ARC Key Centre of Teaching and University of Wollongong - Research Proposal Example

Folic Acid Supplementation and Coronary Heart Diseases among Elderly People A Research Proposal By ARC Key Centre of Teachingand Research University of Wollongong Introduction: Coronary artery disease (CAD) is the greatest killer of this century for the elderly. CAD primary leads to myocardial infarction due to compromise of blood supply to the muscles of the heart or myocardium. The disease that involves the coronary arteries is known as atherosclerosis. This causes hardening of the arteries due to deposition of excess lipids in the arterial wall leading to narrowing of the coronary arteries. Narrowing of the coronary arteries may critically reduce the cross-sectional area of the artery and reduce blood flow distal to that area of narrowing. In the resting state, this percentage reduction of blood flow beyond the area of narrowing may lead to reversible and relative deficit of blood supply to the myocardium of the working heart (Zindrou, D., Taylor, K.M., and Bagger, J.P., 2006). As time proceeds and the disease becomes more severe due to more accumulation of fat or plaque, pathologically, there may be rupture of the plaque (Davies, M.J., 2000). This may initiate a thrombotic process in that locality leading to almost total occlusion of the artery, and the myocardium supplied by that segment of the artery will be deprived of blood supply, hence oxygen. Temporary avascularity of the myocardium due to thrombus or clot generation would lead to death of myocardial tissue which is popularly known as heart attack or medically known as myocardial infarction (Fox, K.A. et al., 1984). While many factors are known to influence the origin, evolution, and persistence of heart disease in the population, it is agreed that abrupt decrease of coronary blood flow results following a thrombotic occlusion of a coronary artery previously narrowed by atherosclerotic cardiovascular disease. In fact, it has been found that myocardial infarction occurs with rapid development of a coronary artery thrombus at the site of vascular endothelial injury caused by rupture or ulceration of a plaque (Roger, V.L. et al., 2006). This leads to activation of platelets, and following the platelet activation, there is generation of thromboxane A2 that promotes a cascade of events leading ultimately to clot formation. Increased homocysteine levels affect the inner lining of the arterial wall, and thus have long been implicated in the causation of thrombosis (Scott, J. and Weir, D., 1996). In fact, increased homocysetine levels associated with syndrome of homocysteinuria are acknowledged to be a cause of intravascular thrombosis. It has been observed that plasma homocysteine is normally converted to methionine co-factored by folic acid correlates in the body. When this reaction is impaired due to deficiency of cobalamine; since cobalamine regulates folate metabolism, it is deranged leading to elevated homocysteine levels (Mayer, E.L., Jacobsen, D.W., and Robinson, K., 1996). High plasma homocysteine, thus, will predispose to increased thrombosis, although it is not yet known whether hyperhomocysteinaemia due to folic acid deficiency predisposes to thrombosis or alters its response to treatment (Welch, G.N. and Loscalzo, J., 1998). This proposal aims to study the effect of folic acid on the elderly in terms of risk of coronary artery disease as relevant to prevention of thrombosis in preexisting atherosclerotic heart disease in terms of incidence of myocardial infarction (Bots, M.L. et al., 1999). Increasingly, healthcare is focusing towards prevention of disease rather than treating it after the catastrophe happens. Coronary artery disease manifested by acute myocardial infraction is one of the most common diagnoses in developed countries throughout the world. The mortality rate of the disease is 30% with over half the patients expiring even before they are able to reach the hospital. Survival from a heart attack is markedly reduced with the elderly, patient's age approaching over 65. Moreover, after an acute event, the cost of management is very high (Hyams, L., and Loop, A., 1969). Therefore, it would not be impertinent to find out a therapeutic way to prevent such acute events precipitated mainly by a thrombotic event within the coronary artery in the elderly. The pharmaceutical role of folic acid has been investigated by many researchers in terms of its effect on prevention of a thrombotic event as related to myocardial infarction, but most of the studies have failed to connect the pathologic factors and demographic factors, hence could not reach a definitive answer to this question (Landgren, F. et al., 1995). Review of Literature: A study undertaken by Hao et al. demonstrates that elevated plasma homocysteine concentrations are associated with low folic acid level, which is an