Chronic stable angina treatment anti-lipid agents
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Differentiating Chronic Stable Angina from Acute Coronary Syndromes | ||
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] 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 hence have been shown to be effective in the primary prevention of various hyperlipidemias and secondary prevention of ischemic heart disease.[1][2] 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[1] and pravastatin[3][4] in patients with coronary artery disease and hence may be used for both primary and secondary prevention.[5][6][7][8] 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.[9] 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.[10] [5]
- 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.[11]
- It has been postulated that statins have anti-inflammatory and anti-thrombotic effects.[12] [13] [14] [15]
- 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:[16]
- 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.[17]
- 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.[3] [9] [18]
- 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.[19]
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.[3][5][9][18]
- In patients with stable angina, pre-treatment with atorvastatin was associated with the reduction of procedural myocardial injury, as assessed by biochemical markers.[17]
- 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.[18][20]
- Statin therapy in diabetics with vascular disease and in the elderly have demonstrated beneficial effects.[9][20][21][22]
- In patients with low HDL and high triglycerides, as an adjunctive to statin therapy, fibrates or niacin may be used.
- 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 fibrate, antibiotics (such as clarithromycins and erythromycins), anti-fungals (such as ketaconazole and itraconazole with any of the statins, increase the risk of myopathy and rhabdomyolysis.[23]
Dosage
In patients with stable angina, an intensive lipid-lowering therapy with atorvastatin 80mg/day has shown to provide significant clinical benefit and improve prognosis.[8]
Adverse effects
- Rhabdomyolysis.[23]
- In patients undergoing coronary bypass surgery, peri-operative statin withdrawal have been associated with increased frequency of cardiac events.[24]
Supportive trial data
- In the Scandinavian Simvastatin Survival Study (4S) that assessed the effect of simvastatin on mortality and morbidity, involved 4444 patients with coronary heart disease who were randomized to either simvastatin or placebo. The study reported that there was a 30% relative reduction in the risk of mortality from all cardiovascular causes with the use of simvastatin.[1]
- In the ASCOT-LLA trial, that assessed the benefit of atorvastatin in the prevention of coronary and stroke events amongst hypertensive patients with a total cholesterol level of ≤6.5 mmol/L, involved 19,342 patients who were randomized to either atorvastatin or placebo. 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.[7]
- In the Heart Protection Study that assessed the effect of simvastatin on the mortality, involved 20,536 patients who were randomized to either simvastatin or placebo. The study concluded 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%.[9]
- In the ASTEROID trial, that 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.[11]
- Prospective meta-analysis that reviewed 14 randomized trials with 90,056 participants assessed the effects on different clinical outcomes per 1.0 mmol/L reduction in LDL cholesterol during a mean follow-up of 5 years. The primary endpoint from all-cause mortality per mmol/L reduction in LDL cholesterol was a 12% proportional reduction 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.[2]
- 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.[25]
ACC/AHA Guidelines- Pharmacotherapy to Prevent MI and Death and Reduce Symptoms (DO NOT EDIT) [26] [27] [28]
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Class I1. 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.
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 IIa1. 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.
4. Therapeutic options to reduce non–HDL-C are:
5. The following lipid management strategies can be beneficial:
Class IIb1. 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) |
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ESC Guidelines- Pharmacological therapy to improve prognosis in patients with stable angina (DO NOT EDIT) [29]
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Class I1. Statin therapy for all patients with coronary disease. (Level of Evidence: A) Class IIa1. High dose statin therapy in high-risk (more than 2% annual CV mortality) patients with proven coronary disease. (Level of Evidence: B) Class IIb1. 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) |
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Vote on and Suggest Revisions to the Current Guidelines
Sources
- The ACC/AHA/ACP–ASIM Guidelines for the Management of Patients With Chronic Stable Angina [26]
- TheACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina [27]
- The 2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of Patients With Chronic Stable Angina [28]
- Guidelines on the management of stable angina pectoris: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology [29]
References
- ↑ 1.0 1.1 1.2 (1994) Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) Lancet 344 (8934):1383-9. PMID: 7968073
- ↑ 2.0 2.1 Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C et al. (2005) Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366 (9493):1267-78. DOI:10.1016/S0140-6736(05)67394-1 PMID: 16214597
