ETIOLOGIC AND PATHOGENETIC PRINCIPLES

ETIOLOGIC AND PATHOGENETIC PRINCIPLES

OF PRIMARY AND SECONDARY PREVENTION OF INTERNAL MEDICINE

Preventive medicine or preventive care consists of measures taken to prevent diseases, rather than curing them or treating their symptoms. This contrasts in method with curative and palliative medicine, and in scope with public health methods (which work at the level of population health rather than individual health). Occupational medicine operates very often within the preventive medicine.

Preventive medicine strategies are typically described as taking place at the primary, secondary, tertiary and quaternary prevention levels. In addition, the term primal prevention has been used to describe all measures taken to ensure fetal well-being and prevent any long-term health consequences from gestational history and/or disease. The rationale for such efforts is the evidence demonstrating the link between fetal well-being, or “primal health,” and adult health. Primal prevention strategies typically focus on providing future parents with: education regarding the consequences of epigenetic influences on their child, sufficient leave time for both parents, and financial support if required. This includes parenting in infancy as well.

 

 

 

 

 

 

Preventive medicine or preventive care refers to measures taken to prevent illness or injury, rather than curing them. It can be contrasted not only with curative medicine, but also with public health methods (which work at the level of population health rather than individual health). This takes place at primary, secondary and tertiary prevention levels.

1.     Primary prevention avoids the development of a disease. Most population-based health promotion activities are primary preventive measures.

2.     Secondary prevention activities are aimed at early disease detection, thereby increasing opportunities for interventions to prevent progression of the disease and emergence of symptoms.

3.     Tertiary prevention reduces the negative impact of an already established disease by restoring function and reducing disease-related complications.

Simple examples of preventive medicine include hand washing and immunizations. Preventive care may include examinations and screening tests tailored to an individual’s age, health, and family history. For example, a person with a family history of certain cancers or other diseases would begin screening at an earlier age and/or more frequently than those with no family history. On the other side of preventive medicine, some non-profit organizations apply epidemiological research towards finding ways to prevent diseases.

Gordon (1987) in the area of disease prevention, and later Kumpfer and Baxley (1997) in the area of substance use proposed a three-tiered preventive intervention classification system: universal, selective, and indicated prevention. Amongst others, this typology has gained favour and is used by the U.S. Institute of Medicine, the NIDA and the European Monitoring Centre for Drugs and Drug Addiction.

1.     Universal prevention addresses the entire population (national, local community, school, district) and aim to prevent or delay the abuse of alcohol, tobacco, and other drugs. All individuals, without screening, are provided with information and skills necessary to prevent the problem.

2.     Selective prevention focuses on groups whose risk of developing problems of alcohol abuse or dependence is above average. The subgroups may be distinguished by characteristics such as age, gender, family history, or economic status. For example, drug campaigns in recreational settings.

3.     Indicated prevention involves a screening process, and aims to identify individuals who exhibit early signs of substance abuse and other problem behaviours. Identifiers may include falling grades among students, known problem consumption or conduct disorders, alienation from parents, school, and positive peer groups etc.

Outside the scope of this three-tier model is environmental prevention. Environmental prevention approaches are typically managed at the regulatory or community level, and focus on interventions to deter drug consumption. Prohibition and bans (e.g. smoking workplace bans, alcohol advertising bans) may be viewed as the ultimate environmental restriction. However, in practice environmental preventions programmes embrace various initiatives at the macro and micro level, from government monopolies for alcohol sales, through roadside sobriety or drug tests, worker/pupil/student drug testing, increased policing in sensitive settings (near schools, at rock festivals), and legislative guidelines aimed at precipitating punishments (warnings, penalties, fines).

Thus, preventive medicine focuses on disease prevention and health promotion through identifying and reducing risk factors for development or transmission of disease. Primary prevention – prevent initial development of disease, secondary – detect early existing disease, tertiary – reduce complications of existing disease.

Leading causes of preventable deaths in the United States in the year 2000.

 

High Cholesterol Symptoms

There are no warning signs for high LDL cholesterol levels. When symptoms finally occur, they usually take the form of angina or heart attack in response to the buildup of atherosclerotic plaque in the patient’s arteries. This is definitely a condition where it pays to invest in preventive medicine before dangerous complications occur.

Atherosclerosis is a disease of the arteries in which fatty material is deposited in the vessel wall, resulting iarrowing and eventual impairment of blood flow. Severely restricted blood flow in the arteries to the heart muscle leads to symptoms such as chest pain. Atherosclerosis shows no symptoms until a complication occurs.

 

 

 

 

 

Physical activity contributes to health by reducing the heart rate, decreasing the risk for cardiovascular disease, and reducing the amount of bone loss that is associated with age and osteoporosis. Physical activity also helps the body use calories more efficiently, thereby helping in weight loss and maintenance. It can increase basal metabolic rate, reduces appetite, and helps in the reduction of body fat.

Proper diet and nutrition act as preventive medicine

 

Nutrition is the provision, to cells and organisms, of the materials necessary, in the form of food to support life. Whereas preventive medicine is the part of medicine useful for preventing disease rather than curing it. Many common health problems can be prevented or alleviated with good nutrition.

Nutrients are the most essential things that may be required for keeping a body healthy. There are mainly six types of nutrients that may be required for keeping a person healthy, they are proteins, fats, carbohydrates, minerals, water and vitamins. Health of a person may become ill if in case the balance of the nutrients (may become excess or deficiency may be there) is disturbed and thus is becomes essential to keep the level of all the six nutrients intact. As the all the nutrients are involved in cell to cell signaling excess or deficiency of these nutrients may affect the hormonal functioning in a person.

According to report by WHO, “Nutrition is an input to and foundation for health and development. Interaction of infection and malnutrition is well-documented. Better nutrition means stronger immune systems, less illness and better health. Better nutrition is a prime entry point to ending poverty and a milestone to achieving better quality of life.”

The relationship between diet and states of health and disease is the nutrition. According to most of the dietitians nutritional supplements are the fuel for a health body. Good nutrition is vital to good health, disease prevention, and essential for healthy growth and development of children and adolescents. These days, a wealth of nutrition information is at your finger tips. From diet books to newspaper articles, everyone seems to have an opinion about what you should be eating. It’s no secret that good nutrition plays an essential role in maintaining health. Diet can also play a major role in recovering from many diseases.

A simple example to quote: According to researchers, taking additional vitamin D every day may help to reduce or eliminate chronic pain due to arthritis, fibromyalgia, chronic fatigue, headaches and other types of pain.

 

 

Primary Prevention of Hypertension

Hypertension can be prevented by complementary application of strategies that target the general population and individuals and groups at higher risk for high blood pressure. Lifestyle interventions are more likely to be successful and the absolute reductions in risk of hypertension are likely to be greater when targeted in persons who are older and those who have a higher risk of developing hypertension compared with their counterparts who are younger or have a lower risk. However, prevention strategies applied early in life provide the greatest long-term potential for avoiding the precursors that lead to hypertension and elevated blood pressure levels and for reducing the overall burden of blood pressure related complications in the community.

Population-Based Strategy

A population-based approach aimed at achieving a downward shift in the distribution of blood pressure in the general population is an important component for any comprehensive plan to prevent hypertension. As shown in the Figure on the next page, a small decrement in the distribution of systolic blood pressure is likely to result in a substantial reduction in the burden of blood pressure-related illness.

In an analysis based on Framingham Heart Study experience, Cook et al. concluded that a 2 mmHg reduction in the population average of diastolic blood pressure for white U.S. residents 35 to 64 years of age would result in a 17 percent decrease in the prevalence of hypertension, a 14 percent reduction in the risk of stroke and transient ischemic attacks, and a 6 percent reduction in the risk of CHD.

Public health approaches, such as lowering sodium content or caloric density in the food supply, and providing attractive, safe, and convenient opportunities for exercise are ideal population-based approaches for reduction of average blood pressure in the community. Enhancing access to appropriate facilities (parks, walking trails, bike paths) and to effective behavior change models is a useful strategy for increasing physical activity in the general population.

 

INTENSIVE TARGETED STRATEGY

More intensive targeted approaches, aimed at achieving a greater reduction in blood pressure in those who are most likely to develop hypertension, complement the previously mentioned population- based strategies for prevention of hypertension. Groups at high risk for hypertension include those with a high-normal blood pressure, a family history of hypertension, African American (black) ancestry, overweight or obesity, a sedentary lifestyle, excess intake of dietary sodium and/or insufficient intake of potassium, and/or excess consumption of alcohol.

Contexts in which intensive targeted interventions can be conducted to prevent hypertension in African Americans and older Americans include not only health care settings but also senior centers and faith-based organizations that have blood pressure screening and referral programs.

WEIGHT LOSS

A comprehensive review of the evidence supporting the value of modest reductions in body weight is provided in the Clinical Guidelines for the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. He et al. reported on the experience of 181 normotensive persons who had participated in Phase I of the Trials of Hypertension Prevention.

During their initial 18 months of active intervention those assigned to the weight loss group reduced their body weight by 7.7 lb (3.5 kg) and their systolic and diastolic blood pressures by 5.8 and 3.2 mmHg, respectively. After 7 years of followup, the incidence of hypertension was 18.9 percent in the weight loss group and 40.5 percent in the control group. These findings suggest that weight loss interventions produce benefits that persist long after the cessation of the active intervention. In phase II of the Trials of Hypertension Prevention, the 595 participants assigned to a weight loss coun seling intervention experienced a 21 percent reductio in incidence compared with 596 counterparts assign to usual care.

Weight loss participants who were able to lose 9.7 lb (4.4 kg) or more and to sustain the weight loss through the 36 month period of followu experienced average reduction in systolic and diastol blood pressure of 5.0 and 7.0 mmHg, respectively.

DIETARY SODIUM REDUCTION

ln a meta-analysis of 12 randomized controlled trials conducted in 1,689 normotensive participants, Cutler and colleagues estimated that an average reduction of 77 mmol /d in dietary intake of sodium resulted in a 1.9 mmHg (95 percent confidence interval [CI], 1.2–2.6 mmHg) decrement in systolic blood pressure and a 1.1 mmHg (95 percent CI, 0.6–1.6 mmHg) decline in diastolic blood pressure.

In a randomized controlled trial (Dietary Approaches to Stop Hypertension [DASH]-Sodium Trial) conducted in 412 persons with an average systolic blood pressure of 120 to 159 mmHg and an average diastolic blood pressure of 80 to 95 mmHg, a reduction in sodium intake from a high level (mean urinary sodium excretion, 142 mmol/d) to an intermediate level (mean urinary sodium excretion, 107 mmol/d) reduced systolic blood pressure by 2.1 mmHg (P<.001) during consumption of a usual American control diet and by 1.3 mmHg (P=.03) during consumption of a DASH diet that was high in fruits and vegetables and lowfat dairy products.