independent risk factor for cardiovascular disease. In this study, low folic acid in aged individuals and independently hyperhomocysteinaemia were ascribed to be the culprit factors, but this study failed to establish a causal relationship between these factors (Hao, L.; Ma, J.; Zhu, J.; and Stampfer, M.J. et al., 2007). In another study, the researchers found no correlation of helpful effect of folic acid on risk of coronary artery disease, hence they concluded that in persons with preexisting vascular disease, folic acid supplementation has no role to play in secondary prevention (Bazzano, L.A., 2007). Plasma homocysteine has been a novel independent risk factor for cardiovascular disease explained by reduced serum folate concentrations in individuals. Some researchers have proposed an association between fasting plasma homocysteine and coronary heart disease, and this may be lowered by dietary folate supplementation. This has been independent of other usual risk factors for coronary heart disease. This study, however, fails to correlate this with the age of the individuals (Chambers, J.C.; Obeid, O.A.; Refsum, H.; Ueland, P et al., 2000). In a study by Ward et al., the authors state that elevated plasma homocysteine, an independent risk factor of CVD is determined by suboptimal status of folic acid. Interventions studies that have been carried out so far cannot be used to theorise that folic acid supplementation causes reduction in prevalence of coronary heart disease since the sample in such study was highly selective in that it only considered samples with markedly raised plasma homocysteine concentration. The effect of folic in prevention of cardiovascular disease in normal elderly population, therefore, was not known (Ward, M.et al., 1997). The question that how folic acid reduces the vascular event has been answered by many researchers in this area. Homocysteine-induced endothelial injury is mediated through oxidative stress. In vitro studies have demonstrated that homocysteine generates peroxide radicles that may cause endothelial dysfunction through lipid peroxidation, thus reducing nitric oxide in the inner lining of the coronary vessels (Upchurch, G.R. Jr., Welch, G.N., Fabian, A.J. et al., 1997), but this study was limited by many factors. The sample study population comprised of people with established coronary atherosclerotic disease, hence had many associated factors other than just hyperhomocysteinaemia. It did not study coronary artery disease per se, rather it concentrated on peripheral vessels. The results, therefore, cannot be extrapolated to the effects of folic acid supplementation in the general population with risk of coronary heart disease. The effectiveness of chronic low-dose folic acid therapy in reducing plasma homocysteine levels and thereby eliminating this independent risk factor lacks a randomised trial to establish the efficacy of folic acid in reduction of incidence of acute coronary vascular events. This study proposes to undertake a randomised trial to study the effect of folic acid supplementation in the elderly population on reduction of risk factors of cardiovascular events as a result of coronary heart disease. Aims: A randomized, double-blind, placebo-controlled trial designed to determine if daily folic acid supplementation alters the risk for Coronary Heart Diseases (CHD) events in elderly people with known CHD risk factors at King Kahled University Hospital in Saudi Arabia. Methods: Subjects: A total of 1590 Saudi male and female patients aged 65 years or more will be included in this study with intention-to-treat analysis. Subjects will be recruited from Internal Medicine Clinics at King Kahled University Hospital (KKUH), Riyadh, Saudi Arabia. Research nurses will screen the medical records and exclude patients who have a history of coronary heart diseases or patients who are taking drugs known to interfere with folic acid, or taking vitamin supplements containing folic acid. Patients will be eligible for inclusion if aged 65 years or more and if their medical histories include two or more of the following conditions: diabetes, hypertension, hyperlipidemia, obesity or smoking. All eligible individuals will receive a letter from the hospital explaining the study, followed by a telephone call inviting them to attend the first visit and instructing them to fast from midnight the night before the visit. At the first visit, all baseline measurements will be taken. Research nurses will take general information, such as, name, age, sex, phone number, address, smoking history, marital status, socioeconomic factors, and the names and phone numbers of two or three friends or relatives who always know how to reach the participants. Drugs history including aspirin or other anticoagulants, antihypertensive, anti-angina, and lipid-lowering drugs will be reviewed. Study procedures will be