Sharon B. Mannheimer, M.D. Date of Preparation of CV Personal data Sharon Mannheimer Birthplace: Cleveland, OH Citizenship: US Academic Appointments 9/10-present Associate Professor of Clinical Medicine (in Epidemiology), College of Physicians & Surgeons of Columbia University, New York, NY 1/11-present Assistant Dean, Student Affairs; Columbia University Affiliation
Bardzo tanie apteki z dostawą w całej Polsce kupic viagra i ogromny wybór pigułek.
Familial hypercholesterolemia: current treatment options and patient selection for low-density lipoprotein apheresisNLA Symposium on Familial Hypercholesterolemia Familial hypercholesterolemia: Current treatment optionsand patient selection for low-density lipoproteinapheresis Cardiology Department, Massachusetts General Hospital, Yawkey Center, Suite 5800, 55 Fruit Street, Boston, MA 02114,USA Abstract: Options for treatment of severe heterozygous and homozygous familial hypercholesterolemia prior to the statin era were limited by significant side effects and morbidity. The advent of both the statins and technology for the selective removal of LDL via apheresis have revolutionized management Ó 2010 National Lipid Association. All rights reserved.
increased 4%. The angiographic and clinical end pointswere positive in this study.
It is useful to look at the past, before looking to the Another one of the older therapies, which is very much present and the future, to remind ourselves of what therapies still a current therapy for FH, is the combination of niacin were for severe heterozygous familial hypercholesterolemia and bile acid sequestrants. This was the best therapy (FH) and homozygous FH before the statin era. Partial ileal available before the statins. In a seminal study by Kuo et bypass, portocaval shunt, liver transplantation, gene ther- published in 1981, LDL was reduced 45%, which was apy, and plasmapheresis—all of these options had consid- very similar to statin therapy, and there was a 22% increase erable morbidity attached to them. The most acceptable one, in HDL. This finding, however, was with 10 g of bile acid plasmapheresis, has now been replaced with selective low- sequestrant three times a day and the administration of 3 to density lipoprotein (LDL) apheresis. Portocaval shunt 7 g of immediate-release niacin, that is, a labor of love and reduced LDL by up to 40% in patients with homozygous FH, but there was the possibility of hepatic encephalopathy, The statin era changed everything for FH. Now with a and over the long term, pulmonary hypertension.
simple small pill with virtually no side effects, a 40% to Partial ileal bypass is like a super bile acid sequestrant, 54% LDL reduction can be achieved in heterozygous FH preventing reabsorption of bile salts. It was the intervention patients.Statins have also been tested extensively in in a large, randomized, controlled angiographic study, the children with FH. Lovastatin, simvastatin, atorvastatin, Program on the Surgical Control of the Hyperlipidemias and rosuvastatin have all been studied in adolesce (POSCH) trialLDL in this trial was lowered 38% by par- and were determined to provide 27%, 41%, 40%, and tial ileal bypass, and high-density lipoprotein (HDL) was 50% reductions in LDL, respectively. Statins were welltolerated, and no deleterious effect has been seen on devel- opment. Currently, there are studies on statins underway in E-mail address: Submitted July 30, 2010. Accepted for publication August 11, 2010.
1933-2874/$ - see front matter Ó 2010 National Lipid Association. All rights reserved.
doi: None of the clinical event trials with statins was done homozygous FH, there is overproduction of apolipoprotein specifically in an FH population. Therefore, what evidence B (apoB), and intrahepatic cholesterol availability is a key do we have of benefit for these patients? The Simon regulator in the secretion of apoB containing lipoproteins.
Broome cohort in United Kingdomretrospectively exam- Statins, by inhibiting hepatic cholesterol synthesis, limit ined their data on the relative risk of coronary heart disease cholesterol availability and therefore secretion of apoB (CHD) mortality for FH patients before and after the wide- lipoproteins in the LDL receptor-negative patient.
spread use of statins. Between 1980 and 1991, there was an Rosuvastatin has also been tested in homozygous FH eightfold increase in risk of CHD mortality for FH patients in a very large study (n 5 44) performed in South Africa between the ages of 20 to 59 years relative to non-FH sub- and the United States.Rosuvastatin at an 80-mg dose pro- jects the same age. Between 1992 and 1995, that changed duced a 21% reduction in LDL in all-comers. In the pa- to a fourfold increase. Even more cause for optimism are tients who were not on LDL apheresis or who had not data from the Netherlands in which myocardial infarction had portocaval shunt, there was a 26% reduction. In a cross- (MI)-free survival in statin-treated FH patients is virtually over to atorvastatin 80 mg, the results were very similar.
