ARTICLE XXII - Balloons and Heart

The entry of balloons has heralded a new era in the world of medicine with profound effects in its various important fields. The strongest ripples were however felt in cardiology and specialties dealing with gastroenterology, anaesthesia and urinary system. In cardiology it has revolutionized the approach to many commonly encountered problems. Many more fields await the application of this exciting ‘balloon technology’!

What can balloon do for us? It has been used to track into blood carrying tube – vessels, as air is lighter than blood, so this travels along the course of the vessels. It has been used for retention of a tube in a cavity, with balloon inflated on an end of tube after the entry has been secured prevents its slippage. Similarly it has been used to retain the urinary catheter in the bladder by inflating the balloon at the end. Tubes used in anaesthesia used to have leaking of air around it, that problem is solved by inflating balloon around it. Balloons have been used to arrest bleeding in patients with bleeding varices in dire emergency by exerting direct pressure on bleeding varices.

The biggest breakthrough came with the realization that these balloon could be employed to ‘blow up’ blockages in various parts of body. Balloons of different sizes and quality mounted on different structures have been successfully used for this purpose. They have been used to open up obstructions in gastrointestinal tract without surgery. Blockages in urinary system have been dilated by balloons with minimal patient discomfort and without surgery.

The epic of balloon technology can be witnessed in cardiology where the whole scenario has changed in cardiac catheterization laboratory. Initially cardiac catheterization laboratory was used truly as a laboratory where different diseases were diagnosed based on the information gleaned from catheterization. Now the emphasis is shifting from diagnosis to therapeutics. With the advent of echocardiography, most diseases can be accurately diagnosed without cardiac catheterization. In cardiac cath lab, catheter based therapeutics is predominantly dependent on “poor old balloon”, small balloons blowing up obstruction in coronary and other vessels with excellent results and large balloons opening up narrowed valves with enviable results obviating the need for surgery.

Valvuloplasty:
Large balloons ranging from 10 to 30 mm in diameter are used to open up different valves. Obviously, size of balloon depends on the target and size of patient. These valves are either congenitally narrow or narrow down in later life due to various disease process. Previously surgery was required to open up the stenosed valves and remove the impediments in blood flow. Not any more! The procedure is performed without anaesthesia. As an initial step baseline data is recorded, then access beyond the narrowed valve is secured by manipulating a flexible catheter across it. A long wire is left across the valve and a narrow balloon mounted catheter is manipulated on the wire across the narrowed valve. Once satisfied with the position, the balloon is inflated, first a waist appears confirming the impinging valve on balloon and then it slowly gives way. The The valve is open! No ugly scar on chest, no confinement to bed for days, no need for prolonged antibiotics, no loss of work and the beauty is that the patient can actually walk home the next day.

Obviously these balloon mounted catheters are made of very sophisticated material and a lot of research has been done to perfect the technique and hardware. The catheter system to open Mitral valve is named after Inoue. The only way to cut down the costs are to reuse the balloon after proper sterilization. The chances of success are more than ninety five percent and complication rate is quite low. The balloon used for Pulmonic and Aortic valves are different in size and shape.

Angioplasty (PCI)
Balloon have only recently been tamed, to be used in small vessels supplying heart. It started with Andrea Grundzick in 1979, when a blockage in a vessel was opened in a patient. Since then there has been an explosion in the cath lab of angioplasties. In USA, it is called ‘occulo dilating reflex’ which implies that as soon as a cardiologist sees an obstruction in a vessel, he has an irrepressible urge to dilate it. Or, according to our not very good friends, cardiologists on seeing a blockage develop severe stomach ache which can only be relived on opening up that lesion. No doubt there has been a mad race in opening of the lesions and technology is witnessing tremendous progress in this field.

Most research taking place in cardiology is focused on small balloons used in vessels supplying heart. The aim is to produce tough balloons which can endure high pressure without deforming, mounted on catheter which should have very small profile so that it can negotiate the bends and cross the blockage, the catheters should have enough strength to be pushed around and cross the lesion. Similar research is taking place in paraphernalia like catheter and guide wire.

How is it done? After identifying the blockage a strategy is devised regarding the approach and hardware to be employed. The procedure is similar to angiography where no anaesthesia is administered. After doing angiography, the lesion is crossed with the help of a very find guide wire. Care is taken to float this wire across the lesion preventing it from going to small branches. It is like going through a large tree to a specific branch which might take a minute or a couple of hours. Once the lesion is crossed balloon mounted catheter is introduced and parked at the lesion. The size of balloon chosen depends on the size of the vessel. Satisfied with the position of catheter, the balloon is inflated under X-ray control. Patient experiences pain when balloon is inflated as blood supply to a part of heart is totally prevented. The balloon is kept inflated for as long as a patient can tolerate, varying from a few seconds to a minute. The appearance of waist and later giving way is apparent on X-ray. The lesion gives way with increase in lumen size.

Balloon are also being used to dilate obstructions in vessels supplying brain, kidneys and extremities. New territories are being ventured into and with the development of proper hardware the need for surgery will be obviated in most cases.

Introduction of balloon technology is a fine example of application of common sense to common problems. Balloons have been used for retention, and opening up blockages. This has proven to be a major advance in medicine and surgery and almost all specialties are benefiting from this simple but very exciting technology.

___________________________________________________
Ref: Heal Thy Heart written by Prof: Dr. Muhammad Hafizullah

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ARTICLE XXI - Heart Transplant - Is it a Viable Option?

“Heart transplants have been successfully performed since 1967. Latest figures tell us that 85 percent of those who receive heart transplants survive for more than one year, and 70 percent live five years following the procedure,” I told John Plant, a 40 years old bank with a dilated and poorly pumping heart. He had been in and out of the hospital many times in the last six months. He was on maximal treatment but his effort tolerance remained severely impaired. We had proposed ‘heart transplant’ to him and his first knee jerk reaction was a big ‘no’. “A dream has been transformed into a reality and many patients are enjoying nearly normal life after heart transplant. Today’s heart transplant recipients live longer after surgery than those who received heart transplants just 10 years ago. Many transplant patients go back to work and many participate in moderately strenuous activities, such as walking, swimming and even running,” I added to convince him and eventually he agreed to go for it. Two years down the lane, he was active, playing golf and enjoying holidays in Paris.

Heart transplant has emerged as an established safe and effective theraphy for patients with severe heart problems. Technique of heart transplantation has made great strides of development over the years. Indeed it is a major surgery, in which a severely diseased or damaged heart is replaced with a healthy heart from a recently deceased person. Mortality during surgery is acceptable and the biggest problems are find a heart and prevention of rejection. Patients continue to face a lengthy waiting list to receive a donor heart. According to the recent figures approximately 3,800 patients were waiting for a heart transplant as of June 2007. Only 2,148 people received a donated heart in 2007. According to the American Heart Association, at the present time all over the world, the majority of heart transplant patients were while males. More than half are between the ages of 50 and 64, and about 20 percent are between the ages of 35 and 49. Researches are working to develop equipment to improve the health and comfort for patients waiting for a donor heart and, ideally, to develop a mechanical heart that could permanently solve the shortage problem.

Who needs heart transplant?
When a patient is diagnosed as having an end-stage heart disease, and all medical interventions have failed, and the patient is stable enough to sustain a major surgery then he or she is considered for transplant. End stage heart disease due to decrease in blood supply – coronary artery disease and disease of heart muscle called cardiomyopathy are the most common conditions that may lead to a heart transplant. Heart diseases due to inborn heart problems which are not amenable to surgery are the most common reasons for heart transplant in children. Patients with failure of a previous bypass and persistent angina and heart failure are considered for heart transplant.

Heart transplants are sometimes performed along with lung transplants for individuals with end-stage lung disease that also involves the heart. These conditions are elevated pressures in right sided circulation called pulmonary hypertension. High blood pressure in blood vessels of lungs arising from right side of heart is consequent to either primary – where the cause is not known or Eisenmenger syndrome where the cause is a congenital heart disease. The condition accounts for nearly half of all heart-lung transplants.

