Biological Science For Practice

Biological Science For Practice


Question:
Discuss about the Biological Science For Practice.

Answer:

Introduction

In New Zealand stroke accounts as the third leading cause of death, about two thousand five hundred people die every year, ninety percent of it occurs in people over 65. On a daily basis twenty-four, New Zealanders have a stroke. Stroke is a medical emergency. However, it is been identifies that in New Zealand majority of stroke sufferers due to various different reason are not able to take the benefit of clinical facilities available to control stroke (Stroke Foundation of New Zealand, 2016). Worldwide stroke causes 5.5 million deaths and forty-nine million disabilities (WHO, 2004).
Over the last decade, despite the advancement in understanding stroke condition and consequences, still the disease continues to rank as a major cause of mortality and morbidity worldwide. However, large clinical trials in hypertension, carotid disease, atrial fibrillation (AF), and antithrombotic and antiplatelet therapies have adequately demonstrated the efficacy of these targeted interventions in reducing stroke incidence (Furie, & Kelly, 2004). 
Among elderly Non-rheumatic arterial fibrillation (AF) possesses an accelerated stroke risk. The non-rheumatic AF consequences usually increase with increasing age. The men possess a 0.04% per year, AF increasing risk rate whereas the risk rate is lower in women compared to men (Ezekowitz et al., 1992).
The occurence of AF in the body is considered to be free risk factor for thromboembolism and stroke. There is International Normalised Ratio (INR) range established between 2.0-3.0 to develop stroke protection in AF sufferers. The target established is to achieve 2.5 INR for AF patient protecting them from stroke risk. There are literature and researches that support the use of warfarin medication to minimise the ischemic stroke risk in AF condition. In comparison to placebo and aspirin, the use of warfarin is highly recommended to manage stroke condition due to 2/3 more functionality than placebo and 30-40% more efficiency than aspirin (Yap & Camm, 2010). 
This study involves a discussion on pathophysiology of AF relating to stroke followed by evidence supporting the effectiveness of warfarin to control stroke in critical conditions of AF. These evidence are three randomised clinical trials (RCT) studies that are described in details in the assignment.

Pathophysiology

Human brain being the complex structure in the body is tough to understand in medical science itself. It is composed of 100 billion nerve cells, called neurons which in turn connects to thousands of other brain cells. Different functions are controlled by different areas of our brains (Brass, 1992).
Brass (1992) says that there is a requirement of continuous oxygen, blood and nutrition (glucose) supply for the brain nerve cells to function properly. Lewis et.al 2014, also explains that in blood flow at 750 to 1000 mL/min nor is 55ml/100g vital. Otherwise, without these, the brain’s function will be impaired which will lead to brain cells death. However, the cardiac arrest event requires thirty seconds in altering neurologic metabolism, metabolism stops within two minutes, and cellular death can happen within five minutes. (Lewis, et.al., 2014). Therefore, cardiac arrest even form of Stroke is considered to be very dangerous as the brain is dependent on continuous blood flow (Brass, 1992).
Stroke is also known as brain attack or cerebrovascular accident (CVA). There are numbers of modifiable risk factors for stroke. However, the greatest are hypertension, heart disease such as atrial fibrillation (AF) which is claimed to be accountable for 20% of all strokes, and diabetes mellitus. Further, some of the other minor risk factors are smoking, alcoholism, lacking physical movements, imbalanced diet, metabolic syndrome, drug abuse, obesity and sleep apnea (Lewis, et.al., 2014). According to Zamani & Verdino, 2015, Non -modifiable risk factors include mostly males, it affects mostly Caucasian compared to African Americans.

