Altering the Pathophysiology of Atherosclerosis: The Multidimensional Role of Statins

Michael B. Clearfield

Abstract

The role of low-density lipoprotein cholesterol (LDL-C) in the pathogenesis of atherosclerosis is well recognized. Recent research has documented the importance of inflammation in atherosclerosis formation and disease progression. Lowering LDL-C with HMG-CoA reductase inhibitors (“statins”) has been shown to decrease atheroma burden and reduce cardiovascular adverse events in patients with acute coronary syndromes as well as in asymptomatic patients with recognized risk factors. In addition, recent primary prevention studies have shown that aggressively lowering LDL-C with statins—even in people with so-called “normal” LDL-C and few cardiovascular risk factors—can substantially reduce the rate of myocardial infarction, stroke, and other cardiovascular outcomes. The impact of treatment is particularly notable in patients with elevated levels of C-reactive protein, a recognized marker of vascular inflammation.

Cardiovascular disease (CVD) has been the number one cause of death in the United States for more than a century and is projected to remain so for many years to come. In 2003, CVD was the direct cause of 37.3% and a contributing cause in 58% of all US deaths.¹ Of deaths blamed on CVD, 152,000 occurred in people under age 65 years.¹

According to the National Health and Nutrition Examination Survey, one in three American adults has some form of CVD. Signs of the disease begin early in life, with one in every six teenagers having evidence of atherosclerosis.² According to longitudinal data from the Framingham Heart Study,³ cardiovascular events occur at a rate of 7 per 1000 men aged 35 to 44 years. This number rises to 63 per 1000 for men aged 85 to 94 years. Comparable rates occur for women starting at age 45 years, with the gender gap narrowing with advancing age.³

Role of LDL-C in Atherosclerosis Plaque Formation

Excess cholesterol in the arterial wall is not just a risk factor for atherosclerosis—it is the cause of atherosclerosis,^3,4 with low-density lipoprotein cholesterol (LDL-C), or “bad cholesterol,” the primary culprit. Typical LDL-C levels are approximately 30 to 35 mg/dL at birth. By age 20 years, 74% of Americans have LDL-C levels above 100 mg/dL, and 98% have an LDL-C above 70 mg/dL.⁵

Buildup of atherosclerotic plaque in the arteries begins with endothelial retention of apo B lipoproteins, which include the LDL and very-low-density lipoprotein particles. The concentration of LDL in the endothelium is approximately equivalent to its concentration in serum (1:1 ratio), whereas in other connective tissues, LDL is at a 1:10 ratio vs serum.⁴ Low-density lipoprotein particles pass in and out of the intima (the inner portion of the endothelial lining), but in excessive quantities, some of the particles tend to become stuck in the endothelial matrix. The first stage of stable lipid accumulation in the vessel, often called fatty streaks, has been observed as early as the teen years.^6,7

Destabilization of Plaque

Stable accumulation of lipids within the blood vessel can progress for many years without producing symptoms. Over the years, the structural makeup of atherosclerotic plaque changes as layers are formed and remodeled.⁶ Usually, it is not the plaque blocking the artery that occludes the vessel, but rather the sudden rupture of plaque and acute thrombus formation.⁸ For this reason, an acute event (eg, myocardial infarction [MI]) often occurs in the absence of any prior warning signs.^9-11 Inflammation characterizes all phases of atherosclerosis and is the critical element that connects plaque formation and acute rupture and leads to occlusion and infarction.¹² The five key steps involved in destabilization of plaque are shown in Figure 1.

