![]() The release of the surgical outcomes data last Friday was like a firework. There was a loud bang and a brief flash when people looked and then it disappeared into the darkness. In fact the story was more about the data that wasn't released than the data that was. Surgeons who defied the call for their data to be published were looked on with suspicion and outed at the behest of Jeremy Hunt, the Health Secretary. Once upon a time the only thing people talked about when it came to the assessment of quality in angioplasty was the number of procedures performed with high volume operators and centres regarded as the best. Part of this was because procedural volume was easy to measure whilst other quality markers were not. Today sees the publication of the coronary angioplasty data which has been collated by the British Cardiovascular Intervention Society (BCIS). The society has been collecting data on angioplasty since 1992 and presenting it as an annual audit on their website. In 2012 it became possible to link an individual angioplasty procedure to the GMC number of the consultant responsible and hence to produce the operator level data which has been published today. BCIS has tried to not turn this a beauty contest between interventional cardiologists and they have made it difficult, but not impossible, to compare the data. They rightly state that it is not possible to compare different cardiologist and this is true since the case mix of one will be different from another. There are some cardiologists who only perform only elective angioplasty on stable angina patients or who work in hospitals that don't perform primary angioplasty for acute heart attacks. These cardiologists should have very low death rates. BCIS have used a measure of self reported in-hospital death rate, stroke rate and requirement for emergency bypass surgery. From this they calculate a MACCE (major adverse cardiac and cerebrovascular event) rate for each interventional cardiologist. Then they calculate an expected MACCE rate and its 95% confidence interval based on patient factors including age, sex, history of stroke, urgency of procedure using a model developed by the North West Quality Improvement study (NWQIP). In a nutshell provided the cardiologist's MACCE rate is less than the 95% confidence interval then they are not regarded as an "outlier" and their practice is regarded as safe. So what determines MACCE? It is dependent on patient, interventional cardiologist and post-procedure factors. In most cases death, stroke and need for emergency bypass surgery are more dependent on the type of presentation, co-morbidity of the patient and severity of the coronary artery disease. The skill of the cardiologist might be better judged in terms of procedural complications such as vascular access site bleeding, the need for urgent repeat coronary intervention, the number of acute stent thrombosis or stent restenosis. These measures whilst more difficult to collect would provide a better estimate of quality. Measuring survival to hospital discharge as an outcome also leads to anomalies. Take this scenario, Cardiologist A treats an elective, stable patient with a stent and the patient is discharged only to be readmitted 48h later with an acute stent thrombosis causing an acute heart attack. This rare complication can sometimes be caused because of stent under-deployment. Cardiologist B is on call and treats the patient in the catheter lab to salvage the acutely blocked artery but sadly the patient dies. In the current analysis this death is recorded as belonging to Cardiologist B not Cardiologist A. A move to the measurement of 30 day mortality is needed but there will be difficulties in apportioning deaths when two cardiologists have treated the same patients. Another important skill, which is very difficult to measure, is that of case selection. Some cardiologists will attempt emergency angioplasty on almost all patients presenting with an acute myocardial infarction even if the chance of survival is very low. With the publication of this data it is likely that cardiologists will start to think twice before taking such patients to the catheter lab where the procedure may be futile, the outcome inevitable and the death counted on their angioplasty statistics. Interventional cardiologists have often been put in a position where an emergency patient has been turned down by a cardiothoracic surgeon because the risk of operation is deemed to high risk and they have then gone on to offer angioplasty. This behaviour may well change as interventional cardiologists are subject to increasing scrutiny. The other issue is training the next generation of interventional cardiologists. If the consultant is responsible for the procedure and the data is going to be published in a public forum how comfortable will they be allowing a fellow or registrar to be the first operator in a difficult case. If a mistake is made by the trainee cardiologist during the procedure this could affect the outcome. On the other hand if we don't train the interventional cardiologists of the future what hope will there be for us when we are old and need intervention ourselves. So what of the data released today. First we have to accept that some of it is missing as not all hospitals contributed so any conclusion drawn here are based on the data that is available. In 2012, 559 consultant cardiologists performed 83,121 angioplasty procedures. There were 22,426 primary angioplasties performed to treat acute ST elevation myocardial infarctions, 30,399 to treat acute