658–1669. Cannon, C.P., Braunwald, E., McCabe, C.H., et al., 2004. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N. Engl. J. Med. 350, 1495–1504. Cannon, C.P., Steinberg, B.A., Murphy, S.A., Mega, J.L., Braunwald, E., 2006. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J. Am. Coll. Cardiol. 48, 438–445.
de Lemos, J.A., Blazing, M.A., Wiviott, S.D., et al., 2004. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase z of the a to z trial. JAMA 292, 1307–1316. FDA, 2011. FDA Drug Safety Communication: new restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. Group, S.S.S.S., 1994. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344, 1383–1389. Group, L.-T.I.w.P.i.I.D.L.S., 1998. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N. Engl. J. Med. 339, 1349–1357. Investigators, T.S.P.b.A.R.i.C.L.S., 2006. High-dose atorvastatin after stroke or transient ischemic attack. N. Engl. J. Med. 355, 549–559. LaRosa, J.C., Grundy, S.M., Waters, D.D., et al., 2005. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N. Engl. J. Med. 352, 1425–1435. Murphy, S.A., Cannon, C.P., Wiviott, S.D., McCabe, C.H., Braunwald, E., 2009. Reduction in recurrent cardiovascular events with intensive lipid-lowering statin therapy compared with moderate lipid-lowering statin therapy after acute coronary syndromes from the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy— Thrombolysis In Myocardial Infarction 22) Trial. J. Am. Coll. Cardiol. 54, 2358–2362. Nicholls, S.J., Ballantyne, C.M., Barter, P.J., et al., 2011. Effect of two intensive statin regimens on progression of coronary disease. N. Engl. J. Med. 365, 2078–2087. Nunes, J.P.L., 2013. Medical therapeutics: from induction to scientific evolution. Perspect. Biol. Med. 56, 568–583. Pedersen, T.R., Faergeman, O., Kastelein, J.P., et al., 2005. High-dose atorvastatin vs usualdose simvastatin for secondary prevention after myocardial infarction: the ideal study: a randomized controlled trial. JAMA 294, 2437–2445. Ridker, P.M., Cook, N.R., 2013. Statins: new American guidelines for prevention of cardiovascular disease. Lancet 382, 1762–1765. Sacks, F.M., Pfeffer, M.A., Moye, L.A., et al., 1996. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N. Engl. J. Med. 335, 1001–1009. Stone, N.J., Robinson, J., Lichtenstein, A.H., et al., 2014. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 129 (suppl. 2), S1–S45.
Contents lists available at ScienceDirect
Preventive Medicine journal homepage: www.elsevier.com/locate/ypmed
Commentary
New cholesterol guidelines and the secondary prevention of cardiovascular disease — A commentary on epistemic aspects José Pedro L. Nunes ⁎ Faculdade de Medicina da Universidade do Porto, Department of Medicine, Alameda Prof. Hernani Monteiro, 4200 Porto, Portugal
a r t i c l e
i n f o
Available online 13 August 2014 Keywords: Cholesterol Guidelines Statins
a b s t r a c t The recommendations contained in the 2013 cholesterol guidelines may be described as either with or without a direct empirical clinical trial basis. Recommendations without a direct empirical clinical trial basis tend to be controversial. Recommendations with and without a direct empirical clinical trial basis are mixed in the same text — while at the same time (rightfully) rejecting previous recommendations, also without a direct empirical clinical trial basis. © 2014 Elsevier Inc. All rights reserved.