As LDL-C interacts with cells in the endothelium, its lipids undergo oxidation, which causes the endothelium to fight the foreign invader by attracting a variety of inflammatory cells, including monocytes, from the circulating blood.⁹ The monocytes mature into macrophages that engulf or “eat” some of the offending LDL particles. Macrophages filled with LDL tend to appear foamy when viewed under a microscope, hence their description as foam cells.¹⁰ Scavenger receptors (CD36 receptors) on the surface of the foam cells actually attract more of the oxidized LDL particles. The foam cells become enmeshed in the endothelium by the interaction of oxidized LDL.¹¹

Over years of gradual buildup, atherosclerotic plaque becomes increasingly unstable and prone to rupture.⁶ Plaque that lines the blood vessel eventually develops a layer or “cap” of collagen fibers overlying a soft, unstable lipid core. However, the endothelium attracts other inflammatory cells such as T lymphocytes and mast cells in an attempt to dismantle the fatty buildup in the vessel wall. If the collagen lining cracks under the inflammatory onslaught, blood from the vessel seeps through and interacts with the unstable lipid core, rapidly forming the substances that build a thrombus (Figure 2).^9,12-13

Effect of Reducing LDL-C on Atherosclerotic Plaque

The amount of coronary narrowing from plaque is approximately the same in patients with symptomatic, nonfatal coronary artery disease (eg, angina) as in those who have fatal coronary events.¹⁴ In fact, little difference in quantity of plaque occurs between the asymptomatic state of atherosclerosis and the symptomatic state. This finding suggests that treating patients with atherosclerosis early—before the patient becomes symptomatic—may be the point of greatest impact in preventing future adverse events.

Atherosclerosis can be reversed. Park et al¹¹ found that cholesterol-filled foam cells trapped at the arterial intima can be remobilized by dynamic exposure to key antioxidants. Several studies have demonstrated that aggressively lowering LDL-C levels significantly reduces atherosclerosis and related clinical outcomes, though the optimal target value for LDL-C remains controversial.^15,16

Studies using intravascular ultrasonography to measure plaque within the coronary arteries have looked at the effects of cholesterol-reducing medications on the lumen. Nissen and colleagues¹⁷ graphed change in atheroma volume according to mean LDL-C level achieved at follow-up in a number of studies of statin treatment for the secondary prevention of cardiovascular events. Lowering LDL-C levels correlated well with decreased plaque progression, and regression of plaque occurred at LDL-C levels of approximately 75 mg/dL or below. This evidence suggests the value of aggressively lowering LDL-C for secondary prevention of acute coronary syndromes.¹⁷

The ASTEROID Trial¹⁵ was one of the first to demonstrate clinically significant regression of atherosclerotic plaque with statin treatment using the rigorous measure of percent atheroma volume (PAV). This open-label study¹⁵ evaluated 349 patients requiring coronary angioplasty who received intensive therapy with rosuvastatin calcium 40 mg per day. After 24 months, participants achieved an average LDL-C of 60.8 mg/dL and increased their HDL-C levels by 14.7%. Those with LDL-C lower than 70 mg/dL had a mean change in PAV of -0.98% (P <.001 vs baseline).

The effect of lowering LDL-C levels on secondary prevention of cardiovascular outcomes has been studied in several controlled trials, including the PROVE IT–TIMI 22 substudy,¹⁸ which evaluated the safety of very low serum LDL-C levels achieved through aggressive statin therapy. Following the index event, 1825 patients with acute coronary syndromes were treated either intensively with atorvastatin 80 mg per day or moderately with pravastatin sodium 40 mg per day for 4 months. Patients who achieved the lowest LDL-C levels (<40 mg/dL or between 40-60 mg/dL) had fewer major cardiac events (eg, death, MI, stroke, recurrent ischemia, need for revascularization) than did those with higher LDL-C levels. No statistically or clinically significant differences were seen in any safety parameters (eg, muscle, liver, retinal abnormalities) among those who achieved LDL-C levels of 40 mg/dL or lower, prompting the authors to title their paper with the intriguing question, “Can low-density lipoprotein be too low?”¹⁸

Figure 1.

Key steps in the destabilization of plaque in patients with acute coronary syndromes. Sources: Moreno PR et al. Circulation. 1994;90(2):775-778;⁹ Mach F et al. Circulation. 1997;96(2):396-399;¹² Hansson GK. N Engl J Med. 2005;352(16):1685-1695.¹³

Key steps in the destabilization of plaque in patients with acute coronary syndromes. Sources: Moreno PR et al. Circulation. 1994;90(2):775-778;9 Mach F et al. Circulation. 1997;96(2):396-399;12 Hansson GK. N Engl J Med. 2005;352(16):1685-1695.13

View Original | Slide (.ppt)

Figure 2.