coronary syndromes and 27,860 to treat stable angina. the rest were coded as other or unknown. The majority of angioplasty in the UK is used to treat emergency patients with only 34% of procedures for stable angina. This is very different from the data from other reports such as the New York State where 83% of PCI procedures were done for stable angina. Some hospitals perform a very large number of procedures. For example Liverpool Heart and Chest performed 2929 with the Freeman in Newcastle coming a close second with 2832 procedures. At the other end of the spectrum are the private hospitals which tend to perform mainly elective PCI usually, though not exclusively, by cardiologists who also work in NHS hospitals as well. Hospitals are supposed to perform 250 cases per year to remain viable, 17 hospitals reported completing less procedures than this. What can we learn from the individual data? BCIS have been careful to present the data in a way in which makes the comparison of different cardiologists very difficult. Each operator's data is presented separately on an individual webpage and so to make any direct comparison laborious. I suspect this was a deliberate measure but it does not make it impossible to abstract the data and to look at differences. Most surprisingly they also do not separate the outcome data into elective and non-elective cases. It is obvious that the MACCE rate for elective angioplasty will be low. Currently patients are quoted a 1% chance of heart attack, stroke, death or need for emergency bypass surgery when they sign the consent form. The actual MACCE rate for this procedure is probably around 0.2%. Compare this to the MACCE rate of more than 50% for a patient presenting with an acute myocardial infarction, cardiogenic shock and following an out of hospital cardiac arrest. No cardiologist had MACCE rate greater 95% of predicted so it appears that everyone is operating within the expect levels. I suspect this reflects the crude nature of the MACCE measurement and the NWQIP model which has been used. Looking at the high volume operators the predicted MACCE rates is running about twice as high as the actual MACCE rate suggesting that it does not predict particularly accurately a contemporary patient population. Statistically out of 559 operators one might expect at least 25 to lie above the 95% confidence interval simply by chance alone - none do, again questioning the accuracy of the risk prediction model and any conclusions regarding safety are dubious. BCIS recommend that interventional cardiologists should perform at least 75 PCI procedures per year in order to maintain competence. Nearly 20% of operators are apparently performing less than this with many of the interventional cardiologists working solely in the private sector doing very small numbers of cases each year. The median number of procedures per cardiologist is 138 although there are some cardiologists performing significantly larger numbers of procedures. Some cardiologists MACCE rates fall very close to the 95% confidence limit and some very far away. For example the largest volume operator in the UK who did 591 cases has a MACCE rate of only 0.17% (95% CI: 3.12%) although 62% of his patients were elective and only 5% primary PCI cases. At the other end of the procedural volume spectrum there is great difficulty in analysing data because of the small numbers. When a cardiologist has done only 25 procedures the confidence interval is so wide as to preclude any meaningful analysis. The publication of the angioplasty data by BCIS is a step in the right direction. Hopefully it will lead to an improvement in the quality of data collection and accuracy. What is sorely needed is the development of more accurate risk and quality control models as well as moving to measurement of 30 day mortality. We are at the beginning of a long and interesting journey and at the end we will see that quality in angioplasty is more than procedural volume. References: Grayson AD, Moore RK, Jackson M, et al. Multivariate prediction of major adverse cardiac events after 9914 percutaneous coronary interventions in the north west of England. Heart 2006 May;92(5):658-63. BCIS Individual Operator Level Data Website PCI in New York State Report 2008-2010
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![]() This expression is heard frequently in the world of education and it is a comment on the perils of measurement for measurements sake. The purpose of weighing the pig is to see whether it has put on weight and from that to see what needs to done to help the it gain weight. The act of weighing it alone is generally not regarded as sufficient. Action it is said, must be taken based on the results. Staff in the NHS spend a lot of time measuring, recording and auditing their clinical activity against a variety of measures such as QOF, QUIPs, CQINS and other targets such as the 4 hour wait, the 2 week cancer and 18 week target. Almost not a month goes by without another edict arriving requiring more measurement to be recorded and reported. This emphasis on the tick box and target culture of the NHS has been criticised by the press and politicians alike although it still abounds. The debate goes on about whether all of this is a help or a hindrance in the care of patients. Comparisons are often drawn with the airline industry and its impressive safety record which relies in no small part to extensive checklists. But is healthcare the same as flying a planeload of passengers across the world? Recently we introduced the World Health