New cholesterol guidelines have been issued in November 2013 (Stone et al., 2014). The development of these guidelines was a meritorious effort, but it is up to the clinical and scientific community to examine the text and feed-back the comments that may seem appropriate for a global discussion on the topic. The text departs from the previous guidelines in several aspects, and may be considered a significant step in the right direction (Ridker and Cook, 2013). Two aspects appear as prominent improvements, at least from the perspective of a better fit between the guidelines and the clinical trial evidence: 1) the focus on statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) as the major type of drugs to be used; and 2) the focus on the use of statins in conditions similar to clinical trials, rather than on the use of arbitrary targets of LDL-C (low density lipoprotein cholesterol). However, a detailed analysis of the text shows that the philosophy chosen which led to the relevant changes outlined above does not appear to have been followed in an entirely complete way, leading to what would seem to be epistemic inconsistencies. In what concerns secondary prevention, the following recommendation is issued: “High-intensity statin therapy should be initiated or continued as first-line therapy in women and men ≤ 75 years of age who have clinical ASCVD, unless contraindicated” (“ASCVD” stands for atherosclerotic cardiovascular disease) (Stone et al., 2014). Highintensity statin therapy is presented as a daily dose that lowers LDL-C on average, by approximately ≥50%. According to the text, atorvastatin 40–80 mg and rosuvastatin 20–40 mg are the drugs and dosages to be chosen in order to produce such an effect. As shown in Table 1, three major clinical trials have compared either simvastatin or pravastatin to placebo in cardiac secondary prevention
⁎ Fax: +351 22 551 3601. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.ypmed.2014.06.035 0091-7435/© 2014 Elsevier Inc. All rights reserved.
(Group, 1994; Group, 1998; Sacks et al., 1996), whereas five further major clinical trials, carried out circa a decade later, compared highdose to a lower dose of statins (Armitage et al., 2010; Cannon et al., 2004; de Lemos et al., 2004; LaRosa et al., 2005; Murphy et al., 2009; Pedersen et al., 2005). Simvastatin and atorvastatin were the two drugs used as high dose statin therapy in the five trials. Since high dose (80 mg daily) simvastatin is no longer recommended due to increased incidence of myopathy (FDA, 2011), we are left with a single drug to be used as high dose in secondary prevention, with the support of at least one major clinical trial carried out in this context — atorvastatin. The indication, in the 2013 cholesterol guidelines, of high dose rosuvastatin to be used in cardiovascular secondary prevention, essentially lacks direct clinical trial supporting evidence, and constitutes a prominent epistemic inconsistency — it does not make sense to “get rid” of nonstatin drugs and insist in keeping drugs in indications with no direct supporting evidence. The same reasoning applies to pitavastatin, a drug for which no major clinical outcome trial was presented in the text, but that is nevertheless recommended, in this case for “low-intensity” and “moderate-intensity statin therapy” — a recommendation with no solid direct empirical basis. The recommendation, mentioned above, to use high dose statin therapy in cardiovascular secondary prevention would seem to be itself debatable. Although it is clear that high dose statins decrease cardiovascular events (Armitage et al., 2010; Cannon et al., 2004; de Lemos et al., 2004; LaRosa et al., 2005; Murphy et al., 2009; Pedersen et al., 2005), this type of therapy does not appear to alter the major parameter to be taken into consideration in this context — total mortality (Cannon et al., 2006). As shown in Fig. 1, it is striking that high dose statin therapy does not decrease the mortality rate, when compared to drugs used in low/standard dose. The same phenomenon was seen in a trial comparing high dose atorvastatin to placebo in stroke/transient ischemic attack
J.P.L. Nunes / Preventive Medicine 69 (2014) 314–316
315
Table 1 Inclusion criteria and drug dosages used in major cardiovascular secondary prevention clinical trials using statins. Study
Inclusion criteria
Drug therapy
4S (1994) (Group, 1994)
- Angina pectoris or previous myocardial infarction - Total cholesterol 5.5–8 mmol/L and triglyceride ≤ 2.5 mmol/L
CARE (1996) (Sacks et al., 1996)
- Myocardial infarction - Total cholesterol b 240 mg/dL, LDL-C of 115–174 mg/dL and triglyceride b 350 mg/dL - Myocardial infarction or unstable angina - Total cholesterol of 155–271 mg/dL and triglyceride b 445 mg/dL - Acute coronary syndrome - Total cholesterol ≤ 240 mg/dL or ≤200 mg/dL if already on lipid-lowering therapy - Acute coronary syndrome (either with or without ST segment elevation) - Total cholesterol level ≤ 250 mg/dL
LIPID (1998) (Group, 1998) PROVE IT TIMI 22 (2004) (Cannon et al., 2004) A TO Z (2004) (de Lemos et al., 2004)
TNT (2005) (LaRosa et al., 2005)
IDEAL (2005) (Pedersen et al., 2005)
SEARCH (2010) (Armitage et al., 2010)
- Stable coronary heart disease - LDL-C 130–250 mg/dL and triglyceride ≤ 600 mg/dL; LDL-C b 130 mg/dL after 8 week run-in period with atorvastatin 10 mg. - History of definite myocardial infarction
- History of myocardial infarction - Total cholesterol of at least 3.5 mmol/L if already on a statin or 4.5 mmol/L if not.