Ischaemic and Haemorrhagic Stroke are two major categories of stroke. Further, Ischaemic stroke has two further subclasses namely thrombotic stroke; wherein blood clots are trapped and formed in a narrowed blood vessel, and embolic strokes wherein an embolus or blood clot and other debris build up blocking the lumen of a blood vessel both these ischaemic stroke types lead to decreased oxygen supply to the brain of the human body (Lewis et.al,.2014) Atherosclerosis develops when plaque is deposited in the inner lining of an artery, making it narrowed. The different combinations of cholesterol, calcium, fats, fibrin and waste products in the body leads to the development of this plaque condition (Brass, 1992).
The embolic stroke being most severe and serious category of stroke occur due to the formation of cardiac emboli. These cardiac emboli take birth from cardiac chambers being huge in size cause critical metabolic stroke in the body (Brass, 1992). An embolic stroke is symptom-free after discharge from the hospital, it can reoccur anytime, and lastly it has a high mortality rate (Arboixa & Alio, 2010). Lewis, et.al. claims that the severity of the loss of function in stroke depends on the area where the stroke happens and the extent of brain damage. (2014).
Atrial fibrillation (AF) is considered to be one of the most common types of dysrhythmia (Lewis, et.al., 2014). It is one of the common cardiac conditions directly related with emboli. (Brass, 1992). Some of the major risk factors or conditions initiating artrial fibrillation are hypertension, thyrotoxicosis, diabetes, rheumatic heart disease and coronary artery disease (Cardiac arrhythmias, 2013).
Further, Lewis et.al., 2014, indicated that atrial electrical activity disorganisation leads to AF where multiple ectopic foci result in failure of atrial contraction activity. This leads to increase in the atrial rate of 350 to 600 beats/minute. Furthermore, AF leads to minimization of cardiac output due to quick ventricular response and/or improper atrial contraction. The atrial thrombi form due to blood stasis that can grow and locomote towards brain region initiating stroke (p.796) During AF, the heartbeat signals are initiated from sinus node as well as in different atrial locations (Cardiac arrhythmias, 2013).
The stasis is linked to conditions like increased amount of D-dimer, fibrinogen and Willebrand factor. This statis are commonly prominent in left atrial appendage indicating a prothrombotic state initiation. Further, in response, the cerebral embolization rate gets accelerated leading to thrombus formation. Therefore, the size of left atrial and left ventricular dysfunction are independent echocardiographic indicators for forming thromboembolism in later stages (Arboixa & Alio, 2010). 
Among the other goals in treating AF, prevention of a stroke is one of them. Lewis, et.al. 2014, mentioned that long-term anticoagulation therapy is required if drugs or cardioversion does not work. Warfarin is the drug of choice and continuous monitoring of the internationalised standard ratio (INR) therapeutic levels is a prerequisite. (p. 797) The National Health Committee further states that the patient having a complicate risk of stroke are recommended with oral anticoagulant therapy considered as the best treatment for stroke occurring in AF condition. In this therapy, the thinning of blood is initiated by anticoagulant to minimise the blood clot formation leading to depression in stroke risk conditions (2015).
The medicine warfarin works as an anticoagulant by hindering the pathway of coagulation factors, II, VII, IX and X. The warfarin leads to carboxylation (vitamin-K mediated) of these coagulating factors that lead to the defect in the phospholipid binding properties of these coagulation factors (Moore, Thomson & Harrington, 2012). The heart foundation adds that there is a delicate balance in deciding between reducing blood clot and warfarin. (2015) 