Organisation surgical checklist into our cardiac catheter laboratory. I though it would be useful to re-read the original New England Journal of Medicine article which provides the scientific evidence for the checklist. Initially I was impressed. Taken at face value implementing this simple checklist would reduce our mortality by 40%. If this were true then it would be remarkable particularly as the intervention is cheap and simple. The study analysed the effects of introducing a surgical safety checklist in 8 hospitals, half in the developed and half in the developing world. Whilst the overall result was impressive, the majority of benefit was seen in hospitals in the developing world where it is likely that patient safety systems were less advanced. Despite this there appeared to be still a small benefit in the hospitals in the developed world which is more difficult to explain since these almost certainly had extensive protocols and surgical checks prior to the implementation of the checklist. One reason to explain why the checklist may have had a beneficial effect is a phenomenon known as the "Hawthorne Effect." The Hawthorne effect describes how people change their performance in response to being observed. The original data comes from a study performed at the Western Electric Hawthorne Factory in Cicero, Illinois. This factory employed more than 40,000 workers to make telephones and switchboards. The employees were assigned to precisely measurable tasks on hundreds of assembly lines. In the 1920s a series of behavioural experiments were performed to try and improve productivity. They studied the effects of lighting on worker efficiency and at the start there was no correlation between productivity and light levels. The workers were then divided into 2 groups for study. Surprisingly just doing this led to a rise in productivity which was equal in both groups. Then they started to progressively reduce the lighting levels until the test group complained they could not see to work. The productivity of both groups again rose in parallel. Next the light bulbs were changed each day in front of the workers and they were told the new bulbs were brighter. The workers commented on the change and increased their productivity even though the new bulbs were no brighter than those that had been removed. These experiments showed that productivity was more related to what the workers believed and not any objective change in their environment. This might be regarded as a workplace demonstration of the placebo effect and may explain why patients who are in the placebo arm of controlled clinical trials usually do better than real world patients. As one cardiologist recently put it: "If I was taken to the emergency room with chest pain the first request I would ask is: Please can I go into a clinical trial?" The Hawthorne effect demonstrated that people change their behaviour when they think they are being watched and this principle has widespread implications in medicine. Simply instituting a checklist may improve the quality of care because the medical staff know they are being monitored. So perhaps in the end you might fatten a pig by weighing it especially if it knows it is going to be weighed and someone is recording the data. ![]() A Surgical Safety Checklist to Reduce Morbidity and Mortality in a Global Population. Harvard Business School and the Hawthorne Experiments (1924-1933) ![]() This week saw the publication of another large clinical trial investigating the effects of dietary supplementation with omega-3 containing fish oil to prevent cardiovascular disease. The use of fish oil to promote good health goes back many hundreds of years however interest grew in the 1960's when there were reports of very low levels of coronary heart disease in Greenland Eskimos. This was attributed to a diet that was rich in marine omega–3 fats and led to the hypothesis that omega-3 supplementation would prevent cardiovascular disease. Today omega-3 is synonymous with good health and supplements are taken widely in the belief that they will prevent heart disease. There has been a large amount of clinical research but much controversy remains as to the effectiveness of these supplements. So what is the evidence that supplementing the diet with fish oils prevents heart disease and are we overlooking other important aspects of the Eskimo diet which might be responsible for their good health? Does fish oil prevent high risk people getting heart disease? A recent study published in NEJM randomised 12,513 patients to take either omega-3 supplements or placebo. The trial subjects had multiple cardiovascular risk factors or clinical evidence of vascular disease. After 5 years 11% of subjects had experienced cardiovascular events but there was no effect of omega-3 treatment. Does fish oil prevent recurrent heart disease after heart attack? In the GISSI-P study diet was supplemented with omega-3 rich fish oil in people who had recently had a heart attack. Over 3.5 years there was a difference of just 1.3% in favour of fish oil in the combined end point of death, non-fatal MI and non-fatal stroke. This study was conducted about 20 years ago and the treatment of patients post MI is now very different. Only 40% of patients were on beta-blockers or ACE inhibitors and only a 25% underwent stenting or had coronary bypass surgery. Clopidogrel, now almost always used after an MI, was not available at that time and the statin mega trials had not been published so at the start of the trial only a few patients were treated with these