Reducing sodium intake from the intermediate level to a lower level (mean urinary sodium excretion, 65 mmol/d) resulted in an additional reduction in systolic blood pressure of 4.6 mmHg during consumption of the control diet (P<.001) and 1.7 mmHg reduction during consumption of the DASH diet (P<.01). The effects of sodium reduction were greater for those who ate the typical American diet, compared with those on the DASH diet.

These findings are consistent with current national recommendations for a moderately low intake of dietary sodium (no more than 100 mmol /d: approximately <6 g of sodium chloride or <2.4 g of sodium per day) by all Americans and suggest that an even lower level of dietary sodium intake may result in a greater reduction in blood pressure. In a large, long-term community-based randomized controlled trial, Whelton et al. reported that a moderate reduction of dietary sodium intake resulted in an additional 4.3 mmHg reduction in systolic blood pressure among older persons with hypertension whose blood pressures were already well controlled by a single antihypertensive medication.

For those assigned to a combined sodium reduction and weight loss intervention, the corresponding additional reduction in systolic blood pressure was 5.5 mmHg. The need for antihypertensive medication during a subsequent 18 month period of followup was reduced by 31 percent and 53 percent in those assigned to sodium reduction and combined sodium reduction and weight loss, respectively. Although not directly relevant to prevention of hypertension, the results of this trial provideadditional evidence in support of the role of weight loss and moderate sodium reduction as means to reduce blood pressure, even for persons who have been taking antihypertensive medication. In the NHANES I Epidemiologic Follow-up Study, He et al. reported that a 100 mmol higher level of sodium intake in overweight persons was associated with a 32 percent increase in stroke incidence, a 89 percent increase in stroke mortality, a 44 percent increase in CHD mortality, a 61 percent increase in CVD mortality, and a 39 percent increase in mortality from all causes.

 

INCREASED PHYSICAL ACTIVITY

A meta-analysis by Whelton et al. in which the experience of 1,108 normotensive persons enrolled in 27 randomized controlled trials was included, identified a 4.04 mmHg (95 percent CI, 2.75–5.32) reduction in systolic blood pressure in those assigned to aerobic exercise compared with the control group. The magnitude of the intervention effect appears to be independent of the intensity of the exercise program. In the Physical Activity and Health: A Report of the Surgeon General it is recommended that persons exercise for at least 30 minutes on most, if not all, days of the week.

 

MODERATION OF ALCOHOL CONSUMPTION

In a meta-analysis of 15 randomized controlled trials, Xin et al. reported that decreased consumption of alcohol (the median reduction in self-reported consumption of alcohol was 76 percent, with a range from 16 percent to 100 percent) was associated with a reduction in blood pressure, and that the relationship between reduction in mean percentage of alcohol and decline in blood pressure was  dose-dependent.

Pooling of the experience of 269 normotensive participants enrolled in 6 randomized controlled trials identified a reduced consumption of alcohol as being associated with a 3.56 mmHg (95 percent CI, 2.51–4.61) lower level of systolic blood pressure and a 1.80 mmHg (95 percent CI, 0.58–3.03) lower level of diastolic blood pressure.

Therefore, it is recommended that alcohol consumption be limited to no more than 1 oz (30 mL) ethanol (e.g., 24 oz [720 mL] beer, 10 oz [300 mL] wine, or 2 oz [60 mL] 100-proof whiskey) per day in most men and to no more than 0.5 oz (15 mL) ethanol per day in women and lighter weight persons.

POTASSIUM SUPPLEMENTATION

Clinical trials and meta-analysis indicate that potassium supplementation lowers blood pressure in both hypertensive and normotensive persons. In a meta-analysis of the results from 12 trials with 1,049 normotensive participants, Whelton et al. reported that potassium supplementation (median, 75 mmol /d) lowered systolic blood pressure by 1.8 mmHg (95 percent CI, 0.6–2.9) and diastolic blood pressure by 1.0 mmHg (95 percent CI, 0.0–2.1).

The effects of potassium supplementation appeared greater in those with higher levels of sodium intake.

MODIFICATION OF WHOLE DIETS

The DASH and DASH-Sodium trials used dietary interventions that incorporated several nutritional recommendations for lowering blood pressure. In the 8 week DASH trial, study participants with a systolic blood pressure less than 160 mmHg and a diastolic blood pressure between 80 and 95 mmHg were randomly assigned to one of the following diet groups: (1) a control diet that was low in fruits, vegetables, and dairy products, with a fat content typical of the average diet in the United States, (2) a similar diet that was rich in fruits and vegetables, or (3) a DASH diet that was rich in fruits, vegetables and low-fat dairy products but reduced in saturated and total fat.

Among the 326 normotensive DASH participants (blood pressure <140/90 mmHg), the DASH diet reduced systolic blood pressure by 3.5 mmHg (P<.001). In a subsequent DASH-Sodium study, normotensive persons assigned to the DASH diet and a low level of urinary sodium excretion (67 mmol/d) reduced their systolic blood pressure by 7.1 mmHg (7.2 mmHg for blacks and 6.9 mmHg for others) compared with counterparts who were assigned to the control diet and a high level of urinary sodium excretion (141 mmol/d).

A significant reduction in diastolic blood pressure was also observed. Furthermore, the beneficial effects of the DASH diet and the DASH diet with reduced sodium occurred broadly in all major subgroups of the population.

 

Lifestyle Modifications for Primary Prevention of Hypertension

1. Engage in regular aerobic physical activity such as brisk walking (at least 30 minutes per day, most days of the week).

2. Maintaiormal body weight for adults (body mass index 18.5–24.9 kg/m² ).

3. Limit alcohol consumption to no more than 1 oz (30 mL) ethanol (e.g., 24 oz [720 mL] of beer, 10 oz [300 mL] of wine, or 2 oz [60 mL] 100-proof whiskey) per day in most men and to no more than 0.5 oz (15 mL) of ethanol per day in women and lighter weight persons.

4. Reduce dietary sodium intake to no more than 100 mmol per day (approximately 2.4 g of sodium or 6 g of sodium chloride).

5. Maintain adequate intake of dietary potassium (more than 90 mmol [3,500 mg] per day).

6. Consume a diet that is rich in fruits and vegetables and in lowfat dairy products with a reduced content of saturated and total fat (Dietary Approaches to Stop Hypertension [DASH] eating plan).

 

The third European guidelines on cardiovascular disease (CVD) prevention, launched at this year’s European Society of Cardiology (ESC) Congress, were influenced by the results of the second European Action on Secondary Prevention through Intervention to Reduce Events (EUROASPIRE II) survey, which was conducted in 15 European countries. EUROASPIRE was part of a major ESC initiative promulgated to update and replace the Framingham database with a data set that is based on current European population demographics. Examination of these new data revealed that the management of patients’ risk factors has not been effective in achieving the goals for CVD prevention set out in the joint European societies’ 1998 guidelines. As a result, the new guidelines differ in several major aspects from the previous ESC guidelines, which were largely based on data from the Framingham Heart Study.

The 2003 guidelines have abandoned the Framingham model and are based on this new, large European database of almost 3 million person-years of observation followed for almost 10 years with > 7000 fatal cardiovascular events as an endpoint. The guidelines are specifically intended to encourage the development of national guidance on cardiovascular disease prevention, acting as a framework that can be adapted to reflect different political, economic, social, and medical circumstances in the different regions of Europe.

The guidelines were prepared by Third Joint European Societies’ Task Force on Prevention of Cardiovascular Disease, chaired by Guy G De Backer, MD (Ghent University Hospital, Belgium). The task force was a partnership of 8 major societies:

·         European Society of Cardiology (ESC)

·         European Society of Atherosclerosis (EAS)

·         European Society of Hypertension (ESH)

·         European Society of General Practice/Family Medicine (ESGP/FM)

·         European Association for the Study of Diabetes (EASD)

·         European Heart Network (EHN)

·         International Society of Behavioural Medicine (ISBM)

·         International Diabetes Federation Europe (IDF-Europe)

plus representatives of the ESC Working Groups on Epidemiology and Prevention, Cardiac Rehabilitation & Exercise Physiology, and Cardiovascular Nursing. The guidelines are endorsed by the parent bodies.

A pocket version of the guidelines is also available in print. The full document will be published later this year in the European Journal of Cardiovascular Prevention & Rehabilitation as well as online.

The objectives of the guidelines are to reduce the incidence of first or recurrent clinical events due to coronary heart disease, ischemic stroke, and peripheral artery disease.

The focus is prevention of disability and early death. To this end, the guidelines address the role of lifestyle changes, the management of major cardiovascular risk factors, and the use of different prophylactic drug therapies.

New Aspects of the Guidelines

1.     The guidelines are concerned with the prevention of CVD rather than just coronary heart disease (CHD). The etiologies of myocardial infarction, ischemic stroke, and peripheral arterial disease are similar, and recent intervention trials have shown that several forms of therapy prevent not only coronary events and revascularizations, but also ischemic stroke and peripheral artery disease. Hence, initiation of specific preventive action is recommended based on estimation of risk of any vascular event.

2.     The risk assessment uses the Systemic COronary Risk Evaluation (SCORE) model and risk charts (see below), which can be adapted to different national conditions, resources, and priorities, and takes into account the heterogeneity in CVD mortality across European populations.

3.     Risk is defined in terms of the absolute 10-year probability of developing a fatal rather than any cardiovascular event.

4.     The threshold for high risk of a fatal cardiovascular event is now defined as ≥ 5% rather than ≥ 20% as previously.

5.     The first priorities in clinical practice are patients with established CVD, peripheral artery disease, or cerebrovascular lesions; asymptomatic individuals at high risk for developing atherosclerotic CVD; and close relatives of both groups.

6.     Updated recommendations are given regarding behavioral changes, risk factor management, and the prophylactic use of drugs. This includes a more professional management of behavioral risk factors, for which the goals remain similar: no smoking, making healthy food choices, and being physically active.

