Chronic stable angina treatment anti-lipid agents

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [mailto:mgibson@perfuse.org] Phone:617-632-7753; Associate Editor(s)-In-Chief: Lakshmi Gopalakrishnan, M.B.B.S.

Overview
Statins by inhibiting HMG-CoA reductase subsequently reduce serum cholesterol levels and have been shown to be effective in the primary prevention of various hyperlipidemias and secondary prevention of ischemic heart disease. The most commonly used statins are simvastatin, atorvastatin, pravastatin and rosuvastatin. The incidence of major cardiovascular mortality was reduced by 30% with the use of simvastatin and pravastatin in patients with coronary artery disease and therefore may be used for both primary and secondary prevention. However, there are no trials specifically performed on patients with stable angina but they form a significant portion in other major trials studying the efficacy of lipid-lowering drugs on the overall mortality from cardiovascular events. In patients with low HDL and high triglycerides as an adjunctive to statin therapy, fibrates or niacin may be used.

Mechanisms of benefit

 * Statins competitively inhibit HMG-CoA reductase that is the rate-limiting enzyme of cholesterol synthesis and hence reduce intracellular cholesterol levels, subsequently, leading to increased clearance of serum LDL.


 * Direct evidence of statin-based cholesterol lowering effect on atherosclerosis was presented in the ASTEROID trial, which demonstrated reduction in LDL-C with accompanied significant increase in HDL-C and subsequently resulting in the regression of atheroma in patients with coronary artery disease.


 * It has been postulated that statins have anti-inﬂammatory and anti-thrombotic effects.


 * Non-lipid related properties of statins might be modulated by interference with isoprenoid synthesis or specific actions of some statins that block cell adhesion receptors and subsequently help to prevent atherosclerosis via:
 * improving endothelial function,
 * modulate inflammatory responses,
 * maintain plaque stability and prevent thrombus formation,
 * increase nitric oxide bioavailability.


 * The non-lipid properties of statins have shown to provide myocardial protection and hence lower the risk of procedural myocardial injury in elective coronary intervention. Such short-term myocardial protection is achieved by pre-treatment with atorvastatin 40mg/day for 7 days.


 * Long-term statin therapy have shown to reduce major cardiovascular events such as MI, stroke, and risk of revascularization in patients with different serum cholesterol levels.


 * Population-based cohort analysis, reported in patients with atherosclerosis, the use of statins have been associated with a reduction in the risk of subsequent sepsis.


 * Torcetrapib, by inhibiting cholesteryl ester transfer protein (CETP), markedly increases HDL-C levels and also decreases LDL-C levels, both when administered as monotherapy and when used concomitantly with statins and hence, may be effective in treating patients with low HDL levels.

Indications

 * In all patients with coronary artery disease, statins are indicated both for primary and secondary prevention, irrespective of the serum cholesterol concentrations, owing to its property of reducing over-all cardiovascular mortality.


 * In patients with stable angina, pre-treatment with atorvastatin was associated with the reduction of procedural myocardial injury, as assessed by biochemical markers.


 * Two randomized placebo-controlled trials reported that the use of simvastatin 40 mg/day and atorvastatin 10 mg/day provided similar primary protection against major cardiovascular events in diabetic patients without high LDL-cholesterol.


 * Statin therapy in diabetics with vascular disease and in the elderly have demonstrated beneficial effects.


 * Patients with coronary artery disease and associated low HDL with high triglycerides, as an adjunctive to statin therapy, fibrates or niacin has shown to be helpful in significantly reducing the risk of major cardiovascular events.


 * Fibrates are also beneficial in patients with diabetes or metabolic syndrome X.

Contra-indications
All statins are contra-indicated in pregnancy and breastfeeding. Use of statin during early pregnancy has been associated to cause congenital anomalies in the fetus.