- ↑ 3.0 3.1 3.2 Sacks FM, Tonkin AM, Shepherd J, Braunwald E, Cobbe S, Hawkins CM et al. (2000) Effect of pravastatin on coronary disease events in subgroups defined by coronary risk factors: the Prospective Pravastatin Pooling Project. Circulation 102 (16):1893-900. PMID: 11034935
- ↑ (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 (19):1349-57. DOI:10.1056/NEJM199811053391902 PMID: 9841303
- ↑ 5.0 5.1 5.2 Grundy SM, Cleeman JI, Merz CN, Brewer HB, Clark LT, Hunninghake DB et al. (2004) Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 44 (3):720-32. DOI:10.1016/j.jacc.2004.07.001 PMID: 15358046
- ↑ Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D et al. (2001) Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA 285 (13):1711-8. PMID: 11277825
- ↑ 7.0 7.1 Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M et al. (2003) Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 361 (9364):1149-58. DOI:10.1016/S0140-6736(03)12948-0 PMID: 12686036
- ↑ 8.0 8.1 LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC et al. (2005) Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 352 (14):1425-35. DOI:10.1056/NEJMoa050461 PMID: 15755765
- ↑ 9.0 9.1 9.2 9.3 9.4 Heart Protection Study Collaborative Group (2002) MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360 (9326):7-22. DOI:10.1016/S0140-6736(02)09327-3 PMID: 12114036
- ↑ Ma PT, Gil G, Südhof TC, Bilheimer DW, Goldstein JL, Brown MS (1986) Mevinolin, an inhibitor of cholesterol synthesis, induces mRNA for low density lipoprotein receptor in livers of hamsters and rabbits. Proc Natl Acad Sci U S A 83 (21):8370-4. PMID: 3464957
- ↑ 11.0 11.1 Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM et al. (2006) Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 295 (13):1556-65. DOI:10.1001/jama.295.13.jpc60002 PMID: 16533939
- ↑ Faggiotto A, Paoletti R (1999) State-of-the-Art lecture. Statins and blockers of the renin-angiotensin system: vascular protection beyond their primary mode of action. Hypertension 34 (4 Pt 2):987-96. PMID: 10523396
- ↑ Bonetti PO, Lerman LO, Napoli C, Lerman A (2003) Statin effects beyond lipid lowering--are they clinically relevant? Eur Heart J 24 (3):225-48. PMID: 12590901
- ↑ Rosenson RS, Tangney CC (1998) Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA 279 (20):1643-50. PMID: 9613915
- ↑ Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH et al. (2005) C-reactive protein levels and outcomes after statin therapy. N Engl J Med 352 (1):20-8. DOI:10.1056/NEJMoa042378 PMID: 15635109
- ↑ Furberg CD (1999) Natural statins and stroke risk. Circulation 99 (2):185-8. PMID: 9892578
- ↑ 17.0 17.1 Pasceri V, Patti G, Nusca A, Pristipino C, Richichi G, Di Sciascio G et al. (2004) Randomized trial of atorvastatin for reduction of myocardial damage during coronary intervention: results from the ARMYDA (Atorvastatin for Reduction of MYocardial Damage during Angioplasty) study. Circulation 110 (6):674-8. DOI:10.1161/01.CIR.0000137828.06205.87 PMID: 15277322
- ↑ 18.0 18.1 18.2 Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ et al. (2004) Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 364 (9435):685-96. DOI:10.1016/S0140-6736(04)16895-5 PMID: 15325833
- ↑ Hackam DG, Mamdani M, Li P, Redelmeier DA (2006) Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis. Lancet 367 (9508):413-8. DOI:10.1016/S0140-6736(06)68041-0 PMID: 16458766
- ↑ 20.0 20.1 Collins R, Armitage J, Parish S, Sleigh P, Peto R, Heart Protection Study Collaborative Group (2003) MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 361 (9374):2005-16. PMID: 12814710
- ↑ Goldberg RB, Mellies MJ, Sacks FM, Moyé LA, Howard BV, Howard WJ et al. (1998) Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The Care Investigators. Circulation 98 (23):2513-9. PMID: 9843456
- ↑ Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM et al. (2002) Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 360 (9346):1623-30. PMID: 12457784
- ↑ 23.0 23.1 Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L et al. (2004) Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA 292 (21):2585-90. DOI:10.1001/jama.292.21.2585 PMID: 15572716
- ↑ Schouten O, Hoeks SE, Welten GM, Davignon J, Kastelein JJ, Vidakovic R et al. (2007) Effect of statin withdrawal on frequency of cardiac events after vascular surgery. Am J Cardiol 100 (2):316-20. DOI:10.1016/j.amjcard.2007.02.093 PMID: 17631090
- ↑ Studer M, Briel M, Leimenstoll B, Glass TR, Bucher HC (2005) Effect of different antilipidemic agents and diets on mortality: a systematic review. Arch Intern Med 165 (7):725-30. DOI:10.1001/archinte.165.7.725 PMID: 15824290
- ↑ 26.0 26.1 Gibbons RJ, Chatterjee K, Daley J, Douglas JS, Fihn SD, Gardin JM et al. (1999)guidelines for the management of patients with chronic stable angina: executive summary and recommendations. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Chronic Stable Angina).Circulation 99 (21):2829-48. PMID: 10351980
- ↑ 27.0 27.1 Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS et al. (2003) ACC/AHA 2002 guideline update for the management of patients with chronic stable angina--summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). Circulation 107 (1):149-58. PMID: 12515758
- ↑ 28.0 28.1 Fraker TD, Fihn SD, Gibbons RJ, Abrams J, Chatterjee K, Daley J et al. (2007)2007 chronic angina focused update of the ACC/AHA 2002 Guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 Guidelines for the management of patients with chronic stable angina. Circulation 116 (23):2762-72.[1] PMID: 17998462
- ↑ 29.0 29.1 Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F; et al. (2006). "Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology". Eur Heart J. 27 (11): 1341–81. doi:10.1093/eurheartj/ehl001. PMID 16735367.