drugs. The overall effect of omega-3 supplementation was small and of low clinical significance. This was further confirmed in a the more contemporary Alpha-Omega Study published in 2010 which again showed no benefit with omega-3 fatty acid rich margarines. A Cochrane systematic review of trials included 36,913 participants and 41 cohort analyses. Pooled trial results did not show a reduction in the risk of total mortality or combined cardiovascular events in those taking additional omega-3 fats no significant effect of omega-3 fats. Although omega-3 supplementation was originally recommended by NICE most local cardiac networks and guidelines groups have strongly indicated that omega-3 is not a high priority to be prescribed for patients ![]() Why doesn't omega-3 prevent heart disease? Whilst there is biochemical and observational research to suggest that omega-3 fatty acids are beneficial to prevent cardiovascular disease the large controlled clinical trials have been very disappointing. The original fish oil hypothesis was formed following the observation of a very low level of cardiovascular disease in Inuit Eskimos. The diet of an Eskimo would be regarded, at first glance, as extremely unhealthy. It contains a large amount of animal protein and fat. The amount of carbohydrate and sugar is very low. The Eskimo diet is like that of a carnivorous animal and very rich in omega-3 fatty acid. Most researchers have focused on the high omega-3 content of the diet forgetting the high fat and protein content. Because of the link between cholesterol and fat to coronary artery disease, the lack of carbohydrate and sugar in the diet were quietly forgotten. So to pick on one component, albeit present at high level in the diet, and expect that supplementing it into a completely different high carbohydrate Western diet would lower heart disease is not particularly credible. Recently the book by Dr John Yudkin - "Pure, White and Deadly has been republished. The thesis of this book was that the rise in coronary heart disease is due to the increased consumption of sugar in the Western diet rather than the traditional belief that it is related to the consumption of saturate fat. It is interesting that the Eskimo diet was very rich in fat and meat but low in sugar. Perhaps if we want to obtain the same low risk of heart disease of the Eskimos we need to follow their marine diet more closely. References: n–3 Fatty Acids in Patients with Multiple Cardiovascular Risk Factors: The Risk and Prevention Study Collaborative Group N Engl J Med 2013; 368:1800-1808 May 9, 2013 DOI:10.1056/NEJMoa1205409 n–3 Fatty Acids and Cardiovascular Events after Myocardial Infarction Daan Kromhout, M.P.H., Ph.D., Erik J. Giltay, M.D., Ph.D., and Johanna M. Geleijnse, Ph.D. for the Alpha Omega Trial Group N Engl J Med 2010; 363:2015-2026 November 18, 2010 DOI: 10.1056/NEJMoa1003603 ![]() The Strand Workhouse, Cleveland Street If you walk down Cleveland Street, in the heart of the London's Fitzrovia, you come across a boarded-up old building which until 2006 housed the out-patient department of the Middlesex Hospital. Architecturally the Georgian building has little merit and its only feature is a stone relief of an old man pointing to an inscription reading: "Avoid idleness and intemperance". 150 years ago this building was the Strand Union Workhouse and those entering it were under probably no illusions as to their fate. The workhouse master, a Mr Catch, shared a close resemblance to the fictional Mr Bumble. Charles Dickens lived on Cleveland Street, which was then known as Norfolk Street, and it isn't difficult to see how the writer's inspiration for Oliver Twist probably came from his personal knowledge of the workhouse just seven doors away from his house. In the latter part of 1854 Dr Joseph Rogers was busy working as a surgeon apothecary (GP) in Soho during a cholera outbreak. A friend told him, "you will live to regret this outbreak, it will ruin the neighbourhood and your practice for many years to come.. and then you will have nothing to do". This prediction came true and the following year with his practice dwindling Dr Rogers found himself as the medical officer of the Strand Workhouse. In Victorian Britain poverty was rooted in illness and old-age and conditions in the Strand Workhouse were terrible. The beds were so close to each other that it was only possible to get out at the end. The infectious sick were housed with the non-infected in an atmosphere of poor ventilation, lack of sanitation, poor nutrition and supervised by drunken pauper nurses who were without qualification. In this atmosphere suffering, disease and despair abounded. Rogers appealed to the Guardians to remove the laundry to the rear yard of the workhouse, enlarge the cellars to provide better accommodation for sick children and he change the gruel-only diet fed to single mothers for nine days after giving birth. One of Roger's most difficult problems was the workhouse master, George Catch. He and his wife treated the inmates badly and also obstructed most of his efforts to improve conditions. Eventually Rogers finally managed to secure his dismissal on the ground of extreme neglect which resulted in some relief of the inmates who were apparently jubilant at his departure. Following the Crimean war there was interest in sanitary problems and the observation that paupers were more likely to die if they entered the workhouse led, Thomas Wakley, the editor of the Lancet established a special commission to investigate the sanitary state of workhouses and the care