Drug interactions
Concomitant use of Fibrates, antibiotics (such as clarithromycin and erythromycin), anti-fungals (such as ketaconazole and itraconazole with any of the statins, increases the risk of myopathy and subsequent rhabdomyolysis. However, the use of fenofibrate has not shown to interfere with the catabolism of pravastatin, hence is less likely to increase the risk of myopathy when used in concomitantly with statins.

Dosage

 * In patients with stable angina, an intensive lipid-lowering therapy with atorvastatin 80 mg/day has shown to provide significant clinical benefit and improve prognosis. However, this occurred with a greater incidence of elevated aminotransferase levels (from 0.2 to 1.2%;p<0.001).


 * Dose reduction of statin with the addition of cholesterol absorption inhibitor such as ezetimibe is indicated when adequate lipid control is not achieved with the highest statin dose or wherein statins are poorly tolerated.

Adverse effects

 * Rhabdomyolysis.


 * High dose atorvastatin is associated with greater incidence of elevated aminotransferases. Hence, liver function tests should be regularly monitored.


 * In patients undergoing coronary bypass surgery, peri-operative statin withdrawal have been associated with increased frequency of cardiac events.

Supportive trial data

 * In the Scandinavian Simvastatin Survival Study (4S), 4444 patients with coronary heart disease were randomized to a double-blind treatment of either, simvastatin or placebo. The goal of the study was to assess the effect of simvastatin on mortality and morbidity. Researchers reported that there was a 30% relative risk reduction in mortality from all cardiovascular causes with the use of simvastatin.


 * In the ASCOT-LLA trial, 19,342 patients, aged 40-79 years, who reported at least three cardiovascular risk factors were randomized to receive one of two antihypertensive regimens, atorvastatin or placebo. The purpose of this study was to assess the benefit of atorvastatin in the prevention of coronary and stroke events amongst hypertensive patients with a total cholesteroal of ≤6.5 mmol/L. The primary endpoint from total cardiovascular events (389 atorvastatin vs 486 placebo, 0.79 [0.69-0.90], p=0.0005), total coronary events (178 vs 247, 0.71 [0.59-0.86], p=0.0005) and stroke (89 vs 121, 0.73 [0.56-0.96], p=0.024), during a median follow-up of 3.3 years, was significantly reduced with atorvastatin.


 * In the Heart Protection Study, 20,536 patients, aged 40-80 years, with coronary artery disease, other occlusive arterial disease, or diabetes were randomized to receive either, simvastatin or placebo. The goal of the study was to assess the effect of simvastatin on mortality. Researchers observed that adding simvastatin reduced the rates of MI (8.7% vs 11.8; p<0.0001), stroke (4.3% vs 5.7%; p<0.0001) and revascularization (9.1% vs 11.7%; p<0.0001). The annual excess risk of myopathy was about 0.01%.


 * In the ASTEROID trial, which assessed the effect of intensive statin therapy on the progression atherosclerosis, demonstrated that use of very high-intensity statin therapy resulted in significant regression of atherosclerosis.


 * A prospective meta-analysis reviewed 14 randomized trials, involving 90,056 patients, to assess the effect of statin therapy on different clinical outcomes, per 1.0 mmol/L reduction in LDL cholesterol during a mean follow-up of 5 years. Researchers observed that within the primary endpoint data there was a 12% proportional reduction in all-cause mortality, per mmol/L reduction, in LDL cholesterol. This was found in conjunction with a 19% significant reduction in coronary mortality and corresponding reductions in myocardial infarction or coronary death, in the need for coronary revascularization and in fatal or non-fatal stroke. Thus, the study concluded that in high-risk patients, prolong statin therapy with substantial LDL-C reduction subsequently reduced the 5-year incidence of incidence of major coronary events, coronary revascularization, and stroke.