Patients With Established CVD and High-Risk Individuals

The guidelines recommend that in patients at potentially high risk of CVD, the risk of total CVD should be assessed by the SCORE system (see below). Goals in these patients and those with established CVD should be:

Lifestyle:

·         Do not smoke

·         Make healthy food choices

·         Be physically active

Risk factors:

·         Blood pressure

o    < 140/90 mm Hg in most

o    < 130/80 mm Hg in some

·         Total cholesterol

o    < 5/0 mmol/L (150 mg/dL) in most

o    < 4.5 mmol/L (175 mg/dL) in some

·         LDL cholesterol

o    < 3.0 mmol/L (115 mg/dL) in most

o    < 2.5 mmol/L (100 mg/dL) in some

·         Good glycemic control in all persons with diabetes

Prophylactic drug therapy should be considered in particular groups. These parameters have been summarized as a mnemonic for the practitioner as the “European heart health telephone number”: 14090530 which is parsed out as:

·         140 (mm Hg) SBP

·         90 (mm Hg) DBP

·         5 (mmol/L) total cholesterol

·         3 (mmol/L) LDL cholesterol

·         0 NO SMOKING

Systemic COronary Risk Evaluation — SCORE

A new European risk prediction system, SCORE , has been developed to define the lifestyle, risk factor, and therapeutic targets for CVD prevention. SCORE is representative of typical European populations, and the risk score system has been optimized for coronary prevention in European clinical practice. Describing the development of the SCORE chart,

Troels F Thomsen, MD, PhD (University Hospital Glostrup, Copenhagen, Denmark), noted the problems with the chart used in the previous ESC guidelines:

1.     The Framingham function overpredicts in European populations with low or medium levels of disease incidence.

2.     It was derived from a relatively small data set with few or no events in some risk factor combinations.

3.     It was impossible to combine > 5 variables.

4.     It used endpoints that could not be reproduced from other data sets and were therefore hard to validate.

5.     It probably underestimated the importance of diabetes.

The SCORE system differs from the European task force chart used in previous guidelines in important ways (Table). SCORE was developed using data from 12 European cohort studies (N = 205,178), some with multiple component cohorts, mainly population studies covering a wide geographic spread of countries at different levels of cardiovascular risk. The SCORE data come from one quarter million persons and contain some 3 million person-years of observation and more than 7000 fatal cardiovascular events. It addresses fatal events rather than total events, total cardiovascular risk rather than just CHD, charts for cholesterol and cholesterol:HDL ratio, and includes more detail for the 50- to 65-year age range. No charts are included for individuals with established disease or diabetes.

Table. ESC Task Force Chart (1998) Compared With the SCORE System (2003)

Task Force Chart	SCORE System
Based on 5000 American individuals	Based on > 200,000 Europeans
Predicts “coronary event”	Predicts CVD
Uses idiosyncratic definition	Uses common definition
Includes nonfatal events	Restricted to fatal events
Cannot be adjusted using national mortality data	Can be customized using national mortality statistics

Risk estimation is based on age, sex, smoking habits, systolic blood pressure (SBP), and either total cholesterol or cholesterol/HDL ratio.[7] Using the SCORE model, risk charts can be provided for all European countries. Total risk can be calculated from SCORE charts, such as those shown in Figures 1 and 2. The low-risk chart is for countries such as Belgium. France, Greece, Italy, Luxembourg, Portugal, Spain, and Switzerland. The high-risk chart is for use in all other European countries. Relative risk is calculated by comparing an individual’s risk category with that of a nonsmoking person of the same age and gender with blood pressure ≤ 140/90 mm Hg and total cholesterol < 5 mmol/L (< 190 mg/dL).

Figure 1. The new European Risk Chart based on SCORE data. For high CVD risk, regions are based on total cholesterol levels. Adapted from Conroy et al, Eur Heart J. 2003;24:987-1003. Copyright© 2003 European Society of Cardiology. All rights reserved.

Figure 2. The new European Risk Chart based on SCORE data. For low CVD risk, regions are based on total cholesterol levels. Adapted from Conroy et al, Eur Heart J. 2003,24:987-1003. Copyright © 2003 European Society of Cardiology. All rights reserved.

 

SCORECARD is the electronic counterpart to the SCORE risk chart, and will be launched in February 2004. It operates with the same risk factors, end points, colors, etc, but shows total risk as a bar chart and the distribution of modifiable risk factors as a pie chart. The expected effect of intervention is calculated from large randomized clinical trials in hypertension and hypercholesterolemia and is also shown in a bar chart. At the end of a consultation, the clinician may print an individual’s health advice based on their actual risk profile. This will be done in the national language, both on the screen and in print. The health promotion advice for the patient will be compiled from endorsed professional sources in each country. SCORECARD has been translated into 47 languages and calibrated to each country’s national mortality statistics. Clinicians will be able to download the nationally tailored version of the program from the ESC homepage

 

Prevention of chronic obstructive pulmonary diseases

 

Chronic obstructive pulmonary diseases (COPD) is a disease state characterized by airflow limitation that is not fully reversible (asthma is typically reversible)

• Airflow limitation is progressive and caused by a mixture of airway disease and parenchymal destruction. It is also associated with an abnormal pulmonary inflammatory response to noxious particles or gases

• Chronic inflammation causes remodeling and narrowing of small airways; lung elastic recoil decreases and expiratory small airways collapse

• Chronic cough and sputum production may or may not be present

• Progressive dyspnea is often present

• Management plan focuses on four main components: assess and monitor; reduce risk factors; manage stable COPD; and manage exacerbations

Incidence and prevalence:

• This disease tends to be significantly under-diagnosed; it is possible that only half of those with COPD are included in prevalence data

• Incidence: New diagnosis of COPD is more common in women, owing to diagnosis in aging women who have smoked since their teenage years

• Prevalence: 6% to 10% of the adult population and up to 50% of smokers have COPD

Demographics:

• Age: COPD prevalence increases with increasing age; number of smoking pack years exposure to cigarette smoke are critical

• Gender: In developed countries, men have been affected more than women, probably because of greater exposure to cigarette smoke in older men. This gap is narrowing. Recent studies of the U.S. population, however, show almost equal prevalence of COPD among men and women, owing to women’s smoking habits over the past 50 years

• Genetics: predisposition to α-1-antitrypsin deficiency

• Geography: There is no evidence of geographic influences; however, long-term exposure to air pollutants has been associated with COPD

• Socioeconomic status: There is no evidence that socioeconomic status is directly linked to COPD; however, people of low socioeconomic status are more likely to smoke cigarettes, are more likely to have low birthweight babies, and are more likely to be exposed to indoor pollutants from cooking and heating fuels, which can increase risk of COPD. More research is needed in this regard

Causes and risk factors

Common causes

• Causative factors for COPD can be separated into two categories: host factors and exposures. The disease state results from interactions between these factors

Host factors:

• Genetic predisposition

• Airway hyperresponsiveness

• Retarded lung growth (history of shortened gestational age, low birthweight, and factors during childhood)

Exposures (total burden of inhaled particles; exposures are additive):

• Tobacco smoke (cigarette smoking is the single most important risk factor for COPD)

• Occupational dusts and chemicals (vapors, irritants, and fumes)

• Environmental exposure to dusts, particles, and chemicals

Rare causes

• Hereditary deficiency of α-1-antitrypsin glycoprotein

Associated disorders

• Cor pulmonale and right heart failure may result from chronic pulmonary vasoconstriction caused by chronic hypoxemia and significantly increased right ventricular afterload

• Cardiac arrhythmias, such as atrial fibrillation, may be associated with COPD

• Other disorders related to smoking such as ischemic heart disease

• Anxiety and depression are common in patients with COPD

• Osteopenia and osteoporosis are prevalent in COPD patients

• Other comorbidities include bronchial carcinoma, sleep apnea, and heart failure

Screening

Summary approach

The routine use of spirometry in asymptomatic patients in primary care settings may potentially lead to unnecessary testing, increased costs and resource utilization, unnecessary disease labeling, and the harms of long-term treatment with no known preventive effect on avoiding future symptoms.

Population at risk

Symptomatic patients (eg, those with dyspnea, chronic cough) suspected of having COPD.

Screening modalities

The American College of Physicians, the American College of Chest Physicians, the American Thoracic Society, and the European Respiratory Society recommend the use of office spirometry by primary care providers as a screening tool in symptomatic patients only and as a means to monitor COPD patients.

Primary prevention

Summary approach

Smoking cessation and avoidance of occupation-related noxious inhalants are the primary effective measures in the prevention of COPD.

Population at risk

• Smokers

• Persons exposed to occupational or environmental particulates and gases

Preventive measures

• Smoking cessation is critical to future prevention of COPD. Exposure to second-hand smoke can also place people at risk for developing COPD

• It is important for patients to limit exposure to inhaled particles and gases, whether in the occupational setting or at home (fuels used for heating and cooking, air pollution)

• Patients with COPD should have the following vaccinations if no contraindications exist:

• Influenza yearly

• Pneumococcal vaccine every 5 years for all patients with a forced expiratory volume in 1 second (FEV₁) of less than 40% if the first dose is given before age 65 years

• People with family members with symptoms of significant COPD before age 40 (particularly in the absence of cigarette smoking) may wish to consider testing for α-1-antitrypsin deficiency

 

 

Prevention of gastric ulcer

Upper gastrointestinal tract integrity is dependent upon the delicate balance betweeaturally occurring protective factors as mucus or prostaglandins and damaging factors as hydrochloric acid present normally in the digestive juices. An imbalance causes peptic ulcer formation and destruction of gastrointestinal tract mucosal lining. Ulcer may develop in the esophagus, stomach, duodenum or other areas of elementary canal. In women, gastric ulcers are more common than duodenal ulcers, while in men the opposite is true.

The ulcer irritates surrounding nerves and causes a considerable amount of pain. Obstruction of the gastrointestinal tract may  occur as a result of spasm or edema in the affected area. The ulcer may also cause the erosion of major blood vessels leading to hemorrhage, hematemesis and/or melena. Deep erosion of the wall of the stomach or the intestine may cause perforation and peritonitis, which is a life-threatening conditioeeding emergency intervention. Duodenal ulcers are almost always benign but stomach ulcers may turn malignant. Although mortality rates of peptic ulcer are low, the high prevalence of the disease, the accompanying pain and its complications are very costly. The ongoing rapidly expanding research in this field provides evidence suggesting that, with therapeutic and dietetic advances, gastric ulcer may become preventable within the next decade. This could be achieved by strengthening the defense mechanisms of the gastric mucosa and, in parallel, limiting the aggression of predisposing factors causing gastric ulceration. The defenses of the gastric mucosa are incredibly efficient under normal mechanical, thermal or chemical conditions. These defenses can endure insults from food, gastric enzymes and acid secretion. Even trauma caused by a biopsy wound is dealt with and can heal relatively fast, within hours. However, under certain condition, some risk factors may contribute to mucosal injury and initiation of gastric ulcer, as psychological stress, increased hydrochloric acid secretion, Zollinger Ellison syndrome and family history of gastric ulcer. Conditions associated with increased risk of gastric ulcer include also  chronic disorders as liver cirrhosis, chronic obstructive pulmonary disease, renal failure, organ transplantation and rheumatoid arthritis. In addition, severe  physical stress as in case of burns, major surgery or head trauma may also contribute as risk factors.

Avoidable risk factors that may predispose to gastric ulcer include smoking, high consumption of alcohol and intake of some medications as non-steroidal anti-inflammatory drugs. Some factors are thought to aggravate already established gastric ulcer, but are no longer considered risk factors predisposing to it, as ingestion of too hot or cold foods or drinks, eating spicy food and intake of caffeine. The key cause of gastric ulcer is now known to be the infection by a certain gram negative bacterium called Helicobacter pylori.