of the sick poor. In 1865 they visited the Strand Workhouse commenting that it had but one redeeming feature "the care and skill of the surgeon and of the master and matron, and the improvements in ward management which the zeal of these officers and the benevolence of the lady visitors have effected. They were less complimentary on the environment stating that the buildings are atrociously bad as a residence for sick persons, and they are incapable of real improvement by any cobbling process. Joseph Rogers founded the Association for the Improvement of London Workhouse Infirmaries and by 1867 the Lancet campaign had borne fruit with the passage of the Metropolitan Poor Act which provided new infirmaries separate from workhouses. During the next decade some 20 new hospitals were built in London providing an extra 10,000 beds.
References
http://www.workhouses.org.uk/Strand/ Richardson, R & Hurwitz B. Dr Joseph Rogers and the reform of workhouse medicine BMJ 299 1507 Richardson, R. Dickens and the Workhouse: Oliver Twist and the London Poor. Oxford University Press. http://www.clevelandstreetworkhouse.org Rogers, J. Reminiscences of a Workhouse Medical Officer ![]() If a patient complains of breathlessness one possible cause is collection of fluid around the lungs called a pleural effusion. This diagnosis can be made easily by tapping the chest with the fingers - a technique known as percussion. Percussion was invented by Joseph Leopold Auenbrugger (1722-1809), the son of an innkeeper from Gratz, in Austria. In 1751, after completion of his medical studies, he became assistant physician at the Holy Trinity and Spanish Military Hospital in Vienna. He discovered that tapping his fingers on the patient's chest produced sounds of varying pitch depending on what structure was underneath. As a child he had seen the barrels in his father’s cellar being tapped to find out how much wine they contained and in his work on percussion he wrote that “empty casks are resonant but they become dull when full of wine”. By systematic percussion over the chest he observed that the note was dull over the heart. Likewise if the pleural cavity surrounding the lungs became filled with fluid, the sound of the percussion note was so muffled it became completely or stony dull. He went on to correlate his percussion findings with conditions found at post-mortem and to prove the existence of fluid inside the chest by withdrawing it with a trocar. Auenbrugger practised the percussion technique for seven years before, in 1761, he published his treatise titled: “Inventum Novum ex Percussione Thoracis Humani Ut Signo Abstrusos Interni Pectoris Morbos Detegendi” which translates as “New Invention, by means of percussing the human chest, as a sign of detecting obscure disease in the interior of the chest”. In the 18th Century publication of anything medically often invoked criticism rather than adulation from colleagues. In the preface of his book he wrote: “In making public my discoveries respecting this matter, I have been actuated neither by an itch for writing, nor a fondness for speculation, but by the desire of submitting to my brethren the fruits of seven years observation and reflection. In doing so, I have not been unconscious of the dangers I must encounter, since it has always been the fate of those who have illustrated or improved the arts and sciences by their discoveries, to be beset by envy, malice, hatred, detraction and calumny”. Auenbrugger’s method of percussion was to strike the chest wall directly with the extended fingertips. He found that the note produced was better if the shirt was tightly drawn across the chest (like the covering of a drum) or if the physician’s hand was covered with a leather glove. Today we lay one hand flat on the chest and strike the back of its middle finger with the tip of the middle finger of the other hand. This prodcues a better percussion note and makes it less uncomfortable for the patient compared to striking the chest directly with the fingertips. After his publication the percussion technique was ignored for many years. Baron van Swieten, Professor of Medicine at Vienna University and Auenbruggers teacher, did not mention it in his 1764 treatise on fluid around the lungs in pulmonary tuberculosis and other contemporaries like Vogel confused it with the Hippocratic practice of succussion whereby the patient was shaken vigerously to detect the presence of fluid and air in the thorax. One favourable review appeared describing the discovery as “a torch that was designed to illumine the darkness in which diseases of the thorax had up to this time lain concealed". The poor reception of his book and being dismissed from the Spanish Military Hospital did not seem to harm Auenbrugger's his career prospects. Private practice prospered and he was popular at the Court of Vienna where he was enobled by the Emperor Joseph II with the title “Edler von Auenbrugger". He was also an accomplished musician and at the Emperor’s request wrote the libretto for a comic opera, Der Rauchfangskehrer (The Chimney Sweep) for the court composer Salieri. Percussion remained hidden until 1808 when Jean Nicholas Corvisart, the personal physician to Napoleon, translated Auenbrugger's work from Latin into French and then the technique rapidly came to world-wide attention and use. Today percussion remains a basic clinical skill learnt by all medical students and practised by doctors on a daily basis. ![]() During the 1930's Karl Link was working to find out why cows were apparently dying from haemorrhage. He