Who donates the heart?
Unlike most organs, the heart can only be obtained from donors who die a “brain death,” meaning that the brain dies while the body remains on life support. Organs are obtained from people who give their consent to have certain organs donated. They can also be obtained by permission of next of kin when a suitable donor is considered to be “brain dead.” Although almost 40 percent of donated kidneys are surgically removed from living donors, most major organ donations (e.g., the heart, lungs and liver) are pledged while living and removed when the donor dies. Because of the great demand for organ donors, generally healthy people are strongly encouraged to become donors.

How the heart is transplanted?
Patients waiting for a donor heart are required to report to the hospital immediately on finding a donor. If the donor heart is in the same hospital as the recipient, then the surgery is performed as soon as all preparations have been made. If the donor heart is being transported by ambulance or by air, then the surgical team responsible for the transfer keeps the hospital team informed of their progress.
When the time is right, the patient is given general anesthesia. An incision is made through the chest and sternum, and the ribs are separated. A heart-lung machine takes over the functions of heart and lungs, freeing heart from its normal function so that it can be removed. Some heart muscle is reserved during extraction to act as a support for the new heart as it is sewn into place. When the new heart is positioned and blood vessels are reattached, a heart incision is closed, heart is restarted and blood circulation and oxygen are stored. The warmth of blood should “wake up” the heart and stimulate it to start beating. If this does not occur, it may be necessary to start the heart using an electric shock (defibrillation). Once blood is flowing through the new heart normally and without any leaks, the heart-lung machine is disconnected and chest incision is closed.

After the heart transplant, patient is kept in ICU and monitored during this critical time by cardiac surgeon, cardiologist and other members of the hospital staff. They watch closely for any signs of heart rejection or infection. Medications that suppress the body’s natural immune system are administered to counter the body’s tendency to reject the new heart, and these medications have dramatically reduced the number of rejections.

Patients are unlikely to be very active in the next couple of days, but should be able to walk around in just three or four days. The total length of a hospital stay after a heart transplant is 10 to 14 days. Once a patient is discharged from the hospital, cardiologist and primary physician provide regular medical support, including biopsies and other diagnostic tests several times a year.

The improved life expectancy of patients after a heart transplant is largely due to a new drug called cyclosporine. It is an immunosuppressive drug that appeared in 1983. From its unique way of suppressing the immune system, cyclosporine has become a mainstay in minimizing the body’s tendency to reject a new heart. This is a major risk associated with transplant surgery. When rejection occurs, the immune system sends out antibodies to destroy the new heart, which is perceived as foreign or ‘invading’ tissue cells. Left unchecked, this rejection can result in extensive damage and failure of the transplanted heart.

Problems after the transplant:
Three main problems associated with transplant are rejection, infection and accelerated atherosclerosis.

a. Rejection: Certain tests are required on a regular basis to predict whether the heart is being rejected. These tests include regular biopsies and serial blood tests. Serial biopsies are done to monitor body’s response to the transplanted heart. This involves using a thin tube to remove a small piece of heart tissue. The tube is inserted through a vein either in the groin or side of the neck. Biopsies are outpatient procedures that can be done in under an hour. They are performed often in the first four months after transplantation and, less frequently, in months and years after that. The risk of transplant failure is three times greater among recipients with high levels of troponin I than those with normal levels of this enzyme.
Patients can monitor themselves, as some symptoms may signal rejection, including dizziness, nausea or vomiting, chest pain, shortness of breath, flu-like symptoms like chills, sore throat and fever. Rejection, however, is not necessarily an irreversible event. It can be controlled with different dosage regimen or timing of medications. Patients are encouraged to immediately contact their transplant centre or team, should any of the above symptoms occur.

b. Infection. Patients are urged to immediately report to their physician if any of the following signs of infection like fever, redness, swelling and drainage of fluid appear.

c. Accelerated atherosclerosis. When patients receive a new heart, they also receive new coronary arteries on the surface of that heart. Although these new coronary arteries may have less blockages than their original coronary arteries, heart transplant recipients are more like to develop coronary artery disease (CAD). This disease is thought to be part of the slow rejection process in the transplanted hearts. About 50 percent of heart transplant patients develop CAD. Therefore, patients must undergo cardiac tests periodically to check for the disease.

A longer-term goal for some researchers is the genetically engineered heart. The organ is composed of human tissues – perhaps one’s own – and is cultured or grown over a period of months to match detailed specifications. Currently, this “heart-in-a-box” project exists only in a university research facility, but researchers have a goal to have cryogenically (defined as ‘low-temperature”; in this case, very cold) stored organs available for transplant in less than a decade.

The dreams of yesterday have worn the attire of reality today. Heart transplant is a viable option in selected patients with heart failure, who do not respond to maximal therapy. Due to recent technological advances, the outlook has improved, survival being more than 83% at one year.

___________________________________________________
Ref: Heal Thy Heart written by Prof: Dr. Muhammad Hafizullah

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ARTICLE XX - Bypass Surgery - Anything new?

Farhan, a thirty five year old banker, underwent bypass surgery three years ago. He is back to work, working full time and enjoying his game of golf every evening. He flies abroad to attend meetings and makes full contribution to his job. He is only taking a couple of tablets and observes a few restrictions in his diet. For all practical purposes, he is leading a very active and productive life. And so are most people at different ages, employed in different jobs, from both sexes who had bypass surgery!

Bypass surgery is the most commonly performed heart surgery for coronary artery disease. Persons who develop blockages in their tubes that supply the heart called coronary arteries are the candidates for such surgery. More than 300,000 people have successful by pass surgery only in the United States each year. Bypass surgery is now being routinely performed in major centres of Pakistan with acceptable morbidity and mortality.

What is bypass operation?
Arteries supplying heart, called coronary arteries, develop blockages and can become clogged. Bypass surgery improves blood flow to heart employing a new route, or by “bypassing” blockages in the clogged or diseased artery. The surgery involves using a part of vein from leg or an artery from chest or another part of body to bypass the blocked part of the diseased coronary artery. This creates a new route for blood to flow, so that the heart muscle gets uninterrupted oxygen-rich blood.

How is bypass operation performed?
During bypass surgery, the breast bone (sternum) is divided, heart is stopped, and blood is circulated through a heart-lung machine which performs the function of heart and lungs. Unlike other forms of heart surgery, the chambers of heart are not opened during the operation. Heartlung machine takes over circulation and given enough time to operation on a stand still heart which makes surgery like this possible. The use of machine allows the surgeon to stop heart while the vital organs continue to receive blood and oxygen. Meticulous surgery can be done without interference from bleeding or heart’s pumping motion. Used successfully for the first time in 1953, the machine has proved to be a revolutionary piece of equipment. A perfusion technologist operates the machine. Before hooking upto this machine, a blood-thinning medicine called an anticoagulant is given to prevent blood from clotting. Two large sized cannulas are put in and sewn in major vessels which carry the blood back from inferior and superior vena cava. This blood is oxygenated by the machine like lungs as blood passes in close vicinity of controlled oxygen. A mortorized system then drives this blood back to body where it is delivered to aorta through a cannula to be further distributed to all over body. Meticulous control of speed of motors is required, drawing blood out of body and then delivering back. The amount of oxygen and anticoagulation has to be managed carefully.

The surgical team is led by a cardiovascular surgeon and includes other assisting surgeons, an anesthesiologist, and surgical nurses. A long piece of vein from leg (the saphenous vein) is removed. This piece of vein is called a graft. One end of the graft is attached to ascending aorta, the large artery that carries oxygen-rich blood out of the heart to the body. Other end of the graft is attached to coronary artery below the blockage. The surgeon may choose to use an artery from the inside of chest wall (the internal mammary artery) instead. Or the surgeon may use both vein and artery. The procedure can take from 1 to 2 hours, depending on the number of bypasses needed. The stay in the hospital is about a week, including at least 1 to 3 days in the Intensive Care Unit (ICE). It may prolong in case of any complications. Usually the patient is up and about after two to three days and is encouraged to walk liberally after that.