Although the mechanism by which the infection by this bacterium leads to ulcer formation is not yet fully understood, it is believed that infection decreases the normal immunity of the gastrointestinal tract wall, which in turn weakens the mucosa and makes it vulnerable to ulceration under the acidic effect of gastric secretions.

Avoiding risk factors is the first line in prevention of gastric ulcer. Smoking cessation and alcoholic consumption minimization may help in  reducing the risk of ulcer formation. In addition, sanitary food and drinking habits to avoid infection with Helicobacter pylori may help in ameliorating the initiation of gastric ulcer and its recurrence. Therapeutic interventions to eradicate Helicobacter pylori can also prevent ulcer formation and its transformation into gastric cancer, one of the major complications of chronic gastric ulcer.

Avoiding unnecessary intake of ulcer-inducing over-the-counter medications may help in reducing the prevalence of gastric ulcers. Active therapeutic measures can aid in preventing gastric ulcers in predisposed groups and in patients with healed gastric ulcer to avoid its recurrence. Such therapeutic interventions may be of natural herbal sources or medicinal drugs. A number of traditional anti-ulcer drugs may be used in prevention as well as in treatment of gastric ulcer. Proton pump inhibitors, histamine H2 receptor antagonists and mucosal protective agents can thus all be used as protective drugs against initiation of gastric ulcer in predisposed groups as well as prevention of remittent attacks. Recent investigations showed that a number of drugs, other than traditional anti-ulcer medications, can help in prevention of gastric ulcer formation. Herbal compounds can also protect against gastric ulcer and they have the advantage of being safer, cheaper and usually having limited, if any, side effects.

In this chapter, a collection of updated recent information published about gastric ulcer protection is gathered. Information in this  chapter can be considered as guidelines for clinical practice to direct medical personnel perception to preferred approaches to prevent gastric ulcer as established by scientifically valid research. Making such information available may also increase public awareness  of preventive means of gastric ulcer, which may aid in decreasing the suffering of a large number of populations exposed to the disease worldwide.

Avoidance of gastric ulcer risk factors

The best and cheapest method to prevent gastric ulceration is the avoidance of risk factors resulting in the occurrence of the disease. Avoiding Helicobacter pylori infection, alternation of life style and substitution of ulcer-inducing medications with less harmful drugs can thus contribute largely to prevent gastric ulcer disease (Fig. 1). Unfortunately, some risk factors are unavoidable. One of the strongest risk factors for initiation of a gastric ulcer is the presence of prior ulcer disease with history of ulcer complications as previous perforation or hemorrhage.

 

 

Zollinger-Ellison Syndrome is another unavoidable cause of gastric ulceration. In this syndrome, tumors producing gastrin hormone (gastrinomas) in the pancreas and duodenum stimulate gastric acid secretion. The large amounts of excess acid produced cause gastro-intestinal ulceration. Ulcers may  form in the stomach, duodenum, jejunum or other atypical sites in the elementary tract. The incidence of this disease is less than 1% and men are more affected than women. The syndrome is suspected in patients with ulcers who are not infected with Helicobacter pylori and who have no history of non-steroidal anti–inflammatory drugs use. Diagnosis is confirmed by measurement of serum gastrin hormone levels which is usually very high, reaching above 1000 pg/ml (normal level is < 100 pg/ml).

Diarrhea may occur before ulcer symptoms. Gastro-esophageal reflux disease may occur and its complications may include narrowing due to strictures of the esophagus. Ulcers associated with this syndrome are usually persistent and difficult to treat. In the past, removing the stomach was the only option for treatment. Nowadays, treatment includes removing the tumors only and therapeutic suppression of acid secretion.

Other unavoidable factors associated with higher incidence of gastric ulcer include sex, as there is higher prevalence of the disease among women then men. People over age 60 years old are also more prone to gastric ulcer disease. In addition, ethnic backgrounds as African-Americans or Hispanics have 2-fold higher risk in developing gastric ulcer. Furthermore, patients suffering from other diseases as congestive heart failure have higher incidence of having gastric ulcer as well. Type O blood group has also been associated with increased incidence of the disease. Genetics is another unavoidable risk factor of gastric ulcer.

Pepsinogen C gene polymorphism, for example, is significantly associated with development of gastric ulcer (Sun et al., 2009). Other relatively rarer predisposing factors to development of gastric ulcer includes Crohn’s disease of the stomach, eosinophilic gastritis, systemic mastocytosis, radiation damage and viral infections by cytomegalovirus or herpes simplex (Malfertheiner et al., 2009).

 

Helicobacter pylori as a risk factor for gastric ulcer

Infection with Helicobacter pylori is the most well-defined risk factor for the development of peptic ulcers. The two Australian scientists who identified Helicobacter pylori as the main cause of stomach ulcers in 1982 were awarded the Nobel Prize in Medicine in 2005 for this discovery. Helicobacter pylori bacteria are found in about 50% of people with gastric ulcer disease. Inflammation of the stomach and stomach ulcers result from the infection by these bacteria, as their corkscrew shape enables them to penetrate the mucus layer of the stomach so that they can attach themselves to the lining. The surfaces of the cells lining the stomach contain a protein, called decay-accelerating factor, which acts as a receptor for the bacterium.

Helicobacter pylori can survive in the highly acidic medium of the stomach by producing urease, an enzyme that generates ammonia to neutralize the acid. These bacteria then produce a number of toxins causing inflammation and damage to the stomach, leading to ulcers especially in predisposed individuals. The bacteria also alter certain immune factors that allow them to evade detection by  the immune system and cause persistent inflammation. Even if ulcers do not develop, the bacterium is considered to be a major cause of active chronic inflammation in the stomach  (gastritis). Helicobacter pylori together with unavoidable risk factors as genetics and concomitant diseases may contribute in gastric ulcer formation and the subsequent metaplasia and dysplasia leading to gastric cancer (Fig. 2). Avoidance of risk factors, therapeutic intervention and some protective herbs can be employed to prevent the initiation of this sequence.

 

Less than 15% of people infected with Helicobacter pylori develop gastric ulcer. Factors that trigger gastric ulcers in Helicobacter pylori  carriers include genetic factors, which explain the higher incidence of development of ulcers in certain ethnicity. Another factor is abnormal immune response, which allows the bacteria to injure the stomach lining. Lifestyle factors as chronic stress, drinking coffee and smoking were long believed to be primary causes of gastric ulcer; it is now thought that they only increase susceptibility to ulcers in some Helicobacter pylori carriers. Interrupted sleep may be another trigger as people who work at night shifts have a significantly higher incidence of ulcers than day workers.

Frequent interruption of sleep is thought to weaken the immune system’s ability to protect against harmful bacterial substances.

Using certain medications as non-steroidal anti-inflammatory drugs or corticosteroids may contribute to higher infection rates of Helicobacter pylori. Patients with prior gastric ulcer Zollinger-Ellison syndrome, congenital stomach malformations, malignant diseases such as mastocytosis and basophilic leukemia, head trauma, severe traumatic injuries, burns radiation, or recently had major surgery are also more prone to Helicobacter pylori infection. Increased risk of Helicobacter pylori infection is seen among people who live in crowded places with unsanitary conditions. Some genetic predispositions for Helicobacter pylori infection cure rate may exist. One example is cytochrome P450-2C19 polymorphism that seems to predict the cure of Helicobacter pylori infection and predisposition to gastric ulcer (Lay and Lin, 2010). Another example is cytokine genes polymorphism that was significantly associated with persistent infection (Abdiev et al., 2010). Polymorphism of multidrug resistance protein 1 also was reported to influence Helicobacter pylori-induced gastric inflammation (Tahara et al., 2011). Such genetic predisposition gives us hope that the infection predisposing to peptic ulcer and gastric cancer may some day be a target for preventive gene therapy in the near future. 

Therapeutic interventions to eradicate Helicobacter pylori are needed to prevent ulcer formation and its transformation to gastric cancer, one of the major complications of chronic gastric ulcer. Helicobacter pylori eradication therapy comprises a combination of two or more drugs including antimicrobials, proton pump inhibitors and gastro-protective agents.

Several eradication methods were suggested. Dual eradication therapy using proton pump inhibitor with amoxicillin was tried (Graham et al., 2010). Triple eradication therapy employing 2 antimicrobials together with proton pump inhibitor also showed some success, but not enough to be considered first-line treatment. Quadruple Helicobacter pylori eradication was also successfully tried and  consisted of 2 antimicrobials, proton pump inhibitor and the gastro-protective agent colloidal bismuth subcitrate (Zheng et al., 2010).

Nowadays, the first line of Helicobacter pylori eradication therapy is a regimen of 7 or 14 days consisting of a proton pump inhibitor as omeprazole (20 mg 12 hourly), in combination with clarithromycin (500 mg 12 hourly) and metronidazole (400 mg 12 hourly). A second regimen that is equally effective is by using omeprazole as previously mentioned, together with less dose of clarithromycin (250 mg 12 hourly) and substituting metronidazole with amoxicillin (1 g 12 hourly). Omeprazole can be replaced with other proton pump inhibitors. Despite that the prevalence of Helicobacter pylori is decreasing in developed countries, as a result of improvements in living standards  and hygiene, Helicobacter pylori is still a common cause of gastric ulcer in developing countries. Attempts to develop effective vaccination against this bacterium reached phase I and II clinical trials, and may present effective preventive strategy in preventing gastric ulcer formation and, more importantly, preventing gastric cancer in the future (Majumdar et al., 2011). 

 

Avoidance of drug-induced gastric ulcers

Patients receiving medications as non-steroidal anti-inflammatory drugs, the anticoagulant drug warfarin, corticosteroids or the anti-osteoporotic drug alendronate may be more prone to gastric ulcer. Non-steroidal anti-inflammatory drugs are valuable therapeutics that act not only as anti-inflammatory, but also as analgesics and antipyretics. They are used in a wide variety of clinical scenarios, including arthritis and other musculoskeletal disorders. Unfortunately, their use has been limited by their gastric ulcer-inducing effects. Nearly 25 % of chronic users of these drugs develop gastric ulcer disease (Lanza et al., 2009). The rate of non-steroidal anti-inflammatory drugs-induced gastric ulcers is increasing, as more people are taking these drugs regularly as over-the-counter self-therapy. In general, the possibility of gastric ulcer initiation of a non-steroidal anti-inflammatory drug with non-selective cyclooxygenase inhibition actions correlates with its anti-inflammatory activity. Non-steroidal anti-inflammatory drugs with a high analgesic effect at doses with low anti-inflammatory activity, such as ibuprofen, are less ulcerogenic than those that have adequate analgesic effects only at doses with high anti-inflammatory activity, as in case of piroxicam. Ibuprofen appears safer compared to other members of this drug group in part because it is frequently prescribed for short durations in a low dose to control temporary mild painful conditions. However, when full anti-inflammatory doses of ibuprofen are given, the risk of gastric ulceration with ibuprofen is comparable with other non-steroidal anti-inflammatory drugs.