Case Presentation

Peterson et al. 1989 performed a placebo- controlled randomised research comparing the effects of aspirin, warfarin and placebo on non-rheumatic AF patients. The participants were patients suffering AF that were collected as per physician instructions from two outpatient electrocardiography (ECG) laboratories. The research participants were 1007 AF patient (ECG verified) with age 18 and above. The resultant measures were determined for death complications and thromboembolic formation in the patient body. The research occurred for 2 years where 336 participants were provided with aspirin 75mg/per day and 335 participants received warfarin openly in a double-blind study.
The participant’s clinical check-up was performed every three months in first six months followed by one check-up half yearly. The participants were analysed to detect their thromboembolic complications and treatment side-effects. The results of research indicated that warfarin group of participants had a low level of thromboembolic complications that were just 5 from 335 participants (2% per year) developing complications whereas these complications were higher in aspirin group 20 out of 336 (5.5% per year) as well as placebo group 21 out of 336 participants (5.5% per year) detected with thromboembolic complication development. Further, the determining the death rate, the warfarin group persisted 3 deaths, aspirin group had 12 deaths and placebo group had 15 deaths.
Further, the side-effects development results indicated that 21 out of 335 in warfarin group developed bleeding complications, 2 out of 336 in aspirin group whereas no bleeding complications observed in the placebo group. The therapeutic range of warfarin group was within the INR values 4.2-2.8 in 42% treatments and 4.2-2.4 in 73% treatment time. However, the drawback of this research is open access to warfarin treatment provided to the participants. But, the overall findings and end points are clearly comparing the effects of all the three treatments for AF patients (Peterson et al., 1989). 
The theoretical perception in medical science indicating that cerebral infarction incidence for AF patients can be controlled using low-intensity anticoagulation’s was tested by Ezekowitz et al. in 1992 y performing a randomised, double-blind placebo-controlled trial experiment. The experiement trial was conducted in sixteen Department of Veterans Affairs Medical Centres. Subjects are mainly male veterans of any age, who had AF validated by two electrocardiograms and have a normal prothrombin time ratio. There are 525 participants out of which 265 were provided placebo treatment and left 260 provided with warfarin.  Outcome measures are determined by cerebral infarction, cerebral haemorrhage and death. There were two study teams at each centre.
With the aim to maintain prothrombin time ratio between 1.2-1.5 in warfarin group to match the INR range (1.4-2.8) participating group the medication determined was 2 mg sodium warfarin. There was a daily dose of 4mg warfarin provided for three years maintain the prothrombin time ratio that was determined on the monthly basis. Therefore, 1mg increments of warfarin were adjusted to maintain this time. In the findings, it was detected that 19 out of 265 participants in placebo group and 4 out of 260 participants in warfarin group lack historical conditions of cerebral infarction and stroke. Further, it was observed that warfarin treatment lead to risk reduction of 0.79 as per 95% confidence interval, 0.52 to 0.90 and p-value of 0.001. The 70 years and above participants of both the groups showed yearly event rate of 0.9% in warfarin group and 4.8% in placebo group.
In the participants, there was only single cerebral haemorrhage among warfarin participants whereas gastrointestinal haemorrhage were observed to be 4 in the placebo group (event rate 0.9%) and 6 in warfarin group yearly (event rate 1.3%). Further, analysing the mortality rate, there were 15 deaths in warfarin group and 22 in placebo group. Further, the occurrence of cerebral infarction was found to be existing in participants persiting cerebral infarction history that were 9.3% in placebo group and 6.1% in warfarin group each year. Lastly, this study clearly supports the utilisation of warfarin as low-intensity anticoagulation to provide protection from non-rheumatic AF and cerebral infarction supporting the theoretical perceptions in medical science where low-intensity anticoagulants are considered better treatment options for AF Ezekowitz et al. (1992). 
For determining the effectiveness of low-dose warfarin as a treatment option for primary stroke condition of AF patient the BAATAF performed a randomised unblinded control trial experiment. In this research 420 participants were the AF sufferers that were divided into two groups, one group was warfarin group having 212 patients and another was control group having 208 patients. The participants were adults with an average age of 68 years having intermittent or sustained chronic AF condition with no mitral stenosis as per their 2D echocardiographic outcomes. The research monitoring period was 2.2 years. There was 80% detection power, stroke reduction rate of 5 per 100 participants yearly and 0.05 2 sided p-value provided to study as per the initial sample size. Further, the warfarin group had the prothrombin time within its target range of 83% of the time. The warfarin group was provided with a weekly dose of 29.7mg. The primary outcome measures were systemic emboli, ischemic stroke, minor and major bleeding condition as well as death. The findings of research indicated that there were 2 stroke (0.4% per year) incidences in warfarin group with 13 strokes (2.99% per year) in the control group. The warfarin group showed 86% reduction in stroke incidence risk ratio of 0.14, 95% confidence interval, 0.04 to 0.49 and p-value 0.002. however, there were 37 deaths in warfarin group but these were lower than the control group (death rate bring 2.25% in warfarin group and 5.97% in control group). Further, bleeding incidences were equal in both the groups and fatal haemorrhage was single in each group. The minor haemorrhage were 38 in warfarin group compared to only 21 in the control group.
Lastly, this study convincingly support that warfarin in low dose works to minimise the stroke risk in elderly AF sufferers. Further, the double-blinding elimination from the experiment was not a limitation factor because the assessment of end points was in central blind fashion (The Boston area anticoagulation trial for atrial fibrillation investigators, 1990).
STUDY
SAMPLE
AIM/INTERVENTION
RESULTS
COMMENTS
The Copenhagen AFASAK Study
(Petersen et al., 1989)

DENMARK

CONTROLLED, RANDOMISED TRIAL (PLACEBO)
Randomised, open (warfarin), double-blind Aspirin (ASA) placebo-controlled study
The study occurred from 1stNovember 1985 to 7th June 1988




Participants:
1007 AF patients 18 years and above
These participants were recruited for research from two ECG laboratories as per the guidance and instruction of general practitioners in those laboratories.
Inclusion Criteria:
·         AF having ECG verification