Advances in bypass surgery:
There have been continuous attempts to make bypass surgery lesser invasive and more patient friendly. Minimally invasive coronary artery bypass surgery has been a major advance. It is done through smaller incisions. It may involve using the mammary artery as a graft. Saphenous veins may also be used. The procedure may be done without stopping heart. Some patients can leave the hospital within 48 hours. This operation is only used for patients whose blockages can be bypassed through this smaller incision and whose risk of complications is low.

Off pump surgery has been heralded as a major step forward to improve post operative course and complications besides reducing the cost. Like conventional bypass surgery, off-pump coronary artery bypass surgery (OPCAB) bypasses blockages in coronary arteries. Off-pump bypass involves the same two procedures that are performed during traditional bypass surgery. In the first, the surgeon removes (harvests) one of the patient’s blood vessels – usually either saphenous vein in leg or mammary artery. In the second procedure, the surgeon uses the blood vessel to create a detour (bypass graft) around the blockages in coronary arteries.

Off-pump bypass allows the surgeon to sew the bypass grafts into place in the chest without stopping heart. This eliminates all risks associated with stopping heart that is necessary during traditional bypass surgery. It also reduces the risk that a patient may experience depression and/or mood swings following surgery – a common side effect with traditional bypass surgery. The surgeon uses certain heart stabilizers and positioners to keep the targeted region of heart virtually motionless while working on a particular coronary artery. The stabilizers restrict heart’s motion to create a stable and nearly still work area for the surgeon. Heart maintains its own rhythm throughout the procedure. In addition, bleeding is greatly reduced, so patients are less likely to need blood transfusion.

What does life promise after bypass?
A person can go back to normal life and job in four to six weeks following an uncomplicated surgery. It may take longer in older age group, those with poor heart function and those with coexistent serious medical problems. One can usually go back to work in 4 to 6 weeks for an office job. Those who have more physically demanding jobs may need to wait longer. In some extreme cases, one may need to find a job that is not as physically demanding. Twenty percent or less of bypass patients may need a second procedure like angioplasty or repeat bypass after 10 years.

Does bypass mean an end to walking and abstinence from cholesterol rich diet?
Is bypass surgery a panacea? Does it give a license to eat and drink as one pleases? Two things are of vital importance after bypass operation: first, meticulous control of risk factors and second, regular exercise. After bypass surgery, the diet has to be modified and one has to limit fat and cholesterol. Risk factors have to be regularly watched and scrupulously controlled. Exercises like walking and swimming are recommended, to get the strength back and develop stamina. The role of exercise has been discussed in details in controlling various risk factors. A cardiac rehabilitation program may be joined on doctor’s recommendation. These programs can help to make lifestyle changes like starting a new diet and exercise program, quitting smoking, and learning to deal with stress.

To conclude, bypass surgery has been a landmark in our fight against coronary artery disease. This is an exquisite application of common sense employing body’s own vessels as alternate paths to deliver blood to viatal parts of heart. The operation has seen many advances and is being done as a routine in many centres. The operative mortality is very acceptable and most patients are back to work in four weeks and most can go back to the previous level of activity.

Heart Transplant - Is it a Viable Option?
“Heart transplants have been successfully performed since 1967. Latest figures tell us that 85 percent of those who receive heart transplants survive for more than one year, and 70 percent live five years following the procedure,” I told John Plant, a 40 years old bank with a dilated and poorly pumping heart. He had been in and out of the hospital many times in the last six months. He was on maximal treatment but his effort tolerance remained severely impaired. We had proposed ‘heart transplant’ to him and his first knee jerk reaction was a big ‘no’. “A dream has been transformed into a reality and many patients are enjoying nearly normal life after heart transplant. Today’s heart transplant recipients live longer after surgery than those who received heart transplants just 10 years ago. Many transplant patients go back to work and many participate in moderately strenuous activities, such as walking, swimming and even running,” I added to convince him and eventually he agreed to go for it. Two years down the lane, he was active, playing golf and enjoying holidays in Paris.

Heart transplant has emerged as an established safe and effective theraphy for patients with severe heart problems. Technique of heart transplantation has made great strides of development over the years. Indeed it is a major surgery, in which a severely diseased or damaged heart is replaced with a healthy heart from a recently deceased person. Mortality during surgery is acceptable and the biggest problems are find a heart and prevention of rejection. Patients continue to face a lengthy waiting list to receive a donor heart. According to the recent figures approximately 3,800 patients were waiting for a heart transplant as of June 2007. Only 2,148 people received a donated heart in 2007. According to the American Heart Association, at the present time all over the world, the majority of heart transplant patients were while males. More than half are between the ages of 50 and 64, and about 20 percent are between the ages of 35 and 49. Researches are working to develop equipment to improve the health and comfort for patients waiting for a donor heart and, ideally, to develop a mechanical heart that could permanently solve the shortage problem.

Who needs heart transplant?
When a patient is diagnosed as having an end-stage heart disease, and all medical interventions have failed, and the patient is stable enough to sustain a major surgery then he or she is considered for transplant. End stage heart disease due to decrease in blood supply – coronary artery disease and disease of heart muscle called cardiomyopathy are the most common conditions that may lead to a heart transplant. Heart diseases due to inborn heart problems which are not amenable to surgery are the most common reasons for heart transplant in children. Patients with failure of a previous bypass and persistent angina and heart failure are considered for heart transplant.

Heart transplants are sometimes performed along with lung transplants for individuals with end-stage lung disease that also involves the heart. These conditions are elevated pressures in right sided circulation called pulmonary hypertension. High blood pressure in blood vessels of lungs arising from right side of heart is consequent to either primary – where the cause is not known or Eisenmenger syndrome where the cause is a congenital heart disease. The condition accounts for nearly half of all heart-lung transplants.

Who donates the heart?
Unlike most organs, the heart can only be obtained from donors who die a “brain death,” meaning that the brain dies while the body remains on life support. Organs are obtained from people who give their consent to have certain organs donated. They can also be obtained by permission of next of kin when a suitable donor is considered to be “brain dead.” Although almost 40 percent of donated kidneys are surgically removed from living donors, most major organ donations (e.g., the heart, lungs and liver) are pledged while living and removed when the donor dies. Because of the great demand for organ donors, generally healthy people are strongly encouraged to become donors.

How the heart is transplanted?
Patients waiting for a donor heart are required to report to the hospital immediately on finding a donor. If the donor heart is in the same hospital as the recipient, then the surgery is performed as soon as all preparations have been made. If the donor heart is being transported by ambulance or by air, then the surgical team responsible for the transfer keeps the hospital team informed of their progress.
When the time is right, the patient is given general anesthesia. An incision is made through the chest and sternum, and the ribs are separated. A heart-lung machine takes over the functions of heart and lungs, freeing heart from its normal function so that it can be removed. Some heart muscle is reserved during extraction to act as a support for the new heart as it is sewn into place. When the new heart is positioned and blood vessels are reattached, a heart incision is closed, heart is restarted and blood circulation and oxygen are stored. The warmth of blood should “wake up” the heart and stimulate it to start beating. If this does not occur, it may be necessary to start the heart using an electric shock (defibrillation). Once blood is flowing through the new heart normally and without any leaks, the heart-lung machine is disconnected and chest incision is closed.

After the heart transplant, patient is kept in ICU and monitored during this critical time by cardiac surgeon, cardiologist and other members of the hospital staff. They watch closely for any signs of heart rejection or infection. Medications that suppress the body’s natural immune system are administered to counter the body’s tendency to reject the new heart, and these medications have dramatically reduced the number of rejections.

Patients are unlikely to be very active in the next couple of days, but should be able to walk around in just three or four days. The total length of a hospital stay after a heart transplant is 10 to 14 days. Once a patient is discharged from the hospital, cardiologist and primary physician provide regular medical support, including biopsies and other diagnostic tests several times a year.

The improved life expectancy of patients after a heart transplant is largely due to a new drug called cyclosporine. It is an immunosuppressive drug that appeared in 1983. From its unique way of suppressing the immune system, cyclosporine has become a mainstay in minimizing the body’s tendency to reject a new heart. This is a major risk associated with transplant surgery. When rejection occurs, the immune system sends out antibodies to destroy the new heart, which is perceived as foreign or ‘invading’ tissue cells. Left unchecked, this rejection can result in extensive damage and failure of the transplanted heart.