One member of this group is indomethacin, which is a frequently clinically used and is also applied to induce experimental animal model of acute gastric ulcer. Indomethacin induces gastric injury by suppressing the  formation of prostaglandins, which control many of the components of mucosal defense system, as they stimulate mucus and bicarbonate secretion, elevate mucosal blood flow, increase the resistance of epithelial cells to injury induced by cytotoxins and suppress the recruitment of leucocytes into the mucosa. Prostaglandins can also inhibit the release of a number of inflammatory mediators, such as tumor necrosis factor-α from macrophages and interleukin-8 from neutrophils. Tumor necrosis factor-α promotes gastric epithelial cell apoptosis and triggers activation of adhesion molecules and leucocyte recruitment, leading to microvascular perturbations. Other mechanisms by which indomethacin induce gastric injury involves gastric hypermotility and the increased production of reactive oxygen species, as well as lipid peroxidation (Morsy et al., 2010).

Physicians prescribing these drugs face two problems; one problem is identification of high-risk patients and the second is selection of appropriate strategies to prevent gastric ulcer. Risk factors of these drugs-induced gastric ulcers include older age, concomitant use of anticoagulants, corticosteroids, other non-steroidal anti-inflammatory drugs including low-dose aspirin, and chronic debilitating disorders, especially cardiovascular diseases. Helicobacter pylori infection increases the risk of this drugs-induced gastric ulcer. Eradication of Helicobacter pylori infection,  if present, in patients requiring long-term therapy by these drugs is recommended.

Patients who require long-term non-steroidal  anti-inflammatory drug therapy can reduce their risk of inducing ulcers by concomitantly taking conventional anti-ulcer therapy. Proton pump inhibitors and/or histamine H2 receptor antagonists can significantly reduce these drug-induced gastric ulcers. The synthetic prostaglandin E1 analog, misoprostol, is also very effective in preventing the development of  gastric ulcers in patients taking these medications. Unfortunately, its use is limited by its gastrointestinal adverse effects.

 

Life style risk factors

Several studies implied that modulating life style factors as dietary factors, controlling stress, reducing smoking and alcohol intake may directly prevent the initiation of gastric ulcers, especially in predisposed people. Some even suggested certain physical exercises to reduce the risk of ulcer formation or recurrence. Such exercises were seen to directly improve psychological and cardiovascular conditions and thus may be indirectly related to decreasing gastric ulcer development. 

 

Diet

Diet rich in fibers may decrease the risk of developing gastric ulcers by about 50%. Fiber found in fruits and vegetables is particularly protective, as vitamin A contained in many of these foods may increase the benefit. Milk, previously thought to aid in decreasing ulcer symptoms, actually encourages  the production of acid in the stomach, although moderate amounts (2-3 cups/day) appear to do no harm. However, yogurt may protect against gastric ulcer, as it contains probiotics. Coffee (caffeinated and decaffeinated), soft drinks and fruit juices with citric acid increase stomach acid production. Although no studies have proven that any of these drinks contribute to ulcers, consuming more than 3 cups of coffee per day may increase susceptibility to Helicobacter pylori infection (University of Maryland Medical Center website).

Studies conducted on spices and peppers have yielded conflicting results. In general, these substances should be used moderately, and should be avoided if they irritate the stomach. Some studies suggest that high amounts of garlic may have some protective properties against stomach cancer, although a recent study concluded that garlic offered no benefits against Helicobacter pylori and, in large amounts, can cause considerable gastrointestinal distress. Studies have shown that phenolic compounds in virgin olive oil may be effective against Helicobacter pylori infection. Although no vitamins have been shown to protect against Helicobacter pylori-induced ulcers, Helicobacter pylori appears to impair the absorption of vitamin C, which may play a role in the higher risk of stomach cancer.

 

Psychological factors: stress

As a body response to stress, many diseases may develop. There is debate as to whether psychological stress can influence the development of gastric ulcers. Some studies still suggest that stress may predispose a person to ulcers or prevent existing ulcers from healing. Some even believe that the relationship between stress and ulcers is so strong that people with ulcers should be treated for psychological conditions. Stress causes the digestive tract to slow down and more gastric acid is allowed to accumulate in the stomach.

Increased stomach acidity may predispose to or aggravate an already present ulcer. Stress can also cause change in appetite, leading to  over-eating or lack of appetite. Overeating causes the stomach to produce more acid while lack of appetite will subject the stomach mucosa to the acid produced in an empty stomach. Although psychological stress is no longer considered a direct cause of ulcers, it surely can delay the healing and aggravate already existing gastric ulcers. Physical stress, however, is definitely a risk factor for developing gastric ulcers, as in patients with injuries such as severe burns or patients undergoing major surgeries.

 

Smoking

Cigarette smoking appears to be a risk factor for the development and recurrence of gastric ulcer. The incidence of gastric ulcer is higher among smokers than non-smokers. Compared with non-smokers, people who smoke cigarettes are twice as likely to develop gastric ulcer.

Smoking may lead to initiation of ulceration,  slow ulcer healing and an increased risk of gastric ulcer recurrence. Smoking may have an inconsistent effect on gastric acid secretion; however it reduces prostaglandin and bicarbonate production, reduces mucosal blood flow, interferes with the action of histamine H2 receptor antagonists and accelerates gastric emptying of liquids. Cessation of smoking or reducing it is usually associated with the prompt relief of already existing gastric ulcer symptoms.

 

Excess alcohol intake

Alcohol increases the production of acid in  the stomach, which may  irritate an existing ulcer. Alcohol also relaxes the lower esophageal sphincter, allowing stomach contents to reflux back up into the esophagus, increasing the discomfort associated with gastric ulcer.

Patients suffering of gastric ulcer should, thus, avoid taking alcohol. People predisposed to gastric ulcer may dilute alcoholic beverages to reduce their concentration, restrict the number of drinks to one or two a day, replace red wine with white wine of less toxic content, or better, have drinks which are non-alcoholic.

 

 

Endogenous protection against gastric ulcer

Astonishingly, despite of the presence of one or more risk factors as smoking, alcohol intake, non-steroidal anti-inflammatory drugs consumption and/or Helicobacter pylori infection, some people still do not develop gastric ulcer. For example, non-steroidal anti-inflammatory drugs induce clinically significant gastric ulceration in 17% of patients receiving these drugs. This is due to the strong natural endogenous  gastric cyto-protection that spares the vast majority of patients at risk. Gastric mucosal barrier together with endogenous mediators comprise a strong defense mechanism against gastric ulceration. Understanding these naturally occurring defense mechanisms is crucial to try to enhance them to prevent gastric damage and ulceration in more vulnerable patients. 

 

Physiological gastric mucosal barrier

The gastric mucosal barrier is considered the main defense system against gastric ulcer formation. Several luminal factors contribute to this barrier (Fig. 3). These factors include secretion of bicarbonates, mucus, phospholipids and immunoglobulins. The gastric epithelial barrier also represents part of the defense system that is remarkably resistant to acids or irritants and has the capability of  rapid repair. The mucosal microcirculation, together with sensory innervations, harmonically defends the mucosal barrier. Sensing acidic diffusion into the gastric mucosa results in neural system-mediated induced endogenous mediator release and hormonal responses leading to increase in mucosal blood flow, which is a critical step in preventing damage and facilitating repair of gastric mucosa.

The mucosal immune system represents another gastric mucosal protective method. Mast cells and macrophage generate immune signals of inflammatory response that contributes to prevention of gastric damage.

 

Luminal gastric protection

The mucus-bicarbonate-phospholipid barrier  comprises the first line of mucosal defense mechanism. This barrier is formed of mucus, bicarbonate and phospholipids. Mucus presents a layer that contains secreted bicarbonate and surfactant phospholipids. Mucus that acts as a physical barrier against luminal digestive enzymes, bicarbonate that maintains an almost neutral pH at the epithelial surface, together with phospholipids of high hydrophobic properties caaturally protect  against mucosal damage. Disruption of this mucus-bicarbonate-phospholipid barrier by ulcerogenic substances, as bile salts or non-steroidal anti-inflammatory drugs causes elevated diffusion of acid into the mucosa and mucosal damage (Allen and Flemstrom, 2005). Helicobacter pylori release phospholipase enzymes and ammonium ions that can reduce the strength of this single and only barrier existing between the epithelium and the lumen. Other protective mechanisms may then interfere to protect against this bacterial induced injury.

 

 

Gastric epithelial barrier

Mucosal surface is formed of a continuous layer of surface epithelial cells that secrete components of the mucus barrier as well  as endogenous protective mediators as prostaglandins, heat shock proteins and cathelicidins (see below; section 3.2). These surface epithelial cells form a physical barrier preventing back-diffusion of gastric acid and digestive enzymes. Basolateral membrane of epithelial parietal cells, that secrete hydrochloric acid in high concentrations into the lumen of the stomach, contains transporters responsible for maintaining intracellular homeostasis. These transporters efflux large amounts of bicarbonate to prevent cell alkalinization. The effluxed bicarbonate, known as alkaline tide, is an integral constituent of mucus-bicarbonate barrier (Tulassay and Herszenyi, 2010). Continuous and rapid cell renewal enhances the resistance of epithelial barrier to damage. Mucosal progenitor cells in gastric epithelium promote cell renewal by continuously replacing surface cells that undergo apoptosis. Proliferation of progenitor cells is controlled by endogenous growth factors’ mediators.

 

Mucosal microcirculation

Mucosal ischemia triggers gastric ulcer by inducing tissue necrosis, free radical formation and cessation of nutrient transport, all resulting from vascular and microvascular injury such as thrombi, constriction or other occlusions.

Mucosal blood flow thus provides gastric lining with adequate vascular perfusion that prevents epithelial damage from progressing to necrosis of deeper layers of the mucosa. Increase in mucosal blood flow occurs as a response to gastric mucosal exposure to an irritant or when acid back-diffusion occurs. Potent vasodilators such as nitric oxide and prostaglandin I2 generated by endothelial cells protect the gastric mucosa against injury and damaging action of vasoconstrictors such as leukotriene C4, thromboxane A2 and endothelin. These potent vasodilators prevent platelet and leucocyte adherence to endothelial cells, maintain the integrity of the gastric epithelium and the mucus barrier and protect the gastrointestinal tract by inhibiting gastric acid secretion from parietal cells. Endogenous mediators that affect mucosal microcirculation as nitric oxide and hydrogen sulfide are further discussed below (section 3.2).