Mechanisms of plaque rupture. Sources: Moreno PR et al. Circulation. 1994;90 (2):775-778;⁹ Mach F et al. Circulation. 1997;96 (2):396-399;¹² Hansson GK. N Engl J Med. 2005;352(16):1685-1695.¹³

Mechanisms of plaque rupture. Sources: Moreno PR et al. Circulation. 1994;90 (2):775-778;9 Mach F et al. Circulation. 1997;96 (2):396-399;12 Hansson GK. N Engl J Med. 2005;352(16):1685-1695.13

View Original | Slide (.ppt)

Although the PROVE IT–TIMI 22 substudy¹⁸ examined LDL-C in a high-risk population of patients with existing acute coronary syndromes, the large-scale JUPITER Trial^16,19,20 evaluated lipid lowering in a broader population of healthy people whose LDL-C levels would not normally warrant treatment. Entry criteria for this primary prevention study that enrolled more than 17,800 subjects included LDL-C lower than 130 mg/dL, C-reactive protein (CRP) levels less than 2.0 mg/L, and no diabetes or prior CVD.¹⁹ In fact, the mean baseline LDL-C of 108 mg/dL was substantially below the level considered appropriate for treatment with statins, particularly in this lower-risk population.

Subjects in the JUPITER trial were initially randomly assigned to receive either rosuvastatin 20 mg per day or placebo for 5 years. However, on the strength of preliminary findings, the independent review board stopped the trial after a median follow-up time of 1.9 years.²⁰ The primary endpoint to first major cardiovascular event decreased to a highly significant extent (P <.00001) among rosuvastatin-treated patients. Treatment with rosuvastatin also significantly reduced the risk of MI, stroke, cardiovascular death, revascularization or hospitalization for unstable angina, and the risk of death from any cause (Table 1).²⁰

Table 1

Key Results From the JUPITER Trial by Endpoint

Endpoint	Result	P Value
▪ Primary
□ Time to first major cardiovascular event*	*Hazard ratio 0.56; 95% CI, 0.46 to 0.69*	*<.00001*
▪ Secondary
*□ Risk of myocardial infarction*	*Reduced 47% vs placebo*	*<.0001*
□ Risk of stroke	Reduced 47% vs placebo	<.0001
*□ Risk of revascularization or hospitalization for unstable angina*	*Reduced 47% vs placebo*	*<.0001*
□ Risk of death by any cause	Reduced 20% vs placebo	.02

Source: Data extracted from: Ridker PM et al. N Engl J Med. 2008; 359(21):2195-2207.²⁰

*Major cardiovascular event was defined as myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.

View Large

Table 1

Key Results From the JUPITER Trial by Endpoint

Endpoint	Result	P Value
▪ Primary
□ Time to first major cardiovascular event*	*Hazard ratio 0.56; 95% CI, 0.46 to 0.69*	*<.00001*
▪ Secondary
*□ Risk of myocardial infarction*	*Reduced 47% vs placebo*	*<.0001*
□ Risk of stroke	Reduced 47% vs placebo	<.0001
*□ Risk of revascularization or hospitalization for unstable angina*	*Reduced 47% vs placebo*	*<.0001*
□ Risk of death by any cause	Reduced 20% vs placebo	.02

Source: Data extracted from: Ridker PM et al. N Engl J Med. 2008; 359(21):2195-2207.²⁰

*Major cardiovascular event was defined as myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.