Problems after the transplant:
Three main problems associated with transplant are rejection, infection and accelerated atherosclerosis.

a. Rejection: Certain tests are required on a regular basis to predict whether the heart is being rejected. These tests include regular biopsies and serial blood tests. Serial biopsies are done to monitor body’s response to the transplanted heart. This involves using a thin tube to remove a small piece of heart tissue. The tube is inserted through a vein either in the groin or side of the neck. Biopsies are outpatient procedures that can be done in under an hour. They are performed often in the first four months after transplantation and, less frequently, in months and years after that. The risk of transplant failure is three times greater among recipients with high levels of troponin I than those with normal levels of this enzyme.
Patients can monitor themselves, as some symptoms may signal rejection, including dizziness, nausea or vomiting, chest pain, shortness of breath, flu-like symptoms like chills, sore throat and fever. Rejection, however, is not necessarily an irreversible event. It can be controlled with different dosage regimen or timing of medications. Patients are encouraged to immediately contact their transplant centre or team, should any of the above symptoms occur.

b. Infection. Patients are urged to immediately report to their physician if any of the following signs of infection like fever, redness, swelling and drainage of fluid appear.

c. Accelerated atherosclerosis. When patients receive a new heart, they also receive new coronary arteries on the surface of that heart. Although these new coronary arteries may have less blockages than their original coronary arteries, heart transplant recipients are more like to develop coronary artery disease (CAD). This disease is thought to be part of the slow rejection process in the transplanted hearts. About 50 percent of heart transplant patients develop CAD. Therefore, patients must undergo cardiac tests periodically to check for the disease.

A longer-term goal for some researchers is the genetically engineered heart. The organ is composed of human tissues – perhaps one’s own – and is cultured or grown over a period of months to match detailed specifications. Currently, this “heart-in-a-box” project exists only in a university research facility, but researchers have a goal to have cryogenically (defined as ‘low-temperature”; in this case, very cold) stored organs available for transplant in less than a decade.

The dreams of yesterday have worn the attire of reality today. Heart transplant is a viable option in selected patients with heart failure, who do not respond to maximal therapy. Due to recent technological advances, the outlook has improved, survival being more than 83% at one year.

Balloons and Heart
The entry of balloons has heralded a new era in the world of medicine with profound effects in its various important fields. The strongest ripples were however felt in cardiology and specialties dealing with gastroenterology, anaesthesia and urinary system. In cardiology it has revolutionized the approach to many commonly encountered problems. Many more fields await the application of this exciting ‘balloon technology’!

What can balloon do for us? It has been used to track into blood carrying tube – vessels, as air is lighter than blood, so this travels along the course of the vessels. It has been used for retention of a tube in a cavity, with balloon inflated on an end of tube after the entry has been secured prevents its slippage. Similarly it has been used to retain the urinary catheter in the bladder by inflating the balloon at the end. Tubes used in anaesthesia used to have leaking of air around it, that problem is solved by inflating balloon around it. Balloons have been used to arrest bleeding in patients with bleeding varices in dire emergency by exerting direct pressure on bleeding varices.

The biggest breakthrough came with the realization that these balloon could be employed to ‘blow up’ blockages in various parts of body. Balloons of different sizes and quality mounted on different structures have been successfully used for this purpose. They have been used to open up obstructions in gastrointestinal tract without surgery. Blockages in urinary system have been dilated by balloons with minimal patient discomfort and without surgery.

The epic of balloon technology can be witnessed in cardiology where the whole scenario has changed in cardiac catheterization laboratory. Initially cardiac catheterization laboratory was used truly as a laboratory where different diseases were diagnosed based on the information gleaned from catheterization. Now the emphasis is shifting from diagnosis to therapeutics. With the advent of echocardiography, most diseases can be accurately diagnosed without cardiac catheterization. In cardiac cath lab, catheter based therapeutics is predominantly dependent on “poor old balloon”, small balloons blowing up obstruction in coronary and other vessels with excellent results and large balloons opening up narrowed valves with enviable results obviating the need for surgery.

Valvuloplasty:
Large balloons ranging from 10 to 30 mm in diameter are used to open up different valves. Obviously, size of balloon depends on the target and size of patient. These valves are either congenitally narrow or narrow down in later life due to various disease process. Previously surgery was required to open up the stenosed valves and remove the impediments in blood flow. Not any more! The procedure is performed without anaesthesia. As an initial step baseline data is recorded, then access beyond the narrowed valve is secured by manipulating a flexible catheter across it. A long wire is left across the valve and a narrow balloon mounted catheter is manipulated on the wire across the narrowed valve. Once satisfied with the position, the balloon is inflated, first a waist appears confirming the impinging valve on balloon and then it slowly gives way. The The valve is open! No ugly scar on chest, no confinement to bed for days, no need for prolonged antibiotics, no loss of work and the beauty is that the patient can actually walk home the next day.

Obviously these balloon mounted catheters are made of very sophisticated material and a lot of research has been done to perfect the technique and hardware. The catheter system to open Mitral valve is named after Inoue. The only way to cut down the costs are to reuse the balloon after proper sterilization. The chances of success are more than ninety five percent and complication rate is quite low. The balloon used for Pulmonic and Aortic valves are different in size and shape.

Angioplasty (PCI)
Balloon have only recently been tamed, to be used in small vessels supplying heart. It started with Andrea Grundzick in 1979, when a blockage in a vessel was opened in a patient. Since then there has been an explosion in the cath lab of angioplasties. In USA, it is called ‘occulo dilating reflex’ which implies that as soon as a cardiologist sees an obstruction in a vessel, he has an irrepressible urge to dilate it. Or, according to our not very good friends, cardiologists on seeing a blockage develop severe stomach ache which can only be relived on opening up that lesion. No doubt there has been a mad race in opening of the lesions and technology is witnessing tremendous progress in this field.

Most research taking place in cardiology is focused on small balloons used in vessels supplying heart. The aim is to produce tough balloons which can endure high pressure without deforming, mounted on catheter which should have very small profile so that it can negotiate the bends and cross the blockage, the catheters should have enough strength to be pushed around and cross the lesion. Similar research is taking place in paraphernalia like catheter and guide wire.

How is it done? After identifying the blockage a strategy is devised regarding the approach and hardware to be employed. The procedure is similar to angiography where no anaesthesia is administered. After doing angiography, the lesion is crossed with the help of a very find guide wire. Care is taken to float this wire across the lesion preventing it from going to small branches. It is like going through a large tree to a specific branch which might take a minute or a couple of hours. Once the lesion is crossed balloon mounted catheter is introduced and parked at the lesion. The size of balloon chosen depends on the size of the vessel. Satisfied with the position of catheter, the balloon is inflated under X-ray control. Patient experiences pain when balloon is inflated as blood supply to a part of heart is totally prevented. The balloon is kept inflated for as long as a patient can tolerate, varying from a few seconds to a minute. The appearance of waist and later giving way is apparent on X-ray. The lesion gives way with increase in lumen size.

Balloon are also being used to dilate obstructions in vessels supplying brain, kidneys and extremities. New territories are being ventured into and with the development of proper hardware the need for surgery will be obviated in most cases.

Introduction of balloon technology is a fine example of application of common sense to common problems. Balloons have been used for retention, and opening up blockages. This has proven to be a major advance in medicine and surgery and almost all specialties are benefiting from this simple but very exciting technology.

Beyond Balloons and Springs
“You people have been creating havoc in tiny little coronary arteries of the heart, what are you people up to now?” is a question very commonly asked. “Nothing much, after blowing up balloons in the depths of chest, now we are venturing on new territories. Shaving off plaque has been on the cards for a long time with the help of ‘atherectomy’ devices, we have been putting up strong metal scaffolding ‘Stents’ in certain obstructions and using laser in the vessels either to create holes or increase the lumen size. Radiotherapy is being used to prevent restenosis. The name of the game is to enlarge the lumen size with balloon or some other technology,” I brief the gentlemen inquisitive about new technology and his heart, “the other major advance had been to put tiny ultrasound probe mounted catheter into the vessels hence opening a new window to study the vessel before and after the dilatation.”