 

Gastric sensory innervation

Gastric mucosal defense is also regulated by the central nervous system innervation. Gastric mucosa and submucosal vessels are innervated by primary afferent sensory neurons. When gastric mucosa gets exposed to damage by gastric acid or other irritating chemicals, afferent neurons are activated and directly start controlling the tone of the submucosal arterioles, which regulate mucosal blood flow. When sensory afferent nerves of the superficial mucosa detect gastric acid, they respond by releasing neurotransmitters as substance P and calcitonin gene-related peptide. These mediators cause relaxation of smooth muscle surrounding gastric mucosal arterioles, resulting in an elevation of mucosal blood flow. In addition, vagal activation increase mucus secretion, while nervous response to stress control central corticotropin-releasing factor signaling pathways. Furthermore, the transient receptor potential vanilloid 1 agonists are effective in protecting gastric mucosa against various experimentally induced ulcer models (Morsy and Fouad, 2008).

 

Mucosal immune system

The mucosal immune system is a key factor of mucosal defense against exogenous and endogenous irritants. Impairment of this immune system can lead to mucosal injury and to impairment of endogenous cyto-protective repair mechanisms. The mucosal immune system is coordinated by innate and adaptive immune response regulated by several mediators released from immuno-regulating cells. Neutrophils and macrophages infiltrate into the gastric mucosa as a response to Helicobacter pylori infection. These cells release lysosomal enzymes, leukotrienes and reactive oxygen species which impairs mucosal defense and drives the immunopathogenetic process of ulcerogenesis. T and B lymphocytes activated by bacterial antigens and pro-inflammatory cytokines regulate the local and systemic immune response with release of further cytokines and antibodies. The type of T-cell response can change the outcome of this infection, as more mucosal damage results from T-helper predominant response, whereas a high regulatory T-cell response with interleukin-10 release confers gastric ulcer protection (Malfertheiner et al., 2009).

 

Endogenous gastro-protective mediators

Some endogenous mediators can work through cyto-protective mechanisms reducing gastrointestinal injury induced by topical irritants, thus preventing the initial steps of gastric inflammation. These endogenous mediators may be inhibited by causative risk factors, leading to gastric ulceration and thus provide a mechanism through which these risk factor contribute in gastric damage. On the other  hand, therapeutic modulation of endogenous gastric mediators can provide a target to improve gastric protection against ulceration.

 

Mediators of cyclooxygenase pathway: prostaglandins and lipoxins

Prostaglandins are fatty acids produced from arachidonic acid via cyclooxygenase enzyme. It is known that suppression of prostaglandin  synthesis is a major mechanism of action of aspirin and other non-steroidal anti-inflammatory drugs, which is probably one of the mechanisms by which these drugs cause gastric ulcers. Prostaglandins modulate a number of components of mucosal defense as they  stimulate mucus and bicarbonate secretion, promote mucosal blood flow, increase the resistance of epithelial cells to cytotoxins-induced injury and suppress the recruitment of leukocytes into gastric mucosa. Prostaglandins can also down regulate the release of a number of other inflammatory mediators that may contribute to the generation of gastric ulcer (Martin and Wallace, 2006). Prostaglandin E receptors have a prominent role in mucosal protection and gastric ulcer healing (Takeuchi, 2010). Prostaglandin E2 has been shown to be a potent inhibitor of tumor necrosis factor-α and interleukin-1 release from macrophages and of leukotriene B4 and interleukin-8 release from neutrophils. Lipoxins are the resultant of consequent conversion of arachidonic acid by cyclooxygenase-2 and 5-lipoxygenase enzymes. Lipoxin-A4 is an endogenous mediator contributing to resolution of the inflammatory state and, thus, has an important role in mucosal defense.

Lipoxin A4 protects the stomach from aspirin-induced damage via suppressing leukocyte adherence within gastric micro-circulation. In addition, Lipoxin A4 can inhibit inflammatory pain processing and regulate trans-epithelial electrical resistance. Antagonism of Lipoxin A4 receptor can significantly exacerbate gastric ulcer (Lim et al., 2009).

 

Proteolytic enzymes

Proteolytic enzymes have important functions in gastric ulcer prevention and healing. It has been shown that impaired fibrinolysis occurs due to alteration of the proteolytic enzymes formed through tissue-type plasminogen activator-inhibitor system. Intramucosal proteases; as cathepsins, are also involved in protection against gastric ulcer initiation and promotion of healing. Cathepsins act as antimicrobial  peptides expressed by the gastric epithelium preventing bacterial colonization and accelerate ulcer healing. The proteolytic enzymes urokinase-type plasminogen activator and plasminogen activator-inhibitor type-1 are involved in angiogenesis process, and thus  has a direct role in cell proliferation, inflammation and ulcer healing. Matrix metalloproteases are involved in extracellular matrix reconstitution and tissue remodeling and thus may have an impact in gastric ulcer healing (Tomita et al., 2009). Secretory leucocyte protease inhibitor exerts antimicrobial and anti-inflammatory effects. Its expression is induced during inflammation. However, the expressiis significantly decreased during Helicobacter pylori-mediated gastritis. This is due to local down-regulation of this proteolytic enzyme in gastric mucosa in response to Helicobacter pylori infection (Tulassay and Herszenyi, 2010).

 

THERAPEUTIC INTERVENTIONS IN PREVENTION OF GASTRIC ULCER

Several therapeutic interventions may aid in  preventing gastric ulcer. Enhancement of normal physical barriers and physiological protective factors can aid in prevention of gastric ulcer. Some endogenous gastro-protective factors (see above) may be enhanced to decrease the risk of gastric ulcer formation. Conventional medications used in treatment of gastric ulcer can also be used in prevention as well, especially in predisposed people. Several investigations also tested drugs not conventionally used in treatment of gastric ulcer for having possible ulcerogenic protective effects. The main aim of most of these studies is to decide which drug to preferentially use in treating conditions presenting concomitantly with high risk of development gastric ulcer.

 

Prevention of gastric ulcer by conventional anti-ulcer drugs

Most anti-ulcer drugs target gastric acid secretion and mucosal defense mechanisms (Table 1). Successful classes in treating gastric ulcer include Helicobacter pylori eradication therapy, prostaglandin analogs, cyto-protective drugs, histamine H2 receptor antagonist and proton pump inhibitor groups. In terms of acid inhibition, proton pump inhibitors possess higher acid inhibitory potency. Histamine H2 receptor antagonists have, thus, been gradually replaced with the more potent class  of acid inhibitory drugs, the proton pump inhibitors. Current ulcer therapy consists of Helicobacter pylori eradication in Helicobacter pylori-positive gastric ulcer and proton pump  inhibitors for healing and preventing peptic ulcers induced by drugs.

Proton pump inhibitors selectively block the H+/K+ ATPase of the parietal cells. These proton pump inhibitors are the most popular  group of drugs used in Helicobacter pylori eradication regimens (see before; section 2.1). Misoprostol, a prostaglandin analog, has been the most widely used but its application is limited by abdominal side-effects as abdominal cramps and diarrhea. Sucralfate and bismuth salts improve mucosal repair. Sucralfate also acts by reducing acid secretion and suppressing Helicobacter pylori infection. Bismuth salts, having mild anti-Helicobacter pylori activity, are used in treatment of gastric ulcer therapy in combination with antibiotics (Malfertheiner et al., 2009).

All of these drugs have been used successfully to treat gastric ulcers and prevent remittent attacks. Nevertheless, their efficiency in prevention of gastric ulcers in individual predisposed groups is still controversial. Histamine H2 receptor antagonist is one example, as their standard dosage succeeded only in reducing the risk of duodenal ulcer, but not gastric ulcer induced by non-steroidal anti-inflammatory drugs. The benefit from histamine H2 receptor antagonists was limited to preventing the risk of ulcers induced by Helicobacter pylori infection (Chan and Graham, 2004). Contrarily, in another study, histamine H2 receptor antagonists were effective for prevention of low dose aspirin-induced ulcers and showed similar potency as proton pump inhibitors (Nakashima et al., 2009). Another example is the use of cyto-protective drugs (as in Table 1) for prevention of gastric ulcer, whose efficacy is still controversial.

Using these conventional anti-ulcer drugs in prevention of  gastric ulceration is, thus, dependent on the type of predisposing risk factor. Risk factors used in assessment are old age, presence of cardiovascular diseases, use  of high dose or multiple non-steroidal anti- inflammatory drugs, concomitant use of low-dose aspirin and other anti-platelet drugs, corticosteroids or warfarin. When one or two  of these factors are present, presenting a moderate risk, an anti-secretory agent or misoprostol may be used. If three or more risk factors are combined, presenting a high risk,  switching from non-selective, to selective cyclooxygenase inhibitors is recommended. In addition, misoprostol can be used for prevention of aspirin- or warfarin-induced gastric ulcers. In very high risk patients, who have been subjected to previous ulcer complications, avoidance of non-steroidal anti-inflammatory drugs and intake of proton pump inhibitor and/or misoprostol is recommended.

 

 

Non-conventional gastro-protective drugs

A number of drugs, other than traditional anti-ulcer medications, were investigated and showed an effect in prevention of gastric ulcer formation. Stress causing hypertension may concomitantly predispose to gastric ulcer. The effect of antihypertensive drugs, namely angiotensin II T1 receptor blocker; telmisartan, was investigated for its effect as gastro-protective agent. The results showed that telmisartan and candesartan can prevent gastric ulcer formation, with higher potency of telmisartan than candesartan. Telmisartan’s protection of gastric mucosa from non-steroidal anti-inflammatory drugs-induced ulceration is possibly through its anti-oxidant action and may also be ascribed, at least in part, to its peroxisome proliferator-activated receptor γ agonistic properties (Morsy et al., 2009). 

Gastric ulcer is also commonly seen concurrently in type 2 diabetic patients. Moreover, peptic ulcers related to the diabetic state are more severe and are often associated  with complications. The possible gastro-protective effects of insulin sensitizers thiazolidinediones; rosiglitazone and metformin were tested. Both drugs have the ability to ameliorate oxidative stress and inflammation, rendering them attractive candidates for the prevention of gastric ulcer in patients with type 2 diabetes. Both rosiglitazone and metformin prevented indomethacin-induced gastric ulcer in diabetic rats. Their gastro-protective effects were probably due to anti-secretory actions, enhanced mucosal protection and anti-oxidant activity. This was reflected on their ability to increase mucin concentrations and gastric mucosal nitric oxide levels. In addition, rosiglitazone increased gastric juice pH, providing superior gastro-protection to metformin (Morsy et al., 2010).

Other investigations tested the effect of another anti-diabetic drug; pioglitazone as a gastro-protective drug. Pioglitazone has an agonist of peroxisome proliferator-activated receptor γ and exerted strong effect in both preventing the formation of gastric ulcers and healing of already existing ones. This gastric ulcer preventing/healing effect of pioglitazone is, at least in part, mediated by endogenous nitric oxide. Astonishingly, under diabetic conditions, pioglitazone gastro-protective effect decreased. The attenuation of pioglitazone action is possibly due to reduction iitric oxide, angiogenesis and increased expression and release of pro-inflammatory cytokines under diabetic conditions (Konturek et al., 2010). Organoselenium compounds were tested in  naproxen- and Helicobacter pylori-induced gastric ulcers and showed not only gastro-protective and ulcer healing effects, but also they possessed antibacterial effect against Helicobacter pylori (Santhosh et al., 2010). When tested on indomethacin-induced gastric ulcer in mice, melatonin demonstrated gastro-protective effects via having angiogenic properties through up-regulation of matrix metalloproteinase-2; an important regulator of angiogenesis (Ganguly et al., 2010).