Ezetimibe is also useful in homozygous FH. In one Diet is always a critical component of therapy in FH study,patients receiving 40 mg of simvastatin or atorvas- patients. Statins are effective; their effectiveness is im- tatin at baseline were then randomized into three groups in proved by appropriate diet. An important metabolic unit which (1) their statin dose was doubled from 40 mg to 80 study performed early in the statin era makes this It mg, (2) ezetimibe was added to the 40-mg dose, or (3) their used a double crossover design: high fat versus low fat, and statin dose was doubled and ezetimibe was added. Dou- lovastatin versus placebo. The high-fat diet was 43% of cal- bling the statin gave the usual 7% additional LDL reduc- ories from fat with a high saturated content, and the low-fat tion; adding ezetimibe to the 40-mg dose provided a 13% diet was 25% calories from fat and high polyunsaturated additional LDL reduction, but doubling the statin and content. Lovastatin was equally effective in the high- and adding ezetimibe provided an additional 27% reduction.
the low-fat diets, providing 30% reduction in LDL inboth. However, the LDL in the lovastatin-treated patientson the high-fat diet was 154 mg/dL, and the LDL in the lovastatin-treated subjects on the low-fat diet was 120mg/dL, or 22% lower. This diet effect is similar to lower- LDL apheresis is the selective removal of all apoB- dose statin effect and underscores the importance of diet containing lipoproteins: LDL, very low-density lipoprotein, and lipoprotein (a). They are lowered acutely by 60% to Ezetimibe appears to be as effective in heterozygous FH 75%. There is little effect on other plasma components.
as it is in the general population of hypercholesterolemic This is where this technique is advantageous over the older patients. Most of the studies in which ezetimibe was added plasmapheresis methodology. HDL is lowered minimally, on to statin therapy were not performed in FH populations, and albumin and immunoglobulin are not affected. The and therefore data are limited. In the Effect of Ezetimibe time averaged lowering with LDL apheresis is approxi- Plus Simvastatin Versus Simvastatin Alone on Atheroscle- mately 50%, and there have been a number of small rosis in the Carotid Artery (ENHANCE) trial, the addition noncontrolled clinical trials in which the authors found of 10 mg of ezetimibe to 80 mg of simvastatin lowered improvement in cardiovascular disease.
LDL an additional 16%.If a similar incremental reduction Indications for LDL apheresis are best considered in the occurs with rosuvastatin, LDL could be reduced 70% with setting of the other guidelines. In the National Cholesterol the combination of this potent statin and ezetimibe in Education Program Adult Treatment Panel III guidelines, the LDL goal for coronary patients is under 100 mg/dL. In Homozygous FH is much more resistant to medical the update in 2004 based on the Heart Protection Study and therapy. In homozygous FH both LDL receptor alleles are the Pravastatin or Atorvastatin Evaluation and Infection affected so that there is little to no LDL receptor activity to Therapy (PROVE-IT) trial, the LDL goal for coronary pa- be up-regulated. Do the statins work in homozygous FH? tients with acute coronary syndromes or multiple risk factors, Initially, with the less potent statins, it was rather discour- especially diabetes, metabolic syndrome, and severe and aging. However, with the advent of the more potent statins, poorly controlled risk factors, was lowered to 70 mg/dL.
a clinically meaningful effect began to be observed in In 2005, with publication of the TNT trial,a growing homozygous FH. In a study of eight homozygous FH consensus would say that all coronary patients, including patients treated with simvastatin 80 mg and 160 mg, the stable patients, should have their LDL lowered to 70 mg/dL.