Balloons have been used for tracking, retention, prevention of leakage, and opening up of stenosis in vessels, valves or other organs. They have been used to track into blood carrying vessels as air is lighter than blood so this travels along the course of the vessel. Swan Ganz catheters are balloon mounted catheters used for pulmonary artery and left heart pressure measurement and determination of cardiac output. Similar balloon tipped catheters have been used as temporary transvenous pacemaker lead. Balloons have been used for retention of the tube in a cavity with balloon inflated on an end of tube after the entry has been secured to prevent its slippage. Most commonly this technique is employed to retain the urinary catheter in the bladed by inflating the balloon at the end.

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Ref: Heal Thy Heart written by Prof: Dr. Muhammad Hafizullah

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ARTICLE XIX - A Drug With Many Roles – Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors)

“We know what we are but we know not what we may be.” Shakespeare (Ophelia, in Hamlet).

Angiotensin converting enzyme inhibitors are a group of drugs for which many more indications were ‘invented’ as the experience accumulated in clinical practice for some time. Initially introduced in early eighties, as a treatment for difficult to control high blood pressure, it has now been used in most heart related diseases. There are very few patients with a significant heart ailment, who leave a cardiology unit without an ACE inhibitor on their discharge slips.

Angiotensin converting enzyme inhibitors are the most widely prescribed drugs in patients with heart problems due to high blood pressure and heart failure. They have an extremely successful track record for lowering systolic and diastolic blood pressure and have been employed usefully in the setting of symptomatic and asymptomatic heart failure and after a heart attack. There are many agents with distinct chemical characteristics and metabolism. Some are given thrice a day and others with long half life are used once a day. They are available in many preparations like Captopril, Enalapril, Lisinopril, Ramipril, Fosinopril etc.

How do they work? They work by inhibiting the formation of a very potent chemical called Angiotensin II, which causes most intense contriction/narrowing of vessels. Due to reduced formation of this agent, vessels are prevented from constricting or conversely allowed to dilate. Besides direct physical effects, it also exerts many other potentially beneficial effects by influencing the hormone release from brain like RAA and sympathetic system.

1. High blood pressure:
They were introduced in the market as potent drugs to reduce both systolic and diastolic blood pressure. They are very effective in bringing blood pressure down in both genders and all age groups. It works quickly and has a sustained effect. Left ventricle – the main pumping chamber develops thickness of walls as a response to pumping blood against high blood pressure. It has been shown to be most effective in reducing this thickness and reversal to normal. It has a benign profile and is well tolerated by majority of patients. As against other classes of anti hypertensive agents, it has no major contraindication so it is a drug of choice in most patients. It is used in preference to others in patients with thickened heartwalls, those in heart failure, poor heart function and after a heart attack. It should not be used in pregnant patients.

2. Heart failure:
Heart failure is the end result of all disease processes effecting the heart. Heart failure implies a condition where heart cannot meet the demands of body. Previously doctors had to solely rely on water tablets to reduce water in body and decrease load on heart. In many short term and long term trials the benefit of ACE inhibitors have been proven to reduce the load on heart – both pre load and after load. In our practice, we ensure that all patients of heart failure receive adequate doses of ACE inhibitors and continue to use them for all times to come. Under the umbrella of ACE inhibitors, the dosage of water tablets called diuretics can be reduced and sometimes totally stopped. Patients feel a lot better with improvement in their symptoms and exercise capacity. The drug can be used for patients in severe, moderate or mild failure. The benefits are equally impressive in all three groups of patients. These effects are independent of blood pressure reduction. Moreover, even patients with low blood pressure, can tolerate adequate doses of ACE inhibitors.

3. Poor heart (LV) function:
Having proven its benefit in patients with obvious heart failure, ACE inhibitors were then tried in patients with no signs of heart failure but having evidence of poor heart function documented on echocardiography or nuclear studies. By using ACE inhibitors in this specific group, patients’ progress to development of symptomatic heart failure can be decreased in a majority of patients or totally avoided in a minority of subjects. This has significant bearing on their eventual outcome in terms of frequency of hospitalizations and death.

4. Heart attack:
In a heart attack a portion of heart is rendered dead/necrotic due to cessation of blood supply. This area stops moving hence makes no contribution towards contraction and pumping of blood. Depending on the site and the vessel involved this may be a small or a large area. Heart tries to compensate for this loss and tries to preserve the output. This puts extra load on adjoining segments. Heart size might increase as the dead tissue is stretched by over zealous contraction of normal segments. This is called remodeling on heart. ACE inhibitors have been used to reverse this process. They have been shown to reverse the remodeling and prevent enlargement of heart size. This would naturally mean lesser number of patients developing heart failure with fewer deaths. ACE inhibitors have become an integral part of treatment for patients sustaining a heart attack.

5. Stroke:
High blood pressure remains the most important contributing factor towards stroke. The reduction of blood pressure is associated with most significant effects on reduction of stroke. Patients with stroke have a high propensity to develop another stroke especially if risk factors are not addressed and corrected. Beyond the reduction of blood pressure, ACE inhibitors have been shown to have a beneficial effect on prevention of stroke and reduction of associated mortality and morbidity. The theory has been postulated that certain ACE inhibitor may have a specific role to play which cannot be explained merely on reduction of blood pressure. Many neurologists, now, routinely use ACE inhibitors in patients after stroke even if the blood pressure is not very high.

6. Stable angina:
Patients with stable angina are normally treated with drugs for symptomatic relief and disease modifying drugs. Whereas Nitrates, Beta blockers and Calcium channel blockers may be employed for symptomatic relief, drugs like Aspirin and Statin have effects on modifying the course of disease. Similarly, ACE inhibitors have now been shown to have disease modifying effects, with significant effects on eventual events like episodes of angina, hospitalization, requirement of procedures like angiography and angioplasty and reduced frequency of death. It has been recommended as a drug to be used in patients with angina with normal or raised blood pressure.

7. High risk patients:
Considering multitude effects of ACE inhibitors, a new challenging role was investigated in a large well conducted trial. Patients with multiple risk factors and higher risk of developing coronary artery disease were studied in a large trial by administering ACE inhibitors and compared with placebo. The results were very encouraging with significant reduction in development of heart attacks and episodes of unstable angina. There was a dramatic decrease in requirement of angiography, angioplasty and bypass surgery. The effects of ACE inhibitors were independent of blood pressure. Here ACE inhibitors are claiming a new role, independent of their ‘traditionally recognised’ effect on blood pressure. Many cardiologists believe that every one with multiple risk factors and high risk of developing heart problems should be prescribed ACE inhibitors for an indefinite time.

8. Renal Protienuria:
At one time patients used to be given Albustix with administration of Captopril – the first ACE inhibitor to monitor any release of protein in urine. The pendulum has swung in opposite direction and beneficial role of ACE inhibitors has been proven in patients with leakage of protein in urine. It has been established in various studies that ACE inhibitors reduce the total amount of protein leaked in twenty four hours with or without its effect on blood pressure.

9. Anti Ischaemia:
Newer ailments are being added to the conditions benefiting from Angiotensin converting enzyme inhibitors. Their new role of possessing anti ischaemic properties has come to limelight only recently. Do angiotensin converting enzyme inhibitors have anti ischaemic properties? ACE inhibitors do not have any consistent short term anti anginal effects. Attention has been focused on the potential long term benefits of ACE inhibitors in preventing ischemic events in patients with stable heart disease. This came as an unexpected finding from large clinical trials conducted in patients with severe, moderate and mild heart failure. A large trial called SOLVD study, for example, demonstrated a reduction in the risk of heart attacks (either first or recurrent) by 23% and the risk of unstable angina by 20% in the treated group. In another study, there was 25% reduction in recurrent heart attack as well as a significant reduction in the rate of revascularization including percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG) in the treated group.