Mean LDL-C levels at the 1-year follow-up point were reduced from 108 to 55 mg/dL among rosuvastatin-treated subjects, while LDL-C levels remained stable in the placebo group. In addition, 1-year CRP levels dropped from a mean of 4.2 mg/L at baseline to 2.2 mg/dL in those who received rosuvastatin.²⁰

C-Reactive Protein—Marker of Vascular Inflammation

The results of the JUPITER Trial helped raise awareness of the importance of inflammation in CVD risk, especially among people viewed as low risk for cardiovascular events. Subjects had clinically low LDL coupled with elevated CRP, a known marker of vascular inflammation. The clinical benefit of statins therefore goes beyond reducing the lipids by reducing inflammatory components and stabilizing plaque.²¹

This concept is supported by a study²² that compared the effects of 3 months' pretreatment with 40 mg pravastatin or placebo in patients scheduled to undergo carotid endarterectomy. Crisby and colleagues²² showed that plaque specimens from pretreated patients had significantly lower lipid content but also fewer macrophages, decreased matrix metalloproteinase, and higher collagen content.

Of several inflammatory markers studied in CVD thus far, CRP is the most effective for predicting vascular events.⁸ It is preferentially found in diseased vessels but is not present in the normal endothelium. Although CRP correlates only modestly with degree of atherosclerosis, stronger correlations have been shown for the propensity for plaque rupture.²¹ Ridker and colleagues⁸ retrospectively analyzed the results of four large cohort studies^23-26 (including the Women's Health Study and Physicians' Health Study) that categorized CRP levels lower than 1 mg/L as low risk, 1 to 3 mg/L as intermediate risk, and 3 mg/L or higher as high risk. In the four large-scale studies examined,^23-26 higher CRP represented an increased risk for a myocardial event.

In a large primary prevention trial known as the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), my colleagues and I examined how reducing LDL-C affected clinical outcomes among more than 6000 low-risk patients.²³ In this study,²³ treatment with lovastatin (20-40 mg/day) significantly reduced the incidence of first acute major coronary events (relative risk 0.63, P <.001) and other secondary cardiovascular outcomes. In a further analysis of AFCAPS/TexCAPS data,²⁴ we stratified the results according to whether subjects had high or low baseline CRP and LDL-C. Among the group with high CRP (>1.6 mg/L) but relatively low cholesterol (LDL-C <150 mg/dL), the number needed to treat (NNT) to prevent 1 event over 5 years was just 43. In contrast, the group with both low CRP (<1.6 mg/L) and low LDL had an NNT of nearly 1000 (Table 2). Because treatment with a statin influenced outcomes in patients with either elevated LDL or elevated CRP, the results suggest a dual goal for statin therapy.

Table 2

AFCAPS/TexCAPS Results: Number Needed to Treat to Prevent One Cardiovascular Event by Baseline Values

Baseline Values
TC/HDL-C, mg/dL	C-Reactive Protein, mg/L	NNT
<6	<1.6	983
<6	*>1.6*	43
>6	<1.6	35
>6	*>1.6*	62

Abbreviations: AFCAPS/TexCAPS, Air Force/Texas Coronary Athersclerosis Prevention Study; HDL-C, high-density lipoprotein cholesterol; TC, total cholesterol; NNT, number needed to treat to prevent 1 cardiovascular event in 5 years.Source: Data extracted from: Ridker PM et al. N Engl J Med. 2001;344:1959-1965.²⁴

View Large

Table 2

AFCAPS/TexCAPS Results: Number Needed to Treat to Prevent One Cardiovascular Event by Baseline Values

Baseline Values
TC/HDL-C, mg/dL	C-Reactive Protein, mg/L	NNT
<6	<1.6	983
<6	*>1.6*	43
>6	<1.6	35
>6	*>1.6*	62

Abbreviations: AFCAPS/TexCAPS, Air Force/Texas Coronary Athersclerosis Prevention Study; HDL-C, high-density lipoprotein cholesterol; TC, total cholesterol; NNT, number needed to treat to prevent 1 cardiovascular event in 5 years.Source: Data extracted from: Ridker PM et al. N Engl J Med. 2001;344:1959-1965.²⁴

Similar findings were reflected in an analysis of CRP measures from PROVE IT–TIMI 22 data of pravastatin treatment for secondary prevention in acute coronary syndromes.²⁵ Patients who achieved both low LDL-C (<70 mg/dL) and low CRP (<2 mg/L) on statin therapy had a decreased cumulative incidence of recurrent MI or death from coronary causes. Those who achieved CRP less than 1 mg/L had an even greater benefit. Finally, in an analysis based on data from the JUPITER Trial,²⁶ those who achieved LDL-C levels lower than 70 mg/dL and CRP less than 1 mg/L had a 79% decrease in events in the approximately 2-year study period. Lowering either LDL-C or CRP reduced cardiovascular risk in these studies, but lowering both of these markers yielded superior results.