explained to all subjects. Subjects who are unlikely to complete follow-up due to plans to move or due to disease likely to be fatal within 4 years, or unwilling to participate will be excluded from the study. Ethics: All subjects will be explained the study protocol, and a written informed consent will be obtained from each subject about the free will to participate in the study, and this study will be reviewed by Saudi Government Ethics Committee. Baseline Measurements: Baseline measurements will include the measurement of the outcome variables which will be demonstrated by the medical history from the medical records and electrocardiogram and cardiac enzymes level (troponin I, creatine phosphokinase (CPK, CK), and lactic acid dehydrogenase, LDH) to make sure that the CHD is not present at the outset. The weight of subject will be measured while they will be wearing minimal clothing and no shoes and recorded to the nearest 0.10 kg. Standing height will be recorded to the nearest 0.10 cm. According to height and weight, obesity will be defined as body mass index more than 30 kg/m. Blood pressure will be measured from the right arm with the subject rested in a sitting position. Systolic and diastolic blood pressures will be recorded to the nearest 2 mmHg. Hypertension will be defined by systolic blood pressure is 160 mmHg and/ or diastolic blood pressure is 90 mmHg or if patient is taking anti-hypertensive medications. Laboratory tests will include fasting blood sugar, Total Cholesterol, Triglycerides (TG), Low-Density Lipoproteins cholesterol (LDL-C), High Density Lipoproteins cholesterol (HDL-C), folate and homocysteine. Hyperlipidemia will be defined by LDL-C 3.36 mmol/L or TG 2.3 mmol/L or HDL-C 0.9 mmol/L or total cholesterol 6.2 mmol/L or if the patient is taking lipid-lowering drugs. Patients will be classifies to be having diabetes if their fasting blood sugar is 7.8 mmol/L or if they are diagnosed before as diabetic patients. All measurements will be taken by research nurses using same equipments in KKUH. Smoking status will be classified as nonsmoker, former smoker, and current smoker depending on the history. Randomisation and Blinding: Subjects who will not be excluded by baseline measurements will be ready for randomization. Randomization procedure will be conducted by a member of staff in the hospital who will not be involved in the study. Subjects will be assigned with equal probability to folic acid supplementation or placebo by using computer-generated random numbers. The subjects, research nurses, and laboratory staff will remain blinded to the supplementation and placebo assignments until the end of the study. Followup: Followup will be every 4 months by phone to assess and enhance compliance and every year for cardiac examinations and ECG. The total follow up period is 4 years. At each visit subject will be asked if they had any hospitalization due to cardiac problem. During the period of study, subjects will receive birthday cards with letter emphasising the scientific importance of adherence to the regimen and followup. Subjects who would discontinue the trial intervention will be followed so that their outcomes will be used in intention-to-treat analysis. The outcomes of subjects who are lost to follow-up will be taken by contacting their friends or relatives. Analysis: The analysis will be by intention-to-treat analysis; comparing outcomes between the study groups with every participant analyzed according to his/her randomized group assignment, regardless of whether he/she received the assigned intervention. The main analysis will compare the occurrence of CHD among subjects assigned to folic acid supplementation and those who assigned to placebo. Hypothesis and sample size estimation: Null hypothesis: the incidence of CHD is the same in elderly on folic acid supplementations and those on placebo. Alternative hypothesis: the incidence of CHD is different in elderly on folic acid supplementations and those on placebo. This author estimated the need to enroll 1590 subjects, assuming CHD rate in the placebo group 0.15 and 0.10 in folic acid group. This author assumed 10% loss to follow up and non-CHD deaths. These assumption resulted in 0.80 power at (two-sided) = 0.05 and = 0.20 Outcomes variables: In this study, CHD is defined to include nonfatal myocardial infarction and CHD death that occur between the date of randomization and the last visit. Nonfatal myocardial infarction could be either symptomatic or silent, and CHD death could be a fetal documented MI, sudden death within one hour of onset of symptoms, or death due to coronary revascularization procedures or congestive heart failure. The diagnosis of nonfatal MI will base on algorithm that takes into account three categories of clinical information from the acute event: ischemic symptoms, ECG abnormalities and elevated cardiac enzyme level. A total of 1590 males and females aged more than 60 years will be assigned randomly to receive tablet containing 600g folic acid or a placebo of identical appearance. Subjects will be evaluated every year for 4 years. The analysis will compare the occurrence of CHD events in subjects assigned to active treatment with the occurrence in those assigned to placebo. The findings of this study will clarify the effect of daily folic acid supplementation on the occurrence of CHD events in elderly people. Timetable: Ethics approval: 90 days Recruitment : 30 days Data collection: 180 days Data analysis: 90 days Report writing: 180 days Budget : 1.People: 1. Senior Researchers x 2 : $ 6000 per month x 19 ------ $228,000 2. Research Nurses x 2 : $3000 per month x 19----------- -------------$114,000 3. Lab technicians x 2 : $2000 per month x 19------------------------$ 76,000 4. Office Bearer x 1 : $1500 per month x 19------------------------$ 28,500 5. Student Assistant for Data x 2 x $5 per hours x 8 hours Per day x 19 months --------------------------------$ 45,600 Consumables $ 100 per head per day x 19 months x 8------------ -------------$ 456,000 Paper $100 per month x 12 months--------------------------------------$ 1,200 Laboratory Rentals $1000 per month x 19-------------------------- -------------$ 19,000 Reagents $2000 per month x 12--------------------------------------$ 24,000 Postage etc ----------------------------------------------------------------------------$ 2,000 Travel----------$100 per day for team x 3 months ------------------------------- $ 90,000 Equipment----------------------------------------------------------------------------- $ 40,000 Total ------------------------------------------------------------------------------------$ 1,124,300 Reference List Bazzano, L.A., (2007). Cardiovascular Research; Folic Acid Supplementation Does Not Decrease The Risk Of Coronary Heart Disease Or Stroke. Journal of the American Medical Association, Cardiovascular Week, Atlanta, p.10. Bots, M.L., Launer, L.J., Lindemans, J., Hoes, A. W., Hofman, A., Witteman, J.C.M., Koudstaal, P.J., and Grobbee, D.E., (1999). Homocysteine and Short-term Risk of Myocardial Infarction and Stroke in the Elderly: The Rotterdam Study, Archives of Internal Medicine; 159: pp. 38 - 44. Chambers, J.C.; Obeid, O.A.; Refsum, H.; Ueland, P et al., (2000). Plasma homocysteine concentrations and risk of coronary heart disease in UK Indian, Asian, and European Men, The Lancet; 355, 9203; Health Module, pg. 523. Davies, M.J., (2000). CORONARY DISEASE: The Pathophysiology Of Acute Coronary Syndromes, Heart; 83: pp. 361 - 366. Fox, K.A., Bergmann, S.R., Mathias, C.J., Powers, W.J., Siegel, B.A., Welch, M.J., and Sobel, B.E., (1984). Scintigraphic detection of coronary artery thrombi in patients with acute myocardial infarction, Journal of American College of Cardiologists; 4: pp. 975 - 986. Hao, L.; Ma, J.; Zhu, J.; and Stampfer, M.J. et al., (2007). High Prevalence of Hyperhomocysteinemia in Chinese Adults Is Associated with Low Folate, Vitamin B12, and Vitamin B6 Status. The Journal of Nutrition; 137, 2; Health Module. Hyams, L., and Loop, A., (1969). The Epidemiology Of Myocardial Infarction At Two Age Levels, American Journal of Epidemiology; 90: pp. 93 - 102. Landgren, F., Israelsson,B., Lindgren, A., Hultberg, B., Andersson, A., and Brattstrom, L., (1995). Plasma Homocysteine In Acute Myocardial Infarction: Homocysteine-Lowering Effect Of Folic Acid. Journal Of Internal Medicine; 237(4): pp. 381-388. Mayer, E.L., Jacobsen, D.W., and Robinson, K., (1996). Homocysteine and coronary atherosclerosis. Journal of American College of Cardiologists; 27: pp. 517-527. Roger, V.L., Killian, J.M., Weston, S.A., Jaffe, A.S., Kors, J., Santrach, P.J., Tunstall-Pedoe, H., and Jacobsen, S.J., (2006). Redefinition of Myocardial Infarction: Prospective Evaluation in the Community, Circulation; 114: pp. 790 - 797. Scott, J. and Weir, D., (1996). Homocysteine and Cardiovascular disease. Quarterly Journal of Medicine; 89:pp. 561-563. Upchurch, G.R. Jr., Welch, G.N., Fabian, A.J. et al., (1997). Homocyst(e)ine decreases bioavailable nitric oxide by a mechanism involving glutathione peroxidase. Journal of Biological Chemistry; 272: pp. 17012-7. Ward, M., McNulty, H., McPartlin, J., Strain, J.J., Weir, D.G., and Scott, J.M., (1997). Plasma Homocysteine, A Risk Factor For Cardiovascular Disease, Is Lowered By Physiological Doses Of Folic Acid, Quarterly Journal of Medicine; 90: pp. 519 - 524. Welch, G.N. and Loscalzo, J., (1998). Homocysteine and Atherothrombosis. New England Journal of Medicine;338: pp. 1042-1050. Zindrou, D., Taylor, K.M., and Bagger, J.P., (2006). Coronary artery size and disease in UK South Asian and Caucasian men, European Journal of Cardiothoracic Surgery; 29: pp. 492 - 495. {Please review the budget, it is approximate, and I do not know the local costings) Read More