patients — decrease in ischemic events with no decrease in mortality (in this case, hemorrhagic stroke was noted to increase in patients treated with atorvastatin) (Investigators, 2006). Clearly, there is more in the human body than the coronary arteries, and effects on the coronary arteries (Nicholls et al., 2011) must be regarded as a surrogate marker in this context. It is the whole set of effects of statins on humans that must be taken into consideration, including cardiovascular and noncardiovascular effects — raising doubts on the decision to write the guidelines focusing on preventing the occurrence of cardiovascular endpoints. The recommendations contained in the 2013 cholesterol guidelines (Stone et al., 2014) may be described as either with or without a direct empirical clinical trial basis (Table 2). Recommendations without a direct empirical clinical trial basis tend to be controversial (Abramson and Redberg, 2013). Epistemic inconsistencies stem from the fact that recommendations with and without a direct empirical clinical trial
- Simvastatin, 20 mg daily, versus placebo. - 37% of patients changed to simvastatin 40 mg, 2 patients changed to 10 mg (goal being of a total cholesterol of 3.0–5–2 mmol/L) - 40 mg pravastatin versus placebo - Dietary counseling and cholestyramine 8–16 g used if LDL-C ≥ 175 mg/dL - 40 mg pravastatin versus placebo - 40 mg pravastatin versus 80 mg atorvastatin - 8% of patients under pravastatin had the dose increased to 80 mg, due to LDL-C N 125 mg/dL - Early intensive statin treatment (simvastatin, 40 mg for 30 days, followed by simvastatin, 80 mg) versus delayed less intensive regimen (placebo four months, followed by simvastatin 20 mg) - Atorvastatin 80 mg versus atorvastatin 10 mg
- Atorvastatin 80 mg versus simvastatin 20 mg - 23% of patients under simvastatin increased dose to 40 mg due to total cholesterol N 190 mg/dL and 13% of patients under atorvastatin decreased dose to 40 mg due to adverse events - Simvastatin 80 mg versus simvastatin 20 mg
basis are mixed in the same text — while at the same time (rightfully) rejecting previous recommendations, also without a direct empirical clinical trial basis. The risk score presented in the 2013 cholesterol guidelines (Stone et al., 2014) has been commented and criticized (Abramson and Redberg, 2013; Ridker and Cook, 2013). Regarding the risk score, its application must obey, at least in part, to a deductive line of reasoning, since it has not been directly applied in clinical trials. From a strict empiricist viewpoint (Nunes, 2013), inductive reasoning, based on clinical trial data, would be a preferable way to guide medical therapeutics. Significant limitations have been shown to exist when attempts are made to use syllogistic-like reasoning in medical therapeutics (Nunes, 2013). Conflict of interest None to declare.