 

 

 

Prevention of chronic kidney disease

Chronic kidney disease is a common disorder and its prevalence is increasing worldwide. Early diagnosis on the basis of presence of proteinuria or reduced estimated glomerular fi ltration rate could permit early intervention to reduce the risks of cardiovascular events, kidney failure, and death that are associated with chronic kidney disease.

In Chronic kidney disease (CKD) is emerging in the 21st century as a global public health issue. Currently, more than 1 million patients with end-stage renal failure (ESRF) are on renal replacement therapy (RRT) worldwide1, with as many as 2 million predicted to require therapy by 20101,2. The majority of these patients come from developed nations that can afford the cost of RRT3, whereas a large number of those requiring treatment in developing countries do not have access to RRT. The cost of RRT is prohibitive for many economies and countries, because there is a clear and direct relationship between gross national product and availability of RRT3,4. It is therefore imperative to shift the emphasis of the global approach to CKD toward early detection and prevention because management of the growing number of patents with ESRF may be beyond even the most affluent of countries. Within the next 10 years, it is estimated that the annual cost of ESRF management in the United States will rise to approximately US $30 billion, consuming a considerable part of the health care budget.

 

 Causes of chronic renal failure in Apollo Hospital

 

 A total of 6420 patients seen in 17 years. It is possible to do something to prevent those which are underlined, 54% of the total.

 

Chronic kidney disease is defi ned by a sustained reduction in glomerular fi  ltration rate or evidence of structural or functional abnormalities of the kidneys on urinalysis, biopsy, or imaging. A five-stage classifi cation system for the disorder has been established by the US National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative and adopted internationally by the

Kidney Disease: Improving Global Outcomes (KDIGO) initiative to guide identifi  cation of cases and facilitate management (table 1).

In the clinical setting, glomerular fi  ltration rate is generally estimated on the basis of creatinine concentration in serum and demographic features (age, sex, and ethnic origin) with the Cockcroft-Gault or MDRD (Modifi cation of Diet in Renal Disease) study equations. The severity of chronic kidney disease in the fi ve-stage scheme is based mainly on glomerular fi  ltration rate (table 1), although risk of complications at a given rate is modifi ed substantially by the amount of proteinuria. The MDRD study equation was developed in a population with chronic kidney disease from the USA, and its precision and accuracy is reduced with increasing glomerular fi ltration rate and in diff  erent ethnic groups.

 Unique prediction equations have been derived and validated for other nationalities.Since the concentration of creatinine in serum alone is insensitive to early disease, identifi cation and staging of chronic kidney disease on the basis of estimated glomerular fi ltration rate was an important advance that facilitated both research and clinical care. Nonetheless, controversy continues to surround the existing classifi  cation system, specifi cally with regard to its propensity to overestimate prevalence; its failure to fully incorporate prognostic information from proteinuria; and the potential for misclassifi cation of some people as having chronic kidney disease in the absence of clinically relevant kidney disease.

New equations for estimation of glomerular fi ltration rate from serum creatinine (eg, the Chronic Kidney Disease Epidemiology Collaboration equation) show enhanced precision and accuracy, particularly at high rates, and could overcome some of these limitations.

 Although current interest exists for use of new markers, such as cystatin C, to detect early chronic kidney disease, or for combination of both serum creatinine and cystatin C for estimation equations to increase accuracy, the clinical role of such markers remains to be defi ned. The current chronic kidney disease staging system is expected to evolve in response to these considerations, and the KDIGO initiative held an international consensus conference to discuss the issue in late 2009.

 

Chronic kidney disease has many potential causes, which vary in frequency between diferent populations (figure 2). In developed countries, age, hypertension, diabetes, increased body-mass index, and smoking are associated consistently with chronic kidney disease, as is a history of established cardiovascular disease.

 

Figure 2: Classifi  cation and selected examples of causes of chronic kidney disease

 

In the developing world, infectious diseases are also important causes of kidney failure, including infections due to bacteria (tuberculosis in India and the Middle East, streptococcal infection in Africa), viruses (HIV and hepatitis B and C in Africa), and parasites (schistosomiasis in Africa and Latin America, leishmaniasis in Africa and Asia, and malaria in Africa).

In Asia, Africa, and the Middle East, chronic kidney disease has been attributed to environmental and occupational exposure tochemicals, including lead, cadmium, and mercury. The rapidly increasing burden of chronic non-communicable diseases that has been seen in many developing nations will probably lead to striking corresponding rises in prevalence of chronic kidney disease and kidney failure in these countries over the next two decades.

Cardiovascular disease is the leading cause of mortality in chronic kidney disease, and even mild reductions in glomerular fi ltration rate are associated with excess cardiovascular risk. At any given level of kidney function, raised amounts of proteinuria are associated with increased cardiovascular morbidity and mortality. In patients with cardiovascular disease, diabetes, or hypertension, presence of chronic kidney disease (especially with proteinuria) is a so-called risk multiplier that identifi  es the subset of individuals who are most likely to have adverse outcomes.

Additional disorders that accompany chronic kidney disease include infection, acute kidney injury, cognitive dysfunction, and impaired physical functioning.

Because availability of renal replacement therapies is limited in countries of low and middle income, most patients around the world with chronic kidney disease will die from kidney failure without receiving dialysis or transplantation. In developed countries, many more people will die from cardiovascular disease rather than progress to kidney failure requiring renal replacement. A low estimated glomerular fi  ltration rate at presentation and the amount of proteinuria are the strongest independent risk factors for kidney failure.

Reduction in level of proteinuria over time correlates with a slowing of the rate of decline in glomerular fi ltration rate, making proteinuria an important prognostic variable and potential therapeutic target.

 

Prevention and intervention

Initial management of chronic kidney disease entails identifi  cation of reversible disorders (such as urinary-tract obstruction, infection, or autoimmune disease) that could respond to specifi c treatment and lead to stabilisation or improvement in kidney function. Irrespective of underlying cause, typical goals of manage ment for all patients with chronic kidney disease include prevention of cardiovascular events and reduction of the rate of progression of the disorder (thereby delaying or preventing kidney failure and other complications). Many clinical trials have been undertaken solely in patients with non-diabetic chronic kidney disease or in those with diabetic chronic kidney disease. Pharmacological therapy for these two groups is discussed below.

 

Pharmacological treatment of non-diabetic chronic kidney disease

Treatment of hypertension is the mainstay of management to slow the progression of chronic kidney disease and reduce cardiovascular risk. Observational work has indicated an increased risk of progression of chronic kidney disease and of kidney failure as blood pressure rises above 130/80 mm Hg.

The current recommended blood pressure target for patients with chronic kidney disease is 125–135/75–85 mm Hg, but all guidelines advocate a goal lower than that for the general population. Findings of the MDRD  and AASK studies  did not show substantial reductions in incidence of kidney failure or death, or decline of glomerular fi  ltration rate when a lower mean arterial blood pressure of 92 mm Hg (equivalent to <125/75 mm Hg) was targeted. Although some suggestion of benefi t has been made with such goals in specifi c subgroups (eg, patients with proteinuria >1 g per day) or with extended follow-up, this outcome remains uncertain. The REIN-2 study examined the eff ect of addition of a non-dihydropyridine  calcium-channel blocker to background treatment with an angiotensin-converting-enzyme inhibitor to achieve a lower-than-usual target blood pressure of less than 130/80 mm Hg. The study was terminated after the first interim analysis when data indicated that the combined intervention to achieve lower blood pressure would not show a reduction in the primary outcome of kidney failure.

Whether achievement of reduced levels of blood pressure with alternative antihypertensive combinations, or maintenance of these levels of blood pressure for a prolonged period, can further preserve kidney function remains unclear.

Angiotensin-converting-enzyme inhibitors are the best-tudied agents for slowing the progression of non-diabetic kidney disease. Their eff ectiveness has been hown most clearly in individuals with proteinuric hronic kidney disease, and they are recommended as fi  rst-line treatment in this subgroup.

Pooled results rom 11 randomised controlled trials (including data rom the landmark Angiotensin-Converting-Enzyme nhibition in Progressive Renal Insufficiency and REIN-studies) indicated that risk of kidney failure or doubling of creatinine concentration in serum was educed by about 40% with an angiotensin-converting-enzyme inhibitor compared with other classes of antihypertensive drugs in patients with chronic kidney disease and proteinuria greater than 0·5 g per day.

In he AASK study, an angiotensin-converting-enzyme nhibitor reduced the risk of loss of kidney function, kidney failure, or death by almost 40% compared with a dihydropyridine calcium-channel blocker in African-American people with hypertensive nephropathy, despite similar levels of blood pressure control. In a randomised trial by Hou and colleagues in China, the renal benefits of angiotensin-converting-enzyme inhibition extended to patients with later stages of chronic kidney disease with proteinuria.

Acute renal failure and hyperkalaemia were infrequent complications of these drugs in trial settings, although their use requires careful laboratory monitoring of electrolyte con centrations, with introduction and dose-adjustment in real-world clinical settings.

Small increases in the amounts of potassium and creatinine in serum are typical and usually tolerated; however, inhibition of the angiotensin system should be avoided in women planning pregnancy.

No evidence is available to favour angiotensin-converting-enzyme inhibitors specifi  cally over other antihypertensive drugs for prevention of renal outcomes in patients without diabetes or with early chronic kidney disease without proteinuria. Secondary analysis of data of the ALLHAT trial showed no diff  erence in rates of kidney failure in individuals treated with an angiotensin-converting-enzyme inhibitor, dihydropyridine calcium-channel blocker, or thiazide diuretic, even in the subgroup with a baseline estimated glomerular fi  ltration rate less than 60 mL per min per 1·73 m².

Urine protein quantification was not done in the ALLHAT study; however, in view of the population studied, proteinuria was probably rare, which could account for the absence of any benefi  cial  eff  ects of angiotensin-converting-enzyme-inhibitor treatment on risk of kidney failure.

Although use of an angiotensin-converting-enzyme inhibitor reduced risk of cardiovascular events in patients with mild renal insufficiency in the HOPE study, whether this outcome is independent of eff ects on blood pressure is unclear.

The eff ects of angiotensin-receptor blockers on pro-gression of non-diabetic chronic kidney disease are less well studied than those of angiotensin-converting-enzyme inhibitors. Angio tensin-receptor blockers are effective anti-hypertensive drugs in patients with chronic kidney disease and reduce proteinuria to a similar level as angio-tensin-converting-enzyme inhibitors.On this basis, they are a good alternative for patients who cannot tolerate an angiotensin-converting-enzyme  inhibitor because of cough or angio-oedema.