80-mg dose produced a 25% reduction in LDL and the So what are the indications for LDL apheresis? The 160-mg dose, Seven of the eight patients were Centers for Medicare and Medicaid Services established receptor defective, but in one receptor-negative patient, the guidelines in the late 1990s. To qualify for LDL apheresis as a coronary patient, one’s LDL has to be greater What is the mechanism of LDL reduction when there are than 200 mg/dL after at least a 6-month trial of maximum no LDL receptors to up-regulate? In both heterozygous and tolerated medical therapy. In the absence of coronary Journal of Clinical Lipidology, Vol 4, No 5, October 2010 disease, LDL has to be greater than 300 mg/dL to qualify day rosuvastatin, achieved good results, but again, the mus- cle weakness recurred. For the better part of 10 years her The following cases from the LDL apheresis unit at the LDL cholesterol was greater than 200 mg/dL. She began Massachusetts General Hospital illustrate some of the com- apheresis in 2007 and has been doing very well.
plexities of decision making and of dealing with the guide- The final patient is not on apheresis. She does not lines set by CMS. The first patient is the only patient who was qualify by strict criteria. This is a young woman, age 46, able to obtain insurance company coverage despite the fact who said she has been tested positive for the Ashkenazi FH that he did not meet the guidelines. He was 42 years old when gene in Israel. No one on her father’s side of the family has he was referred for consideration for LDL apheresis. He had a lived past 55 years of age; most had their first cardiac very strong family history: his father had a carotid endarter- events in their 40s, including an aunt. She does not have ectomy at 43 years and died of an MI at 53 years of age, and he clinical coronary disease, so technically she is primary pre- had four paternal uncles who died of MI in their 40s and 50s.
vention, but her coronary calcium score was 80th percentile When the patient was 37, he had an angioplasty of a severe for her age and sex, and she has a 50% stenosis in her left lesion in his right coronary artery. At 41, he had a stent to a internal carotid artery. Therefore, this is a very nervous new severe lesion in the circumflex, presenting with unstable young woman who also, like the previous patient, has angina. Also at 41, he had another stent in the right coronary, gone through years and years of undergoing therapies for again presenting with an acute coronary syndrome. At 42, he her LDL and being intolerant to them. Her untreated lipids had an atheroembolic renal infarct, and finally, still at age 42, are as follows: total cholesterol, 374 mg/dL; LDL, 320 mg/dL; he had a stent to another new high-grade lesion in the right HDL, 37 mg/dL; triglycerides, 83 mg/dL; and lipoprotein coronary artery, again presenting with unstable angina.
(a), 45 mg/dL. She was finally able to tolerate 40 mg of Through all of this, he was on quadruple lipid therapy: fluvastatin, but her LDL is still 241 mg/dL. Is she primary atorvastatin 80 mg, ezetimibe, gemfibrozil, and intermedi- prevention or is she secondary? Does she qualify? Should ate release niacin. His lipids on this therapy were total she be apheresed? Although the guidelines sound simple, cholesterol, 216 mg/dL; LDL cholesterol, 153 mg/dL; HDL cholesterol, 34 mg/dL; and triglycerides, 146 mg/dL. HisLDL was 153 mg/dL, so he would not qualify according tothe guidelines. Fortunately, his internist, cardiologist, and lipidologist all wrote very strongly worded letters to hisinsurance company, which agreed to cover apheresis for Grant/research support for Dr. Hemphill comes from him. This was begun in the fall of 2006, almost four years ago as of this writing, and the patient has been stable, withhis angina much improved. His pre/post lipids are asfollows: total cholesterol, 220/100 mg/dL; LDL cholesterol, 143/29 mg/dL; HDL cholesterol, 33/32 mg/dL; andtriglycerides, 227/191 mg/dL.
1. Buchwald H, Varco RL, Matts JP, et al., the POSCH Group. Effect of The second case is a common case in LDL apheresis partial ileal bypass surgery on mortality and morbidity from coronary units: the patient with multiple lipid medication intoler- heart disease in patients with hypercholesterolemia: report of the ance. This is a woman with premature coronary disease, Program on the Surgical Control of the Hyperlipidemias (POSCH).
percutaneous intervention at the age of 61, more than 10 2. Kuo PT, Kostis JB, Moreyra AE, Hayes JA. Familial type II years ago, and subsequent interventions in 2004 and 2006.
hyperlipoproteinemia with coronary heart disease: effect of diet- Her untreated lipids qualify her for LDL apheresis because colestipol-nicotinic acid treatment. Chest. 1981;79:286–291.
her LDL was 215 mg/dL. Over the course of 10 years, she 3. Stein EA, Strutt K, Southworth H, Diggle PJ, Miller E. Comparison of has been treated with multiple medications, all of which got rosuvastatin versus atorvastatin in patients with heterozygous familial her LDL well below the cutoff, but she experienced hypercholesterolemia. Am J Cardiol. 2003;92:1287–1293.