Conclusion

Atherosclerosis is a multifactoral condition, related not only to excess circulating LDL-C but by inflammation that accelerates lipid accumulation within the vessel wall and induces plaque instability and rupture. Plaque rupture and resulting thrombosis is the primary precipitating event in most acute coronary syndromes. Reducing LDL-C through statin treatment can greatly reduce the risk of CVD events, not only in higher-risk patients and those with hyperlipidemia, but also in patients with lower LDL-C levels in seemingly low-risk categories. Reducing elevated CRP with statins prevents cardiovascular outcomes regardless of cholesterol levels but is especially effective when both LDL-C and CRP are reduced. Statin therapy has the potential to reduce plaque destabilization at many levels, not only by removing lipids but also by decreasing the instability of the plaque by modifying the inflammatory cellular process.

This article was developed in part from a CME-certified seminar held on Wednesday, November 4, 2009, during the American Osteopathic Association's 114th Annual Osteopathic Medical Conference and Exposition in New Orleans, Louisiana.

DIME staff have assisted faculty with content development.

Dr Clearfield reports that he has consulting agreements with AstraZeneca Pharmaceuticals LP, GlaxoSmithKline, and Merck & Co, Inc. He also has speakers' bureau or honorarium agreements with AstraZeneca Pharmaceuticals LP and provides discussion of off-label, investigational, or experimental drug use for statins. Dr Clearfield has no relevant financial interests or stock ownership.

1

Hoyert DL, Kung HC, Smith BL. Deaths: preliminary data for 2003. Natl Vital Stat Rep. 2005;53 (15):1-48.

2

National Health and Nutrition Examination Survey (NHANES 1999–2002). Centers for Disease Control and Prevention Web site. http://www.cdc.gov/nchs/nhanes/nhanes01-02.htm. Accessed April 3, 2010.

3

Thom T, Haase N, Rosamond W, Howard VJ, Rumsfeld J, Manolio T, et al. Heart disease and stroke statistics—2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee [published online ahead of print January 11, 2006] [published corrections appear in Circulation. 2006;113(14):e696 and 2006;114(23):e630]. Circulation. 2006;113 (6):e85-e151. http://circ.ahajournals.org/cgi/content/full/113/6/e85. Accessed April 3, 2010.

4

Oörni K, Posio P, Ala-Korpela M, Jauhiainen M, Kovanen PT. Sphingomyelinase induces aggregation and fusion of small very low-density lipoprotein and intermediate-density lipoprotein particles and increases their retention to human arterial proteoglycans [published online ahead of print May 5, 2005]. Arterioscler Thromb Vasc Biol. 2005;25(8):1678-1683. http://atvb.ahajournals.org/cgi/content/full/25/8/1678. Accessed April 3, 2010.

5

Williams KJ, Tabas I. Lipoprotein retention—and clues for atheroma regression [editorial]. Arterioscler Thromb Vasc Biol. 2005;25(8):1536-1540. http://atvb.ahajournals.org/cgi/content/full/25/8/1536. Accessed April 3, 2010.

6

Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. A report from the Committee on Vascular Lesions, Council on Arteriosclerosis, American Heart Association. Circulation. 1995;92(5):1355-1374. http://circ.ahajournals.org/cgi/content/full/92/5/1355. Accessed April 3, 2010.

7

Libby P. Atherosclerosis: the new view. Sci Am. 2002;286(5):46-55.