Exclusion Criteria:

·         Historical anticoagulation treatment for AF obtained for more than 6 months by the participant
·         Any incidence of cerebrovascular events in recent few months
·         Contraindications for any therapy like warfarin, aspirin etc.
·         Pregnancy expectations or breastfeeding
·         BP level above 180/100 mm Hg
·         Any Psychiatric illnesses, including depression, alcoholism etc.
·         Any historical event of cardiac surgery having sinus rhythm, valve replacement and rheumatic heart illness.
·         Patient unwillingness to participate in study  

AIM:

Perform a comparative analysis for the effectiveness of anticoagulation by warfarin, aspirin and placebo therapy on non-rheumatic AF patients by determining thromboembolic complications and other side-effects.
OUTCOME MEASURE:

·         Thromboembolic complication

·         Death

INTERVENTION:

Computer-generated randomization
·         Active treatment for 336 patients using ASA 75 mg/daily
·         Control treatment with standard dose of warfarin as per INR range for 335 patients and placebo therapy for 336 patients
The study was accordingly to the second Declaration of Helsinki principles.


The occurrence of vascular mortality and thromboembolic complications were found less in warfarin group when compared to aspirin and placebo group outcomes.
The bleeding was observed more in warfarin group compared to other two groups. It was 20 out of 336 in the aspirin group and 21 out of 336 in the placebo group.

The stroke relative risk reduction was 71% when comparing warfarin and placebo outcomes.

The death were 3 (0.9%) in the warfarin group, 12 (3.6%) in aspirin and 15 (4.5%) in the placebo group.


The study limitation was openly provided warfarin treatment that can lead to research defects and complications
STUDY
SAMPLE
AIM/INTERVENTION
RESULTS
COMMENT
Stroke Prevention N Non-Rheumatic Atrial Fibrillation

SPINAF STUDY

USA

Ezekowitz et al. (1992)

Role of Warfarin to control Stroke related to Nonrheumatic AF

Randomised, double-blind, placebo-controlled phase III trial
·         Conducted in 16 Department of Veterans Affairs medical centres.


Number of Participants

There were 525 AF patients recruited for research where 260 were entered in warfarin group and 265 in the placebo group. It was specified that baseline features of all the patients are similar and suitable for research
Inclusion Criteria:

·         The participants were male patients of non-specified age having AF documented by 2D electrocardiograms that are minimum 4 weeks apart.
·         The baseline prothrombin time ratio had to be within the INR normal range

Exclusion Criteria:

·         Intermittent AF
·         Definite indication of anticoagulant or antiplatelet
·         Contraindication for anticoagulant
·         Coexisting Medical Condition
·         Planned Surgery
·         Uncontrollable Hypertension
·         Inappropriate for the study: administrative criteria
·         The use of nonsteroidal anti-inflammatory agents or aspirin was not allowed in research


AIM:

The research purpose is to prove that theoretical perception that low-intensity anticoagulants work to minimise or control the cerebral infarction incidence for patient suffering non-rheumatic AF.

Outcome Measure:
Cerebral infarction, death and cerebral haemorrhage

Intervention:

Active treatment: Warfarin in low dose (INR 1.2–1.5) (for 260 participants with no historical infarction; n=21 with the previous stroke)
Control treatment: placebo (n=265 with no history of infarction; n=25 with previous stroke)

The clinical conditions of the patients were observed for three years fo study period continuously until study termination point.

The participants having no history of cerebral clinical conditions like stroke and cerebral infarction were only 19 out of 265 in placebo group and 4 out of 260 in the warfarin group.
The risk reduction outcomes in warfarin group were 0.79 as per statistical data of 95% confidence interval, p-value of 0.001, 0.52 to 0.90. further, the annual event rate was 4.8% in 70 years and above patients in the placebo group and 0.9% in the warfarin group.
There was only a single incidence of cerebral haemorrhage that was observed in warfarin group.
Further, gastrointestinal haemorrhage were total 10, 6 in the warfarin group (rate 1.3/year) and 4 in the placebo group (rate 09%/year).
The total death incidence were 37 where 22 occuring in placebo group and 15 in the warfarin group.
Cerebral infarction was occurring commonly in the patient having a history of cerebral infarction incidence whereas no such incidence was observed in the paitent having no such historical events in life.