4. Kastelein JJP, Akdim F, Stroes ESG, et al. Simvastatin with or without multiple side effects in the process. While taking atorvas- ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358: tatin, she developed generalized muscle weakness several months after starting, which persisted for 2 years until 5. Noji Y, Higashikata T, Inazu A, et al. Long-term treatment with pita- finally she saw a neurologist who stopped the atorvastatin.
vastatin (NK-104), a new HMG-CoA reductase inhibitor, of patients The symptoms improved in several weeks and were gone in with heterozygous familial hypercholesterolemia. Atherosclerosis.
a month. Simvastatin was started, the patient’s muscle 6. Clauss SB, Holmes KW, Hopkins P, et al. Efficacy and safety of weakness recurred, and simvastatin was stopped. Pravasta- lovastatin therapy in adolescent girls with heterozygous familial tin was started, the patient’s muscle weakness recurred, and hypercholesterolemia. Pediatrics. 2005;116:682–688.
the pravastatin was stopped. Then a new approach, niacin 7. de Jongh S, Ose L, Szamosi T, et al. Efficacy and safety of statin ther- and bile acid sequestrant, was tried in 2004, which caused apy in children with familial hypercholesterolemia: a randomizeddouble-blind, placebo-controlled trial with simvastatin. Circulation.
intolerable constipation and flushing, so they were stopped.
Ezetimibe was tried in 2006 but caused abdominal distress, 8. McCrindle BW, Ose L, Marais AD. Efficacy and safety of atorvastatin so it was stopped. The patient was tried on the every-other- in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled 14. Marais AD, Raal FJ, Stein EA, et al. A dose-titration and comparative study of rosuvastatin and atorvastatin in patients with homozygous 9. Avis HJ, Hutten BA, Gagne C, et al. Efficacy and safety of rosuvasta- familial hypercholesterolemia. Atherosclerosis. 2008;197:400–406.
tin therapy for children with familial hypercholesterolemia. J Am Coll 15. Gagne C, Gaudet D, Bruckert E. Efficacy and safety of ezetimibe co administered with atorvastatin or simvastatin in patients with homozy- 10. Scientific Steering committee on behalf of the Simon-Broome Regis- gous familial hypercholesterolemia. Circulation. 2002;105:2469–2475.
ter Group. Mortality in treated heterozygous familial hypercholesterol- 16. Expert Panel on Detection, Evaluation, and Treatment of High Blood emia: implication for clinical management. Atherosclerosis. 1999;142: Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on 11. Versmissen J, Oosterveer DM, Yazdanpanah M, et al. Efficacy of Detection, Evaluation, and Treatment of High Blood Cholesterol in statins in familial hypercholesterolemia: a long term cohort study.
Adults (Adult Treatment Panel III). JAMA. 2001;285:2486–2497.
17. Grundy SM, Cleeman JI, Bairey Merz N, et al. for the Coordinating 12. Cobb MM, Teitelbaum HS, Breslow JL. Lovastatin efficacy in reduc- Committee of the National Cholesterol Education Program. Implications ing low-density lipoprotein cholesterol levels on high- vs low-fat diets.
of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004;110:227–239.
13. Raal JR, Pilcher GJ, Illingworth DR, et al. Expanded-dose simvastatin 18. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering is effective in homozygous familial hypercholesterolemia. Atheroscle- with atorvastatin in patients with stable coronary disease. N Engl
Neural Integration II: The Autonomic Nervous System and Higher-Order Functions Operates under conscious control Seldom affects long-term survival SNS controls skeletal muscles Operates without conscious instruction ANS controls visceral effectors Coordinates system functions: cardiovascular, respiratory, digestive, urinary, reproductive Integrative center