8

Ridker PM, Brown NJ, Vaughan DE, Harrison DG, Mehta JL. Established and emerging plasma biomarkers in the prediction of first atherothrombotic events. Circulation. 2004;109(25 suppl 1):IV6-IV19. http://circ.ahajournals.org/cgi/content/full/109/25_suppl_1/IV-6. Accessed April 3, 2010.

9

Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT. Macrophage infiltration in acute coronary syndromes: implications for plaque rupture. Circulation. 1994;90(2):775-778. http://circ.ahajournals.org/cgi/reprint/90/2/775. Accessed April 3, 2010.

10

Curtiss LK. Reversing atherosclerosis? N Engl J Med. 2009;360(11):1144-1146.

11

Park YM, Febbraio M, Silverstein RL. CD36 modulates migration of mouse and human macrophages in response to oxidized LDL and may contribute to macrophage trapping in the arterial intima. J Clin Invest. 2009;119(1):136-145. http://www.jci.org/articles/view/35535. Accessed April 3, 2010.

12

Mach F, Schönbeck U, Bonnefoy JY, Pober JS, Libby P. Activation of monocyte/macrophage functions related to acute atheroma complication by ligation of CD40: induction of collagenase, stromelysin, and tissue factor. Circulation. 1997;96(2):396-399. http://circ.ahajournals.org/cgi/content/full/96/2/396. Accessed April 3, 2010.

13

Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 2005;352 (16):1685-1695.

14

Wexler L, Brundage B, Crouse J, Detrano R, Fuster V, Maddahi J, et al. Coronary artery calcification: pathophysiology, epidemiology, imaging methods, and clinical implications. A statement for health professionals from the American Heart Association Writing Group. Circulation. 1996;94 (5):1175-1192. http://circ.ahajournals.org/cgi/content/full/94/5/1175. Accessed April 3, 2010.

15

Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, et al; ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID Trial [published online ahead of print March 13, 2006]. JAMA. 2006;295(13):1556-1565. http://jama.ama-assn.org/cgi/content/full/295/13/1556. Accessed April 6, 2010.

16

Ridker PM; JUPITER Study Group. Rosuvastatin in the primary prevention of cardiovascular disease among patients with low levels of low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: rationale and design of the JUPITER Trial. Circulation. 2003;108(19):2292-2297. http://circ.ahajournals.org/cgi/content/full/108/19/2292. Accessed April 6, 2010.

17

Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, et al; ILLUSTRATE Investigators. Effect of torcetrapib on the progression of coronary atherosclerosis [published online ahead of print March 26, 2007] [published correction appears in N Engl J Med. 2007;357(8):835]. N Engl J Med. 2007;356:1304-1316.

18

Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, Braunwald E; PROVE IT–TIMI 22 Investigators. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT–TIMI 22 substudy [published correction appears in J Am Coll Cardiol. 2006;47(2):472]. J Am Coll Cardiol. 2005;47(2):1411-1416.

19

Ridker PM, Fonseca FA, Genest J, Gotto AM, Kastelein JJ, Khurmi NS, et al; JUPITER Trial Study Group. Baseline characteristics of participants in the JUPITER trial, a randomized placebo-controlled primary prevention trial of statin therapy among individuals with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein [published online ahead of print October 24, 2007]. Am J Cardiol. 2007;100(11):1659-1664.

20

Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al; JUPITER Trial Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein [published online ahead of print November 9, 2008]. N Engl J Med. 2008;359(21):2195-2207.

21

Ridker PM. The time for cardiovascular inflammation reduction trials has arrived: how low to go for hsCRP? Arterioscler Thromb Vasc Biol. 2008;28(7):1222-1224.

22

Crisby M, Nordin-Fredriksson G, Shah PK, Yano J, Zhu J, Nilsson J. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation. 2001;103(7):926-933. http://circ.ahajournals.org/cgi/content/full/103/7/926. April 6, 2010.

23

Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279 (20):1615-1622. http://jama.ama-assn.org/cgi/content/full/279/20/1615. Accessed April 6, 2010.

24

Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, et al; Air Force/Texas Coronary Atherosclerosis Prevention Study Investigators. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001;344(26):1959-1965.

25

Ridker P, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, et al; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352(1):20-28.