 

As per research findings, it is clear that low-intensity anticoagulants like warfarin are effective for elder patient controlling cerebral infraction in AF sufferers with any noticeable side-effect and risk.
STUDY
SAMPLE
AIM/INTERVENTION
RESULTS
COMMENT
The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators

Low-Dose Warfarin impacts on the stroke risk in AF patients

Randomized, unblinded, controlled phase III study




Number of participants

The participants were 420 patients suffering either chronic, sustained or intermittent non-valvular AF illness. There were 212 patient designated as warfarin group and 208 as control group
Inclusion Criteria:

·         Adults belonging to sustained or intermediate AF chronic condition having no mitral stenosis detection on 2D echocardiography

·         There was compulsory requirement to provide documentation proof for atrial fibrillation in form of two electrocardiogram where the patient with intermittent AF should have ECG documentation with last 18 months.

Exclusion Criteria

·         Patients with transient atrial fibrillation in duration of acute disease condition

·         Other cardiac or neurological reasons

·         Contraindication for anticoagulation

AIM:
The purpose is to determine the effectiveness of warfarin (low-dose) in preventing primary stroke for AF patients
Outcome Measure:
Ischemic stroke, systemic emboli, major and minor bleeding, death

Intervention:

Active treatment: low-dose warfarin (target range for the prothrombin-time ratio: 1.2–1.5 time the control; estimated INR equivalent 1.5–2.7) (n=212)
Control treatment: no treatment (n=208); ASA allowed, but not in the warfarin group
·         The research continued from september 1985 to June 1989 with an average fo 4.1 years.

There were 0.41% stroke incidence rate in warfarin group with 2 strokes per year whereas control group confronted 13 strokes with 2.98% stroke incidence rate per year.
There was 0.14 control incidence rate in warfarin group with statistical data of 95% confidence, p value 0.0022.
The death rate was observed to be very less in warfarin group that is 2.25% compared to control group that was 5.97% with allover 37 death in complete participants
Only one fatal haemorrhage observed in either of the groups with bleeding events and critical clinical conditions in both the groups
The minor haemorrhage was more in warfarin group than the control group
As per this research warfarin even in the low-doses is highly workable and effective to control or minimise the risk of primary stroke in AF patients considered and proven to be safe and effective treatment.


Discussion

The result of these trials has resolved many questions regarding antithrombotic and antiplatelet therapy in individuals with AF by testing in different ways. Each study provided vital information regarding the utilisation of warfarin in decreasing stroke risk for AF patients. These research trials worked as robust proof that warfarin medication is more effective when compared to placebo medication in preventing stroke, and the stroke incidence prevented by warfarin is far more than bleeding incidence occurring due to the intake of warfarin. They also show that aspirin should be saved for those who are not able to take warfarin safely.
Altogether the RCTs gave sufficient details on their subjects and excluded subjects as well as the randomization process. Outcome measures were either thrombolytic complications or death. Subjects were aged 18 and above. SPINAF study concentrated on males as subjects while the rests were mixed men and females. All can be categorized as primary prevention trials. The three RCTs entirely presented general bleeding especially with those receiving warfarin. The positive effect of warfarin in preventing stroke is strongly demonstrated in respect to types of trial used.
SPINAF and BAATAF have similar aims of their study which is to use low dose anticoagulation to minimise the incidence of stroke condition in non-rheumatic AF patients. In contrast, AFASAK’s research purpose was to compare the potential of anticoagulation effect between warfarin; aspirin (75mg); and placebo in the patients suffering thromboembolic complications with chronic non-rheumatic AF. On the other hand, BAATAF was not specifically designed to evaluate the role of aspirin. Also, BAATAF and AFASAK studies were not blinded compared to that of SPINAF. In the study conducted by AFASAK individuals with intermittent AF were excluded and aspirin proved as wrokable for AF subgroups having low stroke risk, although no evidential support was provided for this statement. Among the three studies, only AFASAK research mentioned warfarin group detected with minor haemorrhage that was not or rarely observed in placebo and aspirin groups.
The benefits of warfarin as treatment received in patients with AF outweighs its risk i.e. bleeding, for as long as the dosage is based on the individuals INR results that are monitored on month basis relating to lower risk of bleeding incidence. The use of oral anticoagulation warfarin is determined as per the potential of the paitent, tolerance level, proper INR monitoring and minimum observance of bleeding incidence. Patients with increased risk of alcoholism, gastrointentinal bleeding and renal malfunction should consider warfarin treatment option in atrial fibrillation condition.

References

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