As far as we know, no studies have been undertaken to establish effectiveness of angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers specifi cally for primary prevention of chronic kidney disease in patients without diabetes. Findings of the TRANSCEND study showed no effect of an angio tensin-receptor blocker for primary prevention of renal disease in a population with cardiovascular disease, preserved kidney function, and no proteinuria.

Combination treatment with an angiotensin-converting-enzyme inhibitor and an angiotensin-receptor blocker reduces proteinuria by a greater amount than either agent alone and, thus, has the potential to provide additional renoprotection.

In the ONTARGET study, the combination of angiotensin-converting-enzyme inhibitor and angiotensin-receptor blocker was associated with heightened risk of dialysis (acute or chronic), doubling of creatinine concentration in serum, or death in people with well preserved glomerular filtration rate and infrequent proteinuria.

 Without definitive evidence, the increased risk of adverse eff ects with combination treatment could outweigh the potential benefits for patients at low risk of progression; whether this conclusion applies to individuals with progressive disease needs further study.

Many patients with chronic kidney disease will need several antihypertensive drugs to control their blood pressure. Antihypertensives from any class can be added, although decisions should be made after con sideration of comorbidities. Thiazide or loop diuretics help to reduce blood pressure, and loop diuretics can control extracellular volume fluid overload and hyper-kalaemia as glomerular fi ltration rate declines.

Add-on treatment with non-dihydropyridine calcium-channel blockers might lessen proteinuria further, but conclusive data for long-term benefi ts are scarce.

 

Pharmacological treatment of diabetic chronic kidney disease

Treatment of high blood pressure in patients with diabetes mellitus is advocated irrespective of the presence of chronic kidney disease. In the UK Prospective Diabetes Study (UKPDS), reduction of blood pressure diminished the risk of diabetes-related death, stroke, and microvascular endpoints such as retinopathy.

Findings of observational studies support blood-pressure targets for patients with diabetic chronic kidney disease similar to those for individuals with non-diabetic chronic kidney disease.

Angiotensin-converting-enzyme inhibition shows clear renal benefi ts in patients with diabetic nephropathy. Angiotensin-converting-enzyme inhibitors decrease the risk of death, dialysis, or transplant in individuals with type 1 diabetes and established nephropathy.

Similarly, in patients with nephropathy due to type 2 diabetes, fi  ndings of the RENAAL and IDNT  studies showed that treatment with an angiotensin-receptor blocker resulted in 16–20% reductions in risk of doubling of serum creatinine, kidney failure, or death. The eff ects of angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers for primary prevention of diabetic nephropathy have been variable. Results from the IRMA study and a subgroup analysis of patients with diabetes enrolled in the HOPE study suggested that the onset of macroalbuminuria is decreased in patients treated with angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers. In individuals with type 2 diabetes, normal renal function, and normoalbuminuria in the BENEDICT study, use of ramipril (with or without verapamil) delayed new onset of micro albuminuria.

Reductions in incidence of new cases of microalbuminuria with angiotensin-converting-enzyme inhibition were also reported in two other large randomised controlled trials in patients with type 2 diabetes (EUCLID and ADVANCE) but not in a secondary analysis of the DIRECT studies.

The renoprotective eff ects of angiotensin-converting-enzyme inhibitors and angiotensin-receptor blockers seem to be clinically equivalent in patients with diabetic nephropathy on the basis of longitudinal measure-ments of glomerular filtration rate.

Dual blockade of the renin–angiotensin system with an angiotensin-converting-enzyme inhibitor and an angiotensin-receptor blocker reduces proteinuria in patients with diabetic nephropathy but the effects on clinically relevant renal outcomes are unknown pending results from ongoing studies. Further lowering of albuminuria has beeoted in patients with diabetic nephropathy when a direct renin inhibitor (aliskiren) was added to an angiotensin-receptor blocker. A randomised controlled trial (ALTITUDE) examining the effect of addition of aliskiren to conventional treatment (including an angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker) on cardio vascular and renal outcomes is in progress.

 

Poor glycaemic control has been associated with ncreased risk of diabetic nephropathy and with rapid progression of chronic kidney disease. Findings of the Diabetes Control and Complications (DCCT) study showed that targeting of glycosylated haemoglobin (HbA1c) to a level less than 6% reduced the incidence of new cases of microalbuminuria or macroalbuminuria in patients with type 1 diabetes.

 Similar renal benefits with intensive glycaemic control have been recorded in randomised controlled trials that enrolled people with type 2 diabetes.

However, risk of hypoglycaemic events with tight glucose control can be raised in patients with a low glomerular fi ltration rate because many sulphonylurea drugs and insulieed renal clearance. Thus, the risk-to-benefi t ratio of tight glycaemic control should be considered carefully in individuals with low glomerular fi ltration rate outside the context of a clinical trial.

Other pharmacological treatments to reduce cardiovascular risk

Since few trials have been undertaken specifically in populations with chronic kidney disease, we need to either extrapolate data from randomised controlled trials done in the general population or rely on subgroup analyses of people with chronic kidney disease enrolled in such trials. Although findings of randomized controlled trials of statins undertaken in haemodialysis patients have showo survival benefits,  subgroup results from trials undertaken in the general population suggest that statins signifi  cantly reduce all-cause mortality and cardiovascular events in individuals with an estimated glomerular fi  ltration rate of 30–60 mL per min per 1·73 m². Although secondary analysis of data from cardiovascular randomised controlled trials suggests that statins diminish protein-uria and could result in a small reduction in rate of loss of kidney function, the true renal benefits of these drugs are uncertain.

Aspirin is prescribed frequently to patients with chronic kidney disease because of its established net benefit for secondary prevention of cardiovascular events in the general population, including those in whom chronic kidney disease is typical, such as individuals with hypertension or diabetes.

Whether aspirin has a beneficial effect on progressive loss of kidney function (and whether its beneficial effects on cardiovascular disease outweigh the risk of bleeding associated with advanced chronic kidney disease) remains uncertain.

Data from small studies show no increase in major bleeding rates or other adverse events in patients with chronic kidney disease treated with low-dose aspirin.

In the absence of a large-scale trial, use of low-dose aspirin or other antiplatelet agents must be individualised on the basis of every patient’s cardiovascular and bleeding risks.

 

Additional aspects of medical care

A high frequency of medical encounters, impaired renal clearance of drugs in patients with reduced estimated glomerular filtration rate, and use of agents with potential nephrotoxic effects are all factors that could increase risk of iatrogenic complications in individuals with chronic kidney disease. Patients in the USA admitted to hospital with reduced glomerular filtration rates had increased rates of hip fracture, metabolic derangements, and complications of anaesthesia during surgical admission, and more frequent infections as a result of medical care.

Increasing our awareness of chronic kidney disease, appropriate drug dosing in patients with reduced estimated glomerular filtration rate, and minimisation of exposure to nephrotoxic agents such as iodinated radiocontrast agents and phosphate-based enemas might diminish complications.

 

 

Experts in the subject under consideration are selected by the ACCF and AHA to examine subject-specific data and write guidelines in partnership with representatives from other medical organizations and specialty groups. Writing committees are asked to perform a formal literature review; weigh the strength of evidence for or against particular tests, treatments, or procedures; and include estimates of expected outcomes where such data exist. Patient-specific modifiers, comorbidities, and issues of patient preference that may influence the choice of tests or therapies are considered. When available, information from studies on cost is considered, but data on efficacy and outcomes constitute the primary basis for the recommendations contained herein.

 

In analyzing the data and developing recommendations and supporting text, the writing committee uses evidence-based methodologies developed by the Task Force. The Class of Recommendation (COR) is an estimate of the size of the treatment effect considering risks versus benefits in addition to evidence and/or agreement that a given treatment or procedure is or is not useful/effective or in some situations may cause harm. The Level of Evidence (LOE) is an estimate of the certainty or precision of the treatment effect. The writing committee reviews and ranks evidence supporting each recommendation with the weight of evidence ranked as LOE A, B, or C according to specific definitions that are included in (Table 1). Studies are identified as observational, retrospective, prospective, or randomized where appropriate. For certain conditions for which inadequate data are available, recommendations are based on expert consensus and clinical experience and are ranked as LOE C. When recommendations at LOE C are supported by historical clinical data, appropriate references (including clinical reviews) are cited if available. For issues for which sparse data are available, a survey of current practice among the members of the writing committee is the basis for LOE C recommendations and no references are cited. The schema for COR and LOE is summarized in (Table 1), which also provides suggested phrases for writing recommendations within each COR.

 

A new addition to this methodology is separation of the Class III recommendations to delineate whether the recommendation is determined to be of “no benefit” or is associated with “harm” to the patient. In addition, in view of the increasing number of comparative effectiveness studies, comparator verbs and suggested phrases for writing recommendations for the comparative effectiveness of one treatment or strategy versus another are included for COR I and IIa, LOE A or B only.

In view of the advances in medical therapy across the spectrum of cardiovascular diseases, the Task Force has designated the term guideline-directed medical therapy (GDMT) to represent optimal medical therapy as defined by ACCF/AHA guideline-recommended therapies (primarily Class I). This new term, GDMT, will be used throughout subsequent guidelines.

Because the ACCF/AHA practice guidelines address patient populations (and healthcare providers) residing in North America, drugs that are not currently available in North America are discussed in the text without a specific COR. For studies performed in large numbers of subjects outside North America, each writing committee reviews the potential influence of different practice patterns and patient populations on the treatment effect and relevance to the ACCF/AHA target population to determine whether the findings should inform a specific recommendation.

 

The ACCF/AHA practice guidelines are intended to assist healthcare providers in clinical decision making by describing a range of generally acceptable approaches to the diagnosis, management, and prevention of specific diseases or conditions. The guidelines attempt to define practices that meet the needs of most patients in most circumstances. The ultimate judgment regarding care of a particular patient must be made by the healthcare provider and patient in light of all the circumstances presented by that patient. As a result, situations may arise for which deviations from these guidelines may be appropriate. Clinical decision making should involve consideration of the quality and availability of expertise in the area where care is provided. When these guidelines are used as the basis for regulatory or payer decisions, the goal should be improvement in quality of care. The Task Force recognizes that situations arise in which additional data are needed to inform patient care more effectively; these areas are identified within each respective guideline when appropriate.

 

Prescribed courses of treatment in accordance with these recommendations are effective only if followed. Because lack of patient understanding and adherence may adversely affect outcomes, physicians and other healthcare providers should make every effort to engage the patient’s active participation in prescribed medical regimens and lifestyles. In addition, patients should be informed of the risks, benefits, and alternatives to a particular treatment and should be involved in shared decision making whenever feasible, particularly for COR IIa and IIb, for which the benefit-to-risk ratio may be lower.

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