26

Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al; JUPITER Trial Study Group. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial [published online ahead of print March 28, 2009]. Lancet. 2009;373(9670):1175-1182.

Figure 1.

Key steps in the destabilization of plaque in patients with acute coronary syndromes. Sources: Moreno PR et al. Circulation. 1994;90(2):775-778;⁹ Mach F et al. Circulation. 1997;96(2):396-399;¹² Hansson GK. N Engl J Med. 2005;352(16):1685-1695.¹³

View Original | Slide (.ppt)

Figure 2.

Mechanisms of plaque rupture. Sources: Moreno PR et al. Circulation. 1994;90 (2):775-778;⁹ Mach F et al. Circulation. 1997;96 (2):396-399;¹² Hansson GK. N Engl J Med. 2005;352(16):1685-1695.¹³

View Original | Slide (.ppt)

Table 1

Key Results From the JUPITER Trial by Endpoint

Endpoint	Result	P Value
▪ Primary
□ Time to first major cardiovascular event*	*Hazard ratio 0.56; 95% CI, 0.46 to 0.69*	*<.00001*
▪ Secondary
*□ Risk of myocardial infarction*	*Reduced 47% vs placebo*	*<.0001*
□ Risk of stroke	Reduced 47% vs placebo	<.0001
*□ Risk of revascularization or hospitalization for unstable angina*	*Reduced 47% vs placebo*	*<.0001*
□ Risk of death by any cause	Reduced 20% vs placebo	.02

Source: Data extracted from: Ridker PM et al. N Engl J Med. 2008; 359(21):2195-2207.²⁰

*Major cardiovascular event was defined as myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.

View Large

Table 1

Key Results From the JUPITER Trial by Endpoint

Endpoint	Result	P Value
▪ Primary
□ Time to first major cardiovascular event*	*Hazard ratio 0.56; 95% CI, 0.46 to 0.69*	*<.00001*
▪ Secondary
*□ Risk of myocardial infarction*	*Reduced 47% vs placebo*	*<.0001*
□ Risk of stroke	Reduced 47% vs placebo	<.0001
*□ Risk of revascularization or hospitalization for unstable angina*	*Reduced 47% vs placebo*	*<.0001*
□ Risk of death by any cause	Reduced 20% vs placebo	.02

Source: Data extracted from: Ridker PM et al. N Engl J Med. 2008; 359(21):2195-2207.²⁰

*Major cardiovascular event was defined as myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.

Table 2

AFCAPS/TexCAPS Results: Number Needed to Treat to Prevent One Cardiovascular Event by Baseline Values

Baseline Values
TC/HDL-C, mg/dL	C-Reactive Protein, mg/L	NNT
<6	<1.6	983
<6	*>1.6*	43
>6	<1.6	35
>6	*>1.6*	62

Abbreviations: AFCAPS/TexCAPS, Air Force/Texas Coronary Athersclerosis Prevention Study; HDL-C, high-density lipoprotein cholesterol; TC, total cholesterol; NNT, number needed to treat to prevent 1 cardiovascular event in 5 years.Source: Data extracted from: Ridker PM et al. N Engl J Med. 2001;344:1959-1965.²⁴

View Large

Table 2

AFCAPS/TexCAPS Results: Number Needed to Treat to Prevent One Cardiovascular Event by Baseline Values

Baseline Values
TC/HDL-C, mg/dL	C-Reactive Protein, mg/L	NNT
<6	<1.6	983
<6	*>1.6*	43
>6	<1.6	35
>6	*>1.6*	62

Abbreviations: AFCAPS/TexCAPS, Air Force/Texas Coronary Athersclerosis Prevention Study; HDL-C, high-density lipoprotein cholesterol; TC, total cholesterol; NNT, number needed to treat to prevent 1 cardiovascular event in 5 years.Source: Data extracted from: Ridker PM et al. N Engl J Med. 2001;344:1959-1965.²⁴

Altering the Pathophysiology of Atherosclerosis: The Multidimensional Role of Statins

Related content

Related Topics