It is unlikely that the observed reduction in ischaemic events can be explained by the blood pressure lowering action of ACE inhibitors alone, since the magnitude of risk reduction was substantially larger than that expected from short term modest reductions in blood pressure. In a recent analysis of 14 trials of blood pressure treatment, diastolic blood pressure reduction of 5 mmHg for about 5 years showed a 14% reduction in fatal and nonfatal heart related events. In a large trial, diastolic blood pressure was reduced by an average of 4 mmHg; this was associated with a 23% reduction in fatal or nonfatal heart attacks and a marked reduction in cardiac deaths. Moreover, the risk reduction in ischemic events were similar in patients with different levels of blood pressure at baseline. In another study, the effects of ACEI were studied on stable patients with heart disease, and the results were impressive reduction in adverse heart related events. Similar results were obtained in high risk population with and without heart diseases. ACE inhibitors exert an indirect anti atherogenic action by reducing vascular smooth muscle growth and proliferation, restoring endothelial function and by reducing the propensity for a plaque to rupture.

Side effects:
By and large ACE inhibitors are very well tolerated. The side effects profile is benign except that it produces persistent hacking cough, which does not respond to cough suppressants. This has been reported differently in different trials but can be observed in up to 10-15% of patients. The cough responds only to stopping of the drug. In patients presenting with persistent cough, sister products of ACE inhibitors called Angiotensin receptor blockers have been used with almost similar efficacy but without cough. Many trials have documented the efficacy and safety of this relatively new group of drugs.

To conclude, ACE inhibitors, initially introduced as anti hypertensive agent, in difficult to control patients at high dosage, newer roles have been discovered and the drug is being used in almost all types of heart problems. ACE inhibitors seem to possess some anti ischemic properties and confer the beneficial effects through various mechanisms but more direct evidence should be sought from large clinical trials to further clear the picture. The question that should all patients with heart disease be receiving ACE inhibitors has now entered into a practical phase and needs serious consideration.


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Ref: Heal Thy Heart written by Prof: Dr. Muhammad Hafizullah

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ARTICLE XVIII - Should everyone take statins?

“Statins, especially in combination with a good diet and regular exercise, have been proven to decrease the risk of heart attack and stroke, lessen the need for heart surgery and angioplasty, and reduce the risk of death significantly. An overview of prevention trials using both drugs and diet to lower cholesterol demonstrated an approximate 25% reduction in nonfatal and 14% in fatal (deadly) heart attacks,” explained my cardiologist after diagnosing my illness and reviewing the investigations. This stimulated me to learn more about the subject of high cholesterol and specially about this new class of drugs. The conclusion of my ‘google search’ was, “Statins are the new class of drugs, introduced in the current decade. These have been shown to have a major impact on heart disease progress. They have been studied extensively and have proven to be a safe and effective way to help patients lower their cholesterol levels,”

As a literate patient I wanted to update my self on current information and intend to share it with you. My first priority was to understand, what is primary and secondary prevention? Primary prevention is for people without any evidence of heart problem and secondary prevention is for patients who already have evidence of cardiac problems. My second aim was to look at the basic data and try to learn about the landmark studies which revolutionized the way the patients of coronary artery disease are treated. My aim was to learn the actual figures beyond non specific terms like mild, moderate and severe. Many small and large studies have been conducted with statin in the scenario of primary and secondary prevention and it is not possible to go over all of them, therefore we will confine our discussion to some important trials. My third aim was to look at safety data for personal reassurance.

The importance of high cholesterol as an important risk factors had always been appreciated by doctors and lay people. Many studies done in the past, employing large populations and different cholesterol lowering strategies failed to show any significant reduction in death rate. Statins used in this setting for the first time have shown very reliable data, that shows reduction of death rate in persons without any evidence of coronary artery disease. The data is not only convincing for people with high cholesterol but also very encouraging in patients with not so high cholesterol.

For the first time, the world of medicine received the news of statins’s efficacy in a population with no existing heart problem, by a study done in Scotland. This evaluated the role of statin in primary prevention in a relatively high risk population. After a 5-year period treatment a significant reduction of 31 percent was achieved in the defined primary endpoint. Total death rate was reduced with no increase in noncardiac death rates. When taking into account suspected coronary events, deaths from coronary artery disease decreased by 33 percent. It reported marked reduction in requirement of coronary angiography and revascularization procedures. The trial established the benefit of statin therapy in a high-risk group. The statin (Pravastatin) demonstrated a significant reduction in death and nonfatal heart attacks.

What does it mean to us as patients? Pravastatin therapy in male subjects with similar patient characteristics to the trial would prevent one event in 31 subjects who take statin therapy over a 5-year period. A conservative estimate of the feasibility of treating patients like those was determined to be well within the range of interventions that are considered to be cost effective approximately $ 13,000 US per year of life saved.

After evaluating the effects of lowering cholesterol in high risk patients, I searched for effects of cholesterol lowering in medium or low risk groups. I found a study that examined the potential impact of statin therapy in subjects including both middle-aged men and women whose total cholesterol approximated the average cholesterol. Lovastatin therapy resulted in a statistically significant 37 percent reduction in the incidence of primary endpoint event. Lovastatin therapy resulted in consistent reductions in event rates in the secondary endpoints: a moderate riask reduction in evascularizations, unstable angina, and nonfatal or fatal heart attack. Among patient subgroups in the group (e.g., women, smokers, and hypertensives), the benefit of lovastatin treatment was comparable with the benefit in the overall cohort. This was the first major clinical trial of a statin to demonstrate reductions in first coronary events in a low-risk subgroup whose profile approximates the general population.

Secondary prevention studies are conducted in patients with established coronary artery disease, offering new insights and directions in the management of coronary artery disease. For the first time we have very convincing data that shows mortality benefit by altering cholesterol levels favourably in patients with high and not so high cholesterol and established coronary artery disease.

A new piece of information that set new trends in heart diseases management came from a study called 4S. This landmark trial demonstrated clearly that statin therapy could reduce total mortality in a secondary prevention situation. The most significant impact on mortality was due to the reduction in heart events. A number of substudies were also performed and demonstrated that Simvastatin therapy was effective in women and older patients - age more than 60 years. Cerebrovascular events (strokes) and new carotid bruits were also significantly reduced by the therapy. This was a large-scale trial that evaluated the effect of Simvastatin therapy in patients with high cholesterol who were either heart attack survivors, patients with angina, or both in a 5.4 year trial.
Very interesting and exciting data was provided by an extremely large secondary prevention trial that evaluated statin (Pravastatin) in patients over a period of 6.1 years. Overall death rate was 22 percent less in the group randomized to statin, which was highly statistically significant. The relative risk reduction by statin in deaths from heart diseases was reduced by 24 percent as compared to placebo. A number of secondary endpoints, including the incidence of heart attacks, revascularization procedures like angioplasty and bypass, hospitalization for unstable angina, stroke and hospital days, were significantly reduced by Statin therapy.

This trial provided extremely strong evidence because of its large and diverse population. It showed that treatment with statin (pravastatin) in secondary prevention is of clinical benefit across a broad range of baseline cholesterol values and is associated with a reduction in total and cardiac mortality without an increase in noncardiac deaths. It became easy, to understand the magnitude of benefit, when I learnt that for every 1000 patients assigned to treatment with statin (pravastatin) over a period of 6 years, a total of 30 deaths, 28 nonfatal heart attacks, and nine nonfatal strokes could be avoided.

New trends were set by a remarkable trial called Heart Protection Study (HPS) that involved 20,000 volunteers, who were at high risk of coronary heart disease. Cholesterol lowering with statin treatment, reduced the risk of heart attacks and strokes by at least one-third. It reduced the need for bypass surgery, angioplasty and amputations by one third. Reductions of at least one-third in these ‘major vascular’ events were found in a very wide range of high risk patients for whom, there had previously been uncertainty about using cholesterol lowering therapy: women as well as men, people aged over 70 as well as younger people, people with blood levels of total cholesterol below 200 mg/dl or of ‘bad’ LDL cholesterol below 120 mg/dl, as well as those considered to have ‘high’ levels.

