Residual risk for secondary ischemic events in patients with atherothrombotic disease: Opportunity for future improvements in patient care

Figures & data

Table I. Primary outcomes in selected randomized secondary prevention trials with statins.

Trial name	Treatment groups (mean duration of treatment)	Study population (n)	Primary outcome	Primary outcome rate (relative risk reduction, %; P-value)
4S (37)	Placebo versus Simvastatin 20 mg qd; (5.4 y)	Acute MI or angina pectoris (n=4,444)	Total mortality	Placebo 11.5%, Simvastatin 8.2% (RRR 30%; P=0.0003)
CARE (47)	Placebo versus Pravastatin 40 mg qd; (5 y)	MI (n=4,159)	CAD death or non-fatal MI	Placebo 13.2%, Pravastatin 10.2% (RRR 24%; P=0.003)
LIPID (38)	Placebo versus Pravastatin 40 mg qd; (6.1 y)	MI/UA pectoris (n=9,014)	CAD death or non-fatal MI	Placebo 8.3%, Pravastatin 6.4% (RRR 24%; P<0.001)
PROVE-IT (40)	Atorvastatin 80 mg qd versus Pravastatin 40 mg qd; (2 y)	ACS (MI with or without ST-segment or UA) (n=4,162)	Composite death from any cause, MI, UA requiring hospitalization, revascularization, stroke	Atorvastatin 22.4%, Pravastatin 26.3% (RRR 16%; P=0.005)
TNT (44,48)	Atorvastatin 80 mg qd versus Atorvastatin 10 mg qd; (4.9 y)	Stable CHD (n=10,001)	CHD death, non-fatal MI, resuscitation after cardiac arrest, fatal or non-fatal stroke	Atorvastatin 80 mg 8.7%, Atorvastatin 10 mg 10.9% (RRR 22%; P<0.001)
A-Z (41)	Placebo 4 mo followed by Simvastatin 20 mg qd versus Simvastatin 40 mg qd for 1 mo followed by 80 mg qd; (2 y)	ACS (n=4,500)	CV death, non-fatal MI, readmission for ACS, stroke	Placebo + Simvastatin 20 mg qd 16.7%, Simvastatin 40 mg qd/80 mg qd 14.4% (P=NS)
IDEAL (45)	Atorvastatin 80 mg qd versus Simvastatin 20 mg qd; (4.8 y)	MI (n=8,888)	Coronary death, non-fatal confirmed acute MI, cardiac arrest with resuscitation	Atorvastatin 80 mg 10.4%, Simvastatin 20 mg 9.3% (P=NS)
SPARCL (39)	Placebo versus Atorvastatin 80 mg qd; (4.9 y)	Stroke or TIA (n=4,731)	Fatal or non-fatal stroke	Placebo 13.1%, Atorvastatin 11.2% (RRR 16%; P=0.03)
Primary outcomes in other randomized trials with statins:
CORONA (43)	Rosuvastatin 10 mg versus Placebo	Ischemic systolic HF; aged ≥ 60 y (n=5,011)	CV death, non-fatal MI, or non-fatal stroke	Rosuvastatin 11.4%, Placebo 12.3% (P=NS)
GISSI-HF (42)	Rosuvastatin 10 mg versus Placebo	Chronic HF; aged ≥ 18 y (n=4,574)	Time to death	Rosuvastatin 29%, Placebo 28% (P=NS)
JUPITER (46)^a	Rosuvastatin 10 mg versus Placebo	LDL-C < 130 mg/dL; CRP ≥ 2 mg/L (n=17,802)	MI, stroke, arterial revascularization, hospitalization for UA, or CV death	Rosuvastatin 0.77^b Placebo 1.36^b (P<0.00001)

^aPrimary prevention trial.

^bRates per 100 person-years.