Fig. 1. Meta-analysis of mortality data in five major trials comparing high dose statins to low/standard dose. High — high dose statin. Low/standard — low/standard dose statin. Meta-analysis was carried out by using the Comprehensive Meta-analysis software, version 2.0 (Biostat, NJ, USA), and odds ratios and 95% confidence intervals are presented. Randomeffects analysis was carried out, given the considerable heterogeneity of the data. Data from the original publications (Armitage et al., 2010; de Lemos et al., 2004; LaRosa et al., 2005; Pedersen et al., 2005) were used, except in the case of the PROVE IT-TIMI 22 trial (Cannon et al., 2004), which reported no mortality data in the main report, and the corresponding data were obtained from a later publication (Murphy et al., 2009).
316
J.P.L. Nunes / Preventive Medicine 69 (2014) 314–316
Table 2 Classification of recommendations according to empirical evidence. Recommendations with a direct empirical clinical trial basis
Recommendations without a direct empirical clinical trial basis
Use of simvastatin, pravastatin or atorvastatin in secondary cardiovascular prevention. Drug doses chosen according to clinical trial data. Statins as preferred drugs.
Use of rosuvastatin in secondary prevention, based on effects on surrogate markers and on theoretical models. Use of pitavastatin in the absence of major clinical trial data on “hard” outcomes. Use of a risk score derived from clinical trials but not directly tested in clinical trials.
Funding None. References Abramson, J., Redberg, R., 2013. Don't Give More Patients Statins. The New York Times, New York. Armitage, J., Bowman, L., Wallendszus, K., et al., 2010. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: a double-blind randomised trial. Lancet 376, 1658–1669. Cannon, C.P., Braunwald, E., McCabe, C.H., et al., 2004. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N. Engl. J. Med. 350, 1495–1504. Cannon, C.P., Steinberg, B.A., Murphy, S.A., Mega, J.L., Braunwald, E., 2006. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J. Am. Coll. Cardiol. 48, 438–445.
de Lemos, J.A., Blazing, M.A., Wiviott, S.D., et al., 2004. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase z of the a to z trial. JAMA 292, 1307–1316. FDA, 2011. FDA Drug Safety Communication: new restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. Group, S.S.S.S., 1994. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344, 1383–1389. Group, L.-T.I.w.P.i.I.D.L.S., 1998. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N. Engl. J. Med. 339, 1349–1357. Investigators, T.S.P.b.A.R.i.C.L.S., 2006. High-dose atorvastatin after stroke or transient ischemic attack. N. Engl. J. Med. 355, 549–559. LaRosa, J.C., Grundy, S.M., Waters, D.D., et al., 2005. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N. Engl. J. Med. 352, 1425–1435. Murphy, S.A., Cannon, C.P., Wiviott, S.D., McCabe, C.H., Braunwald, E., 2009. Reduction in recurrent cardiovascular events with intensive lipid-lowering statin therapy compared with moderate lipid-lowering statin therapy after acute coronary syndromes from the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy— Thrombolysis In Myocardial Infarction 22) Trial. J. Am. Coll. Cardiol. 54, 2358–2362. Nicholls, S.J., Ballantyne, C.M., Barter, P.J., et al., 2011. Effect of two intensive statin regimens on progression of coronary disease. N. Engl. J. Med. 365, 2078–2087. Nunes, J.P.L., 2013. Medical therapeutics: from induction to scientific evolution. Perspect. Biol. Med. 56, 568–583. Pedersen, T.R., Faergeman, O., Kastelein, J.P., et al., 2005. High-dose atorvastatin vs usualdose simvastatin for secondary prevention after myocardial infarction: the ideal study: a randomized controlled trial. JAMA 294, 2437–2445. Ridker, P.M., Cook, N.R., 2013. Statins: new American guidelines for prevention of cardiovascular disease. Lancet 382, 1762–1765. Sacks, F.M., Pfeffer, M.A., Moye, L.A., et al., 1996. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N. Engl. J. Med. 335, 1001–1009. Stone, N.J., Robinson, J., Lichtenstein, A.H., et al., 2014. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 129 (suppl. 2), S1–S45.