It was easy for me to understand that about 5 years of statin treatment typically prevents heart attacks, strokes or other major vascular events in: 100 of every 1000 people who previously had a heart attack, 80 of every 1000 people with angina or some other evidence of heart disease, 70 of every 1000 patients who previously had a stroke, 70 of every 1000 people with occlusive disease in leg or other arteries, 70 of every 1000 people with diabetes. I appreciated that in addition, cholesterol lowering reduces the risk of being hospitalized because of worsening angina typically, about 30 fewer admissions per 1000 treated for 5 years. The interesting aspect was that the benefits increased throughout the study treatment period (so more prolonged therapy might be expected to produce even bigger benefits), and are additional to those of other treatments used to prevent heart attacks and strokes.
My third aim was to study the side effects profile. Main side effects pertaining to statins are the effects on muscles and liver. The muscles can be effected by statins ranging from asymptomatic rise in a blood test called creatine kinase and muscle pain to frank rhabdomylosis-destruction of muscles. The evidence that statin drugs may also be associated with development of rhabdomyolysis (destruction of muscles) and kidney failure is understandably of concern. But we have to be careful to understand the extent of problem and not to throw the baby out with the bath water. Whether different statin-fibrate combinations have different risks for rhabdomyolysis (destruction of muscles) is not yet known. In fact, several recent studies have shown other statins and combinations to be effective without evidence of abnormal biochemical test. Results confirm that in large patient data base employing different statins, rhabdomyolysis (destructions of muscles) was extremely rare. Rise in CPK, indicating muscle involvement is comparable with placebo. However this side effect should be kept in mind and drugs which increase the likehood of muscle disese – myopathy should be avoided. Patients on statins presenting with muscle pain and aches should have their CPK checked. The drug should be discontinued if myopathy is suspected, if CPK levels rise markedly, or if the patient has risk factors for rhabdomyolysis (destruction of muscles).

Liver can be effected by statins. Effects can be asymptomatic mild to marked rise of blood test of liver called serum transaminase or frank jaundice. In majority of cases the rise of enzyme is transitory and almost always reversible on discontinuation of therapy. Mild increase in transaminsase (2-4 upper limit of normal), does not warrant cessation of therapy. Close monitoring and reduction of dose is usually sufficient. If the rise is more than 4 times then the drugs should be stopped. A different statin at a lower dose may be initiated and the dose built up slowly. Liver function should be monitored, before treatment is started and periodically checked thereafter like twice a year, for the first year of treatment or until 1 year after the last elevation in dose. Patients titrated to high dosage should receive an additional liver function test at 3 months.

To conclude, it has been proven that an average reduction of cholesterol by 40 mg/dl for about 5 years will result in reduction in non fatal and fatal heart attack by about one fourth. Similar effects are seen in people with no evidence of coronary artery disease and having high or not so high cholesterol. The data is quite encouraging for patients with evidence of coronary artery disease and having high or normal levels of cholesterol. Similar benefits await persons with average or high cholesterol with no heart problem.

The side effects may sound alarming but are very rare and do not require very close monitoring in majority of patients: these side effects should not prevent the more wide spread application of this “new aspirin”.
American College of Cardiology and Amerian Heart Association reassured patients about statin effectiveness and safety and the President of ACC Douglas P Zipes declared.

“While statins like all other drugs have side effects the benefits of using statins to manage patients cholesterol far outweighs the risk of serious side effects from their use. We want to reassure patients that statins have proven to be safe and very effective drugs and we urge patients who are taking statins and have no side effects to continue taking the drug.”

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Ref: Heal Thy Heart written by Prof: Dr. Muhammad Hafizullah

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ARTICLE XVII - Clopidogrel – The Drug of Tomorrow!

Very few drugs have been received in the world of medicine with so much enthusiasm as Clopidogrel. It is one of the few drugs which received wide spread acceptance in its ‘infancy’. It was introduced in the world as Plavix but is available in the country under more than a dozen names like Cloxidil, Noclot, Lowplat, Ogrel, Dogrel, Clogrel, Deplat, Deplug, Platagg, Cumplat etc. Antiplatelet drugs are useful means of preventing acute blockages of vessels causing occlusions in cardiovascular diseases. Clopidogrel is a thienopyridine compound and produces irreversible platelet inhibition.

Clpidogrel inhibits platelet aggregation and that can be seen 2 hours after single oral dose of clopidogrel. Early and more pronounced inhibition can be achieved by using a loading dose using 4-8 tablets providing 300 – 600 mg. Such doeses are used when early inhibition of platelets is required in emergency situations like angioplasty and stenting in unprepared patients and patients presenting with unstable angina and heart attack. Repeated doses of 75 mg clopidogrel per day inhibit platelet aggregation on the first day, and inhibition reaches a steady state between Day 3 and Day 7. Plateleet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days. Absorption is rapid and is not affected by food or antacids. It is extensively metabolized through liver and the elimination half-life is 8 hours.

Many major trials have been conducted to test the efficacy and safety of the drug in various expanding list of indications.

1. Clopidogrel in Angina:

In a large trial employing patients from 16 countries was carried for three years. The aim was to assess the relative efficacy of Clopidogrel and aspirin in reducing the risk of storke, heart attack, or vascular death. There was a relative-risk reduction in favor of Clopidogrel. There were no major differences in terms of safety for both Clopidogrel and Aspirin. So it proved that Clopidogrel was as effective as Aspirin in patients with stable angina and Clopidogrel can be used in patients who cannot tolerate Aspirin.

2. Clopidogrel in Unstable Angina:

Clopidogrel has become the drug of choice in patients presenting with unstable angina. The drug was studied in patients presenting with unstable angina in a study called CURE – Clopidogrel in unstable angina to prevent recurrent events. The aim was to assess the safety and efficacy of combination of clopidogrel and aspirin in tweleve thousand patients presenting within 24 hours of unstable angina. There were significant reduction in primary and secondary outcomes. Significantly fewer patients had recurrent chest pain and underwent angioplasty or surgery. Overall, there was no significant excess of major bleeding episodes after coronary grafting.

3. Clopidogrel in Heart Attack:
The effects of Clopidogrel were studied in a large study employing patients from many centres in China. The trial proved that adding Clopidogrel to Aspirin in acute heart attack prevents around ten major vascular event per thousand treated. There was no excess bleeding in breain-fatal or major. The result confirmed that each million heart attack patients treated for more than two weeks would avoid 5000 deaths and 5000 non-fatal events. Nowe it has become manadatory to administer loading dose 4-8 tablets to patients after a heart attack as soon as possible.

4. Clopidogrel in Angioplasty and Stenting:
One of the major advantages of Clopidogrel lies in prevention of clot formation in patients undergoing stenting with different types of stents. In a large study, patients planned for percutaneous coronary intervention (PCI) were randomized to either Clopidogrel and Aspirin as a loading dose or placebo and aspirin prior to PCI. Patients receiving Clopidogrel with Aspirin showed fewer cases of acute blockage due to clots in the stent. Recent guidelines dictate to start Clopidogrel a few days before the procedure or administer loading dosage of Clopidogrel immediately before the procedure.

The long term effects of antiplatelet therapy in patients following PCI have been evaluated in many trials. The drug has to be continued for long term (3-12 months) in patients receiving bare metal stents and one year to indefinite in those receiving drug eluting stent. The rationale behind this recommendation being the delayed healing of inside layer – endothelium of the vessel after drug eluting stent.

5. Stroke and Transient Ischaemic Attacks:
Clopidogrel is the focus of research in many fields in Cardiology, vascular medicine and neurology. It has been shown to produce salutary effects in prevention of stroke in patients with minor strokes called transient ischemic attack (TIA). Further strokes can be prevented by using Clopidogrel in ischemic stroke patients.

6. Peripheral Vascular Disease:
Clopidogrel has been evaluated in patients with blockages in vessels supplying arms and legs and internal organs. It has been used after surgery, angioplasty and stenting in such vessels and also when intervention is required, with gratifying results. A large trial is being conducted, focusing peripheral arterial disease patients.