 * A meta-analysis reviewed 97 randomized controlled trials to assess the efficacy and safety of various lipid-lowering interventions and compared their impact on the overall cardiovascular mortality. The risk ratios for overall mortality in comparison to control group, was 0.87 for statins, 1.00 for fibrates, 0.84 for resins, 0.96 for niacin, 0.77 for n-3 fatty acids, and 0.97 for diet, while the risk ratios for cardiac mortality indicated a significant benefit from statins (0.78; 95% CI, 0.72-0.84), resins (0.70; 95% CI, 0.50-0.99) and n-3 fatty acids (0.68; 95% CI, 0.52-0.90). Thus, the study concluded statins and n-3 fatty acids provided better outcomes by reducing the risk of mortality and also concluded that any potential reduction in cardiac mortality from fibrates was counterbalanced by an increased risk of death from non-cardiovascular causes.


 * In the FIELD study, that assessed the effect of fenofibrate on cardiovascular events, involved 9,795 diabetic patients who were randomized to either fenofibrate or placebo. The study reported no significant reduction in the primary endpoint of coronary death and non-fatal MI, but a reduction in the total cardiovascular events was observed. Hence, the study concluded no significant benefit with the use of fenofibrate.


 * In the ILLUSTRATE trial, 1188 coronary artery disease patients with corrected LDL-C level of less than 100 mg/dL achieved with atorvastatin pre-treatment, who underwent intravascular ultrasonography at baseline, were randomized to receive either a combination of torcetrapib and atorvastatin or atorvastatin alone, to assess the effect of CETP inhibition and HDL elevation in reducing the progression of atherosclerosis. At 24-month follow-up, approximately 61% relative increase in HDL cholesterol levels and a 20% relative decrease in LDL cholesterol levels with a subsequent LDL:HDL ratio of less than 1.0 was observed in the combined torcetrapib-atorvastatin group. However, no significant difference in the change of percent atheroma volume between the 2 groups were observed. Thus, the study concluded that the CETP inhibitor torcetrapib was associated with a substantial increase in HDL cholesterol and decrease in LDL cholesterol levels with no significant reduction in the progression of atherosclerosis and was associated with an increase in blood pressure.


 * In the RADIANCE 2 trial to assess the effect of CETP inhibitor, torcetrapib, on carotid atherosclerosis progression involving 752 patients with mixed dyslipidemia who have high triglycerides, low HDL-C and high LDL-C levels. The study reported significant increase in the HDL-C levels and decrease in the LDL-C levels observed in patients receiving torcetrapib. However, similar to the ILLUSTRATE trial, no significant reduction in the progression of carotid atherosclerosis with an associated increase in blood pressure was observed.


 * In the ILLUMINATE trial, 15,067 patients with a high cardiovascular risk were randomized in double-blind study of lipid level management on its impact on clinical cardiovascular events. Patients received either, a potent CETP inhibtor such as torcetrapib in addition to atorvastatin or atorvastatin alone. Premature termination of the study was due to an increased risk of cardiovascular events and death (82 deaths observed in the combined therapy group and 51 deaths in patients taking atorvastatin alone). Despite, the beneficial effects of significant LDL-cholesterol reduction and increase in the HDL cholesterol associated with torcetrapib use, the disadvantage of higher rates of MI, revascularization, heart failure, angina are presumably compound-specific.

==ACC/AHA Guidelines- Pharmacotherapy to Prevent MI and Death and Reduce Symptoms (DO NOT EDIT)  == {{cquote|

Class I
1. Dietary therapy for all patients should include reduced intake of saturated fats (to less than 7% of total calories), transfatty acids, and cholesterol (to less than 200 mg per day). (Level of Evidence: B)

2. Daily physical activity and weight management are recommended for all patients. (Level of Evidence: B)

3. Recommended lipid management includes assessment of a fasting lipid profile.
 * a. LDL-C should be less than 100 mg per dL. (Level of Evidence: A)
 * b. If baseline LDL-C is greater than or equal to 100 mg per dL, LDL-lowering drug therapy should be initiated in addition to therapeutic lifestyle changes. When LDL-lowering medications are used in high-risk or moderately high-risk persons, it is recommended that intensity of therapy be sufficient to achieve a 30% to 40% reduction in LDL-C levels. (Level of Evidence: A)
 * c. If on-treatment LDL-C is greater than or equal to 100 mg per dL, LDL-lowering drug therapy should be intensified. (Level of Evidence: A)
 * d. If TG are 200 to 499 mg per dL, non–HDL-C should be less than 130 mg per dL. (Level of Evidence: B)
 * e. If TG are greater than or equal to 500 mg per dL, therapeutic options to lower the TG to reduce the risk of pancreatitis are fibrate or niacin; these should be initiated before LDL-C lowering therapy. The goal is to achieve non–HDL-C less than 130 mg per dL if possible. (Level of Evidence: C)