ACS = acute coronary syndromes; CAD = coronary artery disease; CHD = coronary heart disease; CRP = C-reactive protein; CV = cardiovascular; HF = heart failure; LDL-C = low-density lipoprotein cholesterol; MI = myocardial infarction; NS = not significant; qd = once daily; TIA = transient ischemic attack; UA = unstable angina.

Figure 1. Event rates in patient subgroups allocated simvastatin versus placebo in the Heart Protection Study (HPS) (3). A: The rate of the primary end-point of all-cause mortality was significantly lower in patients allocated simvastatin (12.9%) versus placebo (14.7%) in the total study population in the HPS (12% relative risk reduction, 88% residual risk; P=0.003). B: The rate of the first major vascular event was significantly lower in patients receiving simvastatin (19.8%) than in those receiving placebo (25.2%) in the total study population (21% relative risk reduction, 79% residual risk; P<0.001), as well as in patients with prior myocardial infarction (MI) (23.5% versus 29.4%; 20% relative risk reduction, 80% residual risk; P<0.001), patients with cerebrovascular disease (18.7% versus 23.6%; 21% relative risk reduction, 79% residual risk; P<0.001), and patients with peripheral vascular disease (PVD) (24.7% versus 30.5%; 19% relative risk reduction, 81% residual risk; P<0.001). Green arrows indicate relative risk reduction between treatment arms. Red arrows indicate residual risk for recurrent events.

Figure 2. Primary end-point rate in the CHARISMA trial (83,84). No significant difference was obtained in the primary end-point rate (composite of myocardial infarction, stroke, or death from cardiovascular causes) between placebo+aspirin versus clopidogrel+aspirin groups in the overall study population and in the primary prevention cohort (83). Significant reductions in favor of clopidogrel+aspirin were evident in the secondary prevention cohort (83) and in the CAPRIE-like population (84). Green arrows indicate relative risk reduction between treatment arms. Red arrows indicate residual risk for recurrent events.

Figure 3. Residual atherothrombotic risk: rates of cardiovascular (CV) death and myocardial infarction (MI) persisting with active treatments from meta-analyses of trials of secondary prevention with statins (52), angiotensin-converting enzyme (ACE) inhibitors (60), β-blockers (71), antiplatelets (2), and warfarin (80). Treatment and comparator arms consisted of the following: high-dose versus standard-dose statins; ACE inhibitor versus placebo; β-blocker versus placebo or other antihypertensive agents; antiplatelet therapy versus control; and warfarin+aspirin versus aspirin. *Event rate is shown for coronary death/MI for statin meta-analysis (individual rates for MI not available). OR = odds ratio.

Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7–22.

 PubMed Web of Science ®Google Scholar

Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, . Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354:1706–17.

 PubMed Web of Science ®Google Scholar

Bhatt DL, Flather MD, Hacke W, Berger PB, Black HR, Boden WE, . Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol. 2007;49:1982–8.

 PubMed Web of Science ®Google Scholar

Cannon CP, Steinberg BA, Murphy SA, Mega JL, Braunwald E. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol. 2006;48:438–45.

 PubMed Web of Science ®Google Scholar

Saha SA, Molnar J, Arora RR. Tissue ACE inhibitors for secondary prevention of cardiovascular disease in patients with preserved left ventricular function: a pooled meta-analysis of randomized placebo-controlled trials. J Cardiovasc Pharmacol Ther. 2007;12:192–204.

 PubMed Web of Science ®Google Scholar

Bangalore S, Wetterslev J, Pranesh S, Sawhney S, Gluud C, Messerli FH. Perioperative beta blockers in patients having non-cardiac surgery: a meta-analysis. Lancet. 2008;372:1962–76.

 PubMed Web of Science ®Google Scholar

Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71–86.

 PubMed Web of Science ®Google Scholar

Rothberg MB, Celestin C, Fiore LD, Lawler E, Cook JR. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann Intern Med. 2005;143:241–50.

 PubMed Web of Science ®Google Scholar