7. Irregular Beating of Heart:
Patients with irregular beating of hear called atrial fibrillation develop pooling of blood in left sided storage chamber called left atrium. This stasis of blood can lead to formation of clot, which can dislodge and hit any vessel/part of the body. This results in blockage of that vessel hence cessation fo blood supply to that organ or part. Stroke and heart attack can be result of embolism of clot to brain or heart. Blood can be thinned down and such clots can be prevented by using Dispirin and Clopidogrel on their own or in combination.

Clopidogrel Compared To Other Antiplatelet:
It has some major advantages over ticlopidine – another potent antiplatelet drug. Clopidogrel is six times more potent thatn ticlopidine. It has reduced metabolic burden on liver – the main site of clearance. It has an improved benefit/risk ratio. Clopidogrel related reduction in white blood cells called neutropenia has not been reported whereas all of the earlier trials on ticlopidine reported severe neutropenia.

Side Effects Associated with Clopidogrel:
Clopidogrell may cause side effects, most frequent side effects are rash, bleeding, gastrointestinal upset, and gastro –intestinal bleeding. The personal physician should be informed if a patient experiences excessive tiredness, headache, dizziness, upset stomach, stomach pain, diarrhea, or nose blood. Some side effects can be serious. The following symptoms are uncommon, but if experienced one should report to doctor immediately; black and tarry stools, blood in stools, bloody vomit, vomiting material that looks like coffee ground, unusual bleeding or bruising, fever, sore throat, chills, and other sings of infection, slow or difficult speech, weakness or numbness of an arm or a leg or vision loss.

Clopidogrel is a novel antiplatelet, has definite advantages over aspirin like less severe gastro intestinal bleeding and superiority in reducing major ischemic events. In most of clinical indications clopidogrel is combined with aspirin but it can safely substitute aspirin if the drug cannot be tolerated due to stomach upet. With every passing day, newer indications are being discovered. There has been an exponential increase in the usage of the drug on both sides of Atlantic. All this has been possible because of well conducted mega trials proving the efficacy and safety in large groups of patients.

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Ref: Heal Thy Heart written by Prof: Dr. Muhammad Hafizullah

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ARTICLE XVI - Aspirin – A Panacea?

If Aspirin was to be discovered today, the discoverer will be a nominee for Nobel prize and the drug will be sold in the market fifty times of its current price. This has been one of the most ‘wonderful’ discoveries in the world of science but the credit goes to the ‘rediscovery’ of its many ‘potentials’. The story of Aspirin is that of ‘rags to riches’ starting from a very humble background, it has become one of the most widely prescribed drugs. To start with, it was used only as a pain killer and now it has an application in almost all the fields of medicine directly and indirectly.

The strongest effects have been felt in the field of cardiology. Anyone with the diagnosis of a heart ailment has to have Aspirin. There was a time when ‘digoxin’ was synonymous with cardiac problems and every one with the ‘possibility’ of a heart problem would be prescribed the drug, the same is now true for aspirin. More than that we have entered in an era where it is being ‘over prescribed’ and we have to make special efforts to rationalize its usage to the ones who really need to have it.

The utility of Aspirin has been proven in the courts of statistics – the world of numbers by conducting large clinical trials where it was tested in a ‘blind’ fashion again placebo and other drugs. The results are very impressive and highly significant. The essential role of Aspirin is to reduce the aggregability or stickiness of an important constituent of blood called platelets. Platelets stick together and form a plug which blocks the tubes carrying the nutrition – blood. Hence they reduce or in many cases totally block the blood supply to a part of body which may happen to be heart, brain or kidney.

There is an elaborate system of blood supply, operating in the body which ensures optimal nutrition/blood to each and every part of body and at the same time same medium is used for getting rid of toxic material. Any blockage in the system causes reduction of blood supply to that particular part of body which results in impairment of function of that part or system. Some of the blockages may be due to inborn problems but mostly they are due to the process of atherosclerosis (athero – cheesy and sclerosis-hardening). This is a process by which cheesy material is deposited inside the tube or vessels. This process starts early in life and is progressive. Known risk factors like diabetes, high blood pressure, high cholesterol and smoking predispose to this process and accelerate it. On top of these blockages blood supply may be further reduced with the formation of platelets plugs. Aspirin prevents formation of these plugs hence it has its application in preserving the blood supply to all the systems of the body.

The major advantage is found in preventing the blockage in the blood supply system to heart and brain. It is an important player in ischaemic heart disease presenting as angina, acute coronary syndrome and heart attack. The most convincing effects are seen in the setting of acute myocardial infarction where Aspirin is recommended to be chewed for quick action as soon as possible. Very few treatment modalities have been so well and widely received and practiced as aspirin in heart attack. Aspirin in does of 40 mg can acetylate all the platelet cyclo-oxycenase hence reducing the aggregation property of platelets. In a summary of 33 trials conducted in heart attack, mortalilty in patients on aspirin was reduced from 25% to 11%. The effects are comparable to the use of clot dissolving drugs like streptokinase. It is mandatory for all doctors and paramedical staff to administer a tablet of Aspirin to anyone who presents with chest pain and is suspected to have a heart attack. In the setting of CCU first thing to be given to the patient should be Aspirin. Many doctors carry Aspirin with them, to be taken in case of an emergency.

In patients presenting with unstable angina or acute coronary syndrome Aspirin has been shown to be highly effective in reducing platelets stickiness and restoring blood supply to heart. The usage has been shown to reduce the complications and further progress of disease. Similar salutary effects are seen in patients labeled as stable angina experiencing chest pain on exertion. Every patient with suspicion of heart attack, unstable angina or stable angina should take Aspirin and continue indefinitely in dosage of 75mg per day. Various enteric coated brands are available in the market to reduce hyperacidity.

As a step further, Aspirin is being recommended for patients who have risk factors for developing heart problems. In patients who are diabetic, have high blood pressure or elevated cholesterol, the introduction of Aspirin has been shown to decrease the risks for further problems. Many doctors recommend Aspirin to all the patients above forty years of age, regardless of other risk factors. The evidence to support such treatment is not very robust. In the present day scenario Aspirin is being used in all the presentations and even for the prevention of Ishaemic heart disease.

Aspirin has been used for ages as a first choice in a disease which afflicts the joints and heart at the same time called rheumatic fever. This is a disease, still quite prevalent in the developing countries, in the lower social strata and in childhood. This results in damaging the valves-doors of heart causing heart failure in young children. Many of these children require operation of the valve and some succumb to it. The response to Aspirin is dramatic and quick. The response is taken as evidence of the validity of the diagnosis.

The usage has increased in other cardiovascular diseases where platelets are discouraged to stick together and form clumps. Patients with irregular beating of heart called a trial fibrillation have the propensity of clot formation due to whirling of blood in left storing chamber. These clots can get dislodged and find their way into different circulations. Aspirin is indicated in such situations to prevent clump formation and prevention of stroke.

Aspirin is being used for the prevention of stroke and in patients of transient ischaemic attacks (TIA) enthusiastically in the light of over whelming evidence provided by many large well conducted trials. An analogy can be drawn between stroke and TIA to heart attack and acute coronary syndrome respectively. Blockages in blood supply produce symptoms and these blockages can be prevented by Aspirin. Same as ischaemic heart disease, people at a higher risk of developing stroke are treated with Aspirin for the prevention. Same risk factors as for heart attack are taken into account and treated aggressively.

A unique role for Aspirin has been discovered in pregnancy. Certain patients go into premature labour before their due time. Aspirin plays an important role in preventing that through its action on arachidonic acid. This has been a new tool in the hands of Obstetricians with very good response.

Aspirin can potentially cause gastric erosions and ulcers beside hyperacidity. Paitnets with proven ulcer on endoscopy or barium meal, history of gastrointestinal bleeding or thos receiving antiulcer treatment should not be given aspirin. Patients with known allergy should not be given aspirin. Other platelet inhibitors may be considered in patients who have allergy or who cannot tolerate aspirin.

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Ref: Heal Thy Heart written by Prof: Dr. Muhammad Hafizullah

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