4. Drug combinations are beneficial for patients on lipid lowering therapy who are unable to achieve LDL-C less than 100 mg per dL. (Level of Evidence: C)

5. Lipid-lowering therapy in patients with documented CAD and LDL-LDL cholesterol greater than 130 mg/dL with a target LDL of less than 100 mg/dL. (Level of Evidence: A)

Class IIa
1. Adding plant stanol or sterols (2 g per day) and/or viscous fiber (greater than 10 g per day) is reasonable to further lower LDL-C. (Level of Evidence: B)

2. Lipid-lowering therapy in patients with documented CAD and LDL cholesterol 100 to 129 mg/dL, with a target LDL of 100 mg/dL. (Level of Evidence: B)

3. Recommended lipid management includes assessment of a fasting lipid profile.
 * a. Reduction of LDL-C to less than 70 mg per dL or high-dose statin therapy is reasonable. (Level of Evidence: A)
 * b. If baseline LDL-C is 70 to 100 mg per dL, it is reasonable to treat LDL-C to less than 70 mg per dL. (Level of Evidence: B)
 * c. Further reduction of non–HDL-C to less than 100 mg per dL is reasonable, if TG are greater than or equal to 200 to 499 mg per dL. (Level of Evidence: B)

4. Therapeutic options to reduce non–HDL-C are:
 * a. Niacin can be useful as a therapeutic option to reduce non–HDL-C (after LDL-C–lowering therapy) (Level of Evidence: B)
 * b. Fibrate therapy as a therapeutic option can be useful to reduce non–HDL-C (after LDL-C–lowering therapy). (Level of Evidence: B)

5. The following lipid management strategies can be beneficial:
 * a. If LDL-C less than 70 mg per dL is the chosen target, consider drug titration to achieve this level to minimize side effects and cost. When LDL-C less than 70 mg per dL is not achievable because of high baseline LDL-C levels, it generally is possible to achieve reductions of greater than 50% in LDL-C levels by either statins or LDL-C–lowering drug combinations. (Level of Evidence: C)

Class IIb
1. For all patients, encouraging consumption of omega-3 fatty acids in the form of fish or in capsule form (1 g per day) for risk reduction may be reasonable. For treatment of elevated TG, higher doses are usually necessary for risk reduction. (Level of Evidence: B)}}

==ESC Guidelines- Pharmacological therapy to improve prognosis in patients with stable angina (DO NOT EDIT) == {{cquote|

Class I
1. Statin therapy for all patients with coronary disease. (Level of Evidence: A)

Class IIa
1. High dose statin therapy in high-risk (more than 2% annual CV mortality) patients with proven coronary disease. (Level of Evidence: B)

Class IIb
1. Fibrate therapy in patients with low HDL and high triglycerides who have diabetes or the metabolic syndrome. (Level of evidence: B)

2. Fibrate or nicotinic acid as adjunctive therapy to statin in patients with low HDL and high triglycerides at high risk (more than 2% annual CV mortality). (Level of evidence: C)}}

Vote on and Suggest Revisions to the Current Guidelines

 * The Chronic Stable Angina Living Guidelines: Vote on current recommendations and suggest revisions to the guidelines

Guidelines Resources

 * The ACC/AHA/ACP–ASIM Guidelines for the Management of Patients With Chronic Stable Angina


 * The ACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina


 * The 2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of Patients With Chronic Stable Angina


 * Guidelines on the management of stable angina pectoris: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology