ASSESSMENTOF THE EFFECT OF STATINS IN LOWRING THE RISK OF STROKE AND PREVENTINGCEREBRAL ISCHEMIA IN PATIENTS WITH HYPERCHOLESTEROLEMIA
Cerebralischemia and stroke occur as coincidence with most of thecardiovascular and lifelong diseases. Their medication with statinshave bore fruits in reducing incidences of ischemic stroke among manypatients. They are therefore fit to be produced among patientssusceptible to such stroke cases for the purposes of prevention.
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Assessmentof the Effect of Statins in Lowering the Risk of Stroke andPreventing Cerebral Ischemia in Patients with Hypercholesterolemia
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ASSESMENT OF THE EFFECT OFSTATINS IN LOWRING THE RISK OF STROKE AND PREVENTING CEREBRALISCHEMIA IN PATIENTS WITH HYPERCHOLESTEROLEMIA
Thereare numerous analyses that have been published to determine statinsaffect stroke incidence and how they relate to the occurrence ofcerebral ischemia in hypercholesterolemic patients. The risk ofdeveloping the two conditions is found to reduce by up to 30%. Themystery is whether this reduction is attributed to the drugs actionof reducing low density lipoprotein(LDL), a type of cholesterol.These trials have been performed in more than 100,000 patients andthe negative association with stroke and cerebral ischemia has beendetermined.
Randomizedcontrol tests were analyzed and systematic review performed alongsideintense research in reliable sources such as PubMed. Separately,analysis was done to evaluate risk ratio reduction for stroke andthickness of carotid intima thickness that is likely to causecerebral ischemia. In general, stroke incidence reduced by 20% to 35%whereas the thickness of the arteries supplying the cerebrum reducedby more than 0.73%.
Manydrugs administered to prevent stroke have a long term effect ofinducing hemorrhagic shock, fortunately statins have no associationwith hemorrhagic shock. This is majorly attributed to its extent ofreducing LDL cholesterol. This effective reduction in LDL levels isalso responsible for reducing the thickening of arterial walls thatsupply the brain tissue.
TABLE OF CONTENTS
READER APPROVAL PAGE…………………………………………………………..iii
TABLE OF CONTENTS v
LIST OF TABLES vi
METHODS (research-based)/PUBLISHED STUDIES (lit-based) 6
CURRICULUM VITAE 20
LIST OF TABLES
Trials of statin use and primary stroke prevention
patients with cardiovascular disease
Relationship between ORs for stroke events and correspondingLDL-C reduction. The regression line has been plottedand weighted for the inverse of the variance of ORs.
Means of age, IMT and LDL-C, and percentage of male gender on entry to study in all randomised patients †mean IMT value is given ‡average of maximumIMT value is given §right side of the neck was examined only.
Strokeis a worldwide common disease with its occurrence depending onmultiple risk factors involved, one of which is high bloodcholesterol and LDL level, it is thought that lower cholesterol leveldecreases the incidence of cerebrovascular ischemia (1),which has been concluded from many clinical trials conducted for thepurpose of understanding the adverse effects of statins, drugs thathave been manufactured primarily for the purpose of controlling bloodcholesterol level, statins are defined as a family of drugs thatcontrol and inhibit cholesterol production by acting through bindingto 3-hydroxymethyl-3-glutaryl coenzyme A (HMG-CoA) reductase, by thismechanism the end result will be a lower LDL level in the blood whichin turn benefits the outcome of many states of disease includingcardiovascular disease and stroke (2).
Statinshave multiple organ effects by affecting the liver, musculoskeletalsystem and the nervous system, controlled clinical trials withrandomized blinded assignment of treatment groups to patients treatedwith statins and placebo was conducted, hence valid data aboutadverse effects of statins were obtained(3).The Stroke Prevention by Aggressive Reduction in Cholesterol Levels(SPARCL) Investigators conducted a study in which patients withhistory of transient ischemic attack or thrombotic stroke wereallocated into two groups, one treated with statin and the othergroup with placebo, after conducting this study there was evidencethat treatment with statins allows for an enough significantprotection against strokes due to vascular damage i.e. thromboticstroke (4).New evidence revealed that treatment with statin prior to theoccurrence of severe ischemic stroke is effective in providing abetter neurologic presentation and lower death rate yet anon-favorable effect of statin is an increased incidence of brainhemorrhage (5).
AlthoughStatin family of drugs was not primarily designed to be protectiveagainst ischemic stroke there is significant evidence in randomizedstudies that it lowers the incidence of cerebrovascular events. AnHPS random clinical trial of subgroup analysis of the effect ofstatin treatment on reoccurrence of ischemic stroke with a largesample size of patients suffering from previous cerebrovascularischemia have shown a significant benefit in lowering thereoccurrence of ischemic stroke in those patients (Table 1) (1),to furthermore establish and confirm the strong evident relationshipbetween statin treated high serum LDL and lower incidence of ischemicstroke a meta-analysis and systemic review of available datapertaining to frequency of occurrence of ischemic stroke andtransient ischemic attacks to the year 2015 were analyzed and thenumber of included patients was 3374 individuals diagnosed withheterozygous familial hypercholesterolemia, the general population inthe same area were considered as the control group, the data analyzedin the period of time before the year 1987 i.e. before statinadministration to patients with heterozygous familialhypercholesterolemia and after the year 1987 when lovastatin wasreleased, the conclusion of the conducted analysis showed thatpatients treated with statin had lower chance of ischemic strokeincidence with odds ratio = 0.251 and p<0.01 in comparison to ahigher risk of stroke incidence for patients not treated with statinwith odds ratio = 7.658 and p<0.01, these results indicates thatafter statins were used the risk of cerebrovascular events wasreduced in patients with heterozygous familial hypercholesterolemiawhich furthermore confirms the beneficial relation between statin useand lower incidence of stroke (6).
Thereare other therapeutic lipid lowering drugs available for use forpatients with high blood LDL such as fibrates, omega-3 fatty acidsand bile acid sequestrants (resins), yet their effect on improvingcerebrovascular events when used has not yet been proven, statinsremain the first line therapy for patients with high blood LDL (7).
It isnow clearly evident based on numerous clinical trials, randomizeddouble blind clinical trials, meta-analysis of epidemiological dataand subgroup analysis of data pertaining to patients suffering fromhypercholesterolemia that before the era of statin use patients withhigh blood LDL level had high risk of incidence of cerebrovascularevents with higher death rate, meta-analysis of patients data aftergeneralization of statin therapy to patients with high blood LDLlevel showed the clear benefit of lower risk of cerebrovascularevents and decreased neurological deficit at presentation of strokelower mortality when statin therapy is administered prior to ischemicbrain events.
High LDL blood plasma level is acondition where there is increased risk of heart disease andcerebrovascular events this increase in LDL blood plasma level couldbe a result of familial hypercholesterolemia or systemic disease or adiet high in content with cholesterol, this condition is one of themost important risk factor for cerebrovascular events mostimportantly ischemic stroke, before the launching of lipid loweringdrugs the incidence of stroke due to uncontrolled high cholesterollevel was high, after the start of statin use it has been proven thatthere is a strong association between statin therapy as a first linetreatment for hypercholesterolemia and a lower incidence of stroke,reduced neurologic deficit after, lower death rate and possibleprimary prevention of ischemic stroke, this study aims atinvestigating the following objective:
To determine if statins lipid lowering agents can be administered as preventive therapy for stroke in patients diagnosed with hypercholesterolemia for prevention of ischemic stroke.
To determine the adverse effects of administration of statins to the hypercholesterolemic patients and how to handle such cases
To identify the mechanism of action of statins in preventing ischemic stroke
METHODS(research-based)/PUBLISHED STUDIES (lit-based)
Asmentioned above, the major objective of this research was todetermine if statins lipid lowering agents can be administered aspreventive therapy for stroke in patients diagnosed withhypercholesterolemia for prevention of ischemic stroke (8).
Theother objective was to determine how the magnitude of LDL reductionand extent of reduction in carotid artery thickness reduces ischemicstroke occurrence and to what level.
Astep by step review of the randomized control tests on statins lipidlowering drugs and thorough analysis on previously published works(9). This was performed with the aid of medical research database,that is, PubMed. In this search, Pravastatin, Lovastatin,Atorvastatin, Fluvastatin, Cerivastatin, Simvastatin, HMGCoAreductaseinhibitor, lipid lowering drugs and statins were majorly used in theguided search (10).
Forthe articles found that were related to this study, their referencelists proved to be essential in gathering more information. Thetrials identified were also used for the research.
Patientswere randomly assigned to a specific drug in the statin class andtrials were included. Events related to stroke and cerebral ischemiawere recorded and a report was generated from the results obtainedfrom the practice (11). The trials were approved for the purpose ofstudies after tests were done by relevant authorities.Ifcontradicting results were obtained in the study, the owner of thearticle bearing the information was contacted through their email(12). Those preexisting studies that lacked proper evidenceaccompanying their works were excluded from the list (13).
Theeffects of statin therapy on the incidence of ischemia induced strokewere summarized (14). This summary was based on all kinds of strokes,including fatal cases. Odds ratios were used in this case. Crossproduct of cell count was put alongside the sum of reciprocal cellcount in a 2 by 2 table (15). The same method was used to study theeffects of statin on the incidence of strike, precisely hemorrhagicstroke. A funnel plot was also used to assess the evidence of bias.
Blindingwas used whereby subjects and researchers could not know thefinancers, the assignment of the research as well as the authors.Data was then extracted from the subjects by reviewers (two) using adata extraction form for each. These had to be cross checked by afinal reviewer so that errors made can be rectified before reaching afinal stage (12).Foreasy understanding of the data obtained, categories were made such astreatment data, patient data, clinical outcomes and study data (13).This method ensured data validity and appropriateness were upheld byawarding points from 1 to 5 to enable readers and future researchersidentify the data that they can rely on more (14). Most of thearticles that were used for this research scored a validity point of3. This is average and reliable.Patientscould be understood better after mentioning more about their pastmedical history and biodata (15). Those suffering from myocardialinfarction, diabetes mellitus, angina pectoris, dyslipidemia andsmokers could be assessed for complications or even drug to druginteractions in case they use some (16).Lossto follow-up is unpredictable. Due to that, this had to be documented(17). Those that were not easily understood by researchers were alsoput in a special category that analysts would understand better.RESULTS
Only26 trials of statin satisfied the criteria used for selection. 1large statin trial was used with the randomized control trials.Generalizing strokes, their summary effects were significant.Heterogeneity was not evident between the trials. Sensitivity andspecificity did not change effectively in this finding (18). The oddsratio for stroke incidence was found to reduce by a greatsignificance as well.
Mortalitydue to stroke was another factor. Fatal and non-fatal stroke couldnot be easily documented since the major trials involved in thisdifferentiation were not used. These can be found in ASCOT-LLA,Post-CABG and AFCAPS/TexCAPS (19). From the trials used, eight ofthem had zero fatality and they were not given much emphasis in theanalysis of data obtained.
Hemorrhagicstroke association was observed in 12 trials. Randomized patients inthis procedure were 49 843 (19). 8 trials were used whereas fourother trials were not used in the analysis section. In the controlgroup, 84 patients experienced hemorrhagic shock whereas 78 patientsexperienced the same in the statin group. This result was the samewhen KLIS was included and when it was withdrawn (20).
Forthe precise effects of statins on development of stroke or conditionsthat cause it, the duration and regimen brings about the difference.This is attributed to dosage, chemical structure and the main reasonthat prompted the administration of the drug (21).
Studieson statins have now been carried out in a number of regions to showtheir therapeutic effects, adverse effects, contraindications, druginteractions and associations with other health conditions (22). Someeffects are desirable whereas others are not. It has been found thatthey reduce the incidence of all strokes without causing hemorrhageor hemostasis in the brain (20). However, death that arises due tostroke cannot be reduced by this lipid powering drug.
Incases of hypertension, hypercholesterolemia, diabetes, previous,stroke, elderly, normocholesterolemia and coronary heart disease theincidence of stroke is significantly reduced (23). This is attributedto the vascular events that follow the administration of these drugs(24). The vascular events are revascularization, main coronary eventsand stroke.
Therewas no increase in hemorrhagic stroke. More studies showed that thereis a positive association of high cholesterol levels with hemorrhagicstroke incidence (25). Magnetic Resonance Imaging (MRI) showed thatLDL levels in the brain were lower in patients who are under thesedrugs leading to micro-bleeding. There is also a higher associationwith weight loss, chronic illnesses and handicap (14). These can alsobe due to hemorrhagic stroke.
Statinsare also able to reduce blood pressure up to 5mmHg and this directlyreduces the incidence of stroke by approximately 27%. However, otherstudies show that there is no change to diastolic and systolicpressure from the beginning of drug trial to the end (26). This islikely to suggest that the change is only in the peripheral parts ofthe cardiovascular system (27). This prompts more research onhypertensives to see the trend in reducing incidences of stroke.
Statinsalso have anti-inflammatory effects by binding to importantbiological markers and also inhibiting the function ofchemoattractants that induce inflammation. This, therefore, inhibitthe instability of plaques and development of atherosclerosis (28).
Theyreduce media and intima thickness. It also reduces the presence ofLDL cholesterol from the surface of blood vessels giving no room forattachment of other materials that can lead to reduction in lumensize (18). Statins have pleiotropic effects but the main one is LDLreduction.
Theresults of this study had potential bias and this was establishedduring meta-analyses. The drawbacks are that the sources weresecondary, they were also not from individual research but on anumber of researches (29). Some authors did not attach informationthat would have been relatively vital to aid the research. One of thestudies with limited accompanying documentations is hemorrhagicstroke incidence in subgroups – based on age, LDL levels and gender(30). Cerebral ischemia as well as ischemic stroke was not given muchweight in the previous research documents. Its subtypes such asatherothrombotic and cryptogenetic strokes were not mentioned at all.
The following categorizationswere excluded from the study
Patients in which statins are prescribed to at discharge
Patients who have very low LDL cholesterol levels at the onset of the study, levels less than 100 mg/dl
Reason for which Statins were prescribed to the patient
Patients using statins as second line treatment
What activity of HMGCoAreductase inhibitors make them selective for blood vessels laden with cholesterol?
What expectations have we for abstraction of measures?
Who are the most ideal patients for the study?
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