made the link between the bleeding problems and spoiled hay and in 1941 isolated an anticoagulant from the hay called dicumarol. This chemical reduced the clotting of blood and was highly toxic to rodents. Link assigned the patent on the chemical to the Wisconsin Alumni Research Foundation, which patented the substance in 1948 under the name “warfarin” and began to market the product as a commercial rodenticide. Subsequently it started to be used to treat patients with heart problems to prevent blood clots. Although a number of warfarin like drugs were synthesized they are all vitamin K antagonists and for the last 60 years have been the only available oral anticoagulants. Warfarin has always been a difficult drug to prescribe and use in clinical having multiple drug and food interactions, complex pharmacokinetics and the need for close monitoring. Dosing is complex since the tablet taken today doesn't affect blood clotting until 48-72h later. Many patients are anxious if warfarin is recommnended by their doctor and they are usually reluctant to take the drug. This usually requires a great deal of explanation from the prescribing physician. However when warfarin is used carefully it is a highly effective medicine invaluable for patients when used in conditions such as atrial fibrillation, pulmonary embolism and deep vein thrombosis. Warfarin also enabled valve replacement surgery to be performed with metallic valves which could never have otherwise occurred. If you were a pharmaceutical company looking for a blockbuster drug then developing a replacement for warfarin would have been pretty high up your agenda. In 2004 Ximelagatran was launched as the first orally available anticoagulant and was shown to be non-inferior to warfarin in the SPORTIFF III trial published in the Lancet. Ximelagatran underwent an extensive clinical programme which unfortunately showed significant liver toxicity when used for more than 35 days and because of this it was withdrawn. However In the last 2 years three more new oral anti-coagulants (NOACs) have been launched. Dabigatran is a direct thrombin inhibitor and rivaroxaban and apixaban are factor Xa inhibitors. Each drug has been investigated in a large clinical trial and compared against warfarin. In the trials it was shown that the NOACs were either more effective than warfarin (dabigatran at the 150mg dose) or non-inferior to warfarin (dabigatran at the 110mg dose, rivaroxaban 20mg and apixaban 5mg). The drugs are taken at a fixed dose and unlike warfarin do not need to be monitored with blood tests. Rivaroxaban is a once daily medicine whereas the others are twice daily. Dose adjustment is recommended in the elderly (>80 years) and the drugs are not suitable for people with severe kidney impairment but some can be used in moderate impairment. Clinical experience with these drugs is still limited and a number of questions remain. They do not affect the normal clotting tests undertaken in hospitals and so it is vital that patients inform medical staff if they are taking these medicines especially if they are admitted to hospital as an emergency. There are issues of compliance since blood tests are not required to evaluate the anticoagulant effect and what it is now know how significant the omission of one or two doses would be. It may be more complex to manage patients who bleeding whilst taking NOACs since there are no antidotes are currently available. There are still unknowns such as whether it is safe to cardiovert a person from atrial fibrillation to sinus rhythm on a NOAC. There is data available from the RELY-AF trial subgroup and also recently a subgroup analysis from the ROCKET trial with rivaroxaban has been published but not trial has been done specifically to address this question. We are entering a new era of anti-coagulant treatment. There will always be a role for warfarin but I think we will see it used less and less as clinical experience with the NOACs grows. Much of this is currently being driven by patient choice and apparent ease of prescribing but we need to be cautious whiclinical experience with these medicines grows. RELY-AF Trial ROCKET Trial ARISTOTLE Trial RELY-AF Trial: Cardioversion Substudy ROCKET: Cardioversion Subgroup ![]() Euticals, Prince William Avenue, Sandycroft Doctors and patients probably don't give too much thought to how the medicines they prescribe and take are produced. Cardiologists focus on clinical trials and evidence to guide practice but the actual manufacture of a medicine is something that we take for granted. Until that is we are informed that a particular medicine is just not available because of supply problems. This is the current situation with the drug isosorbide mononitrate (ISMO) which is used to treat patients with heart disease. The medicine is used to treat angina and heart failure and is very widely prescribed. ISMO is a member of a family of medicines known as nitrovasodilators. These drugs work by releasing a chemical called nitric oxide which dilates the arteries and veins and is used to treat chest pain. The other medicines in this family include glyceryl trinitrate and isosorbide dinitrate. Glyceryl trinitrate, also known as GTN, is a supplied as a spray or a tablet to be placed under the tongue. Chemically GTN is the same as nitroglycerine, the explosive component of dynamite. Nitroglycerine was discovered by Asciano Sobrero in 1847 in Turin. He made it by mixing nitric acid with glycerol and then slowly adding sulphuric acid. This reaction produced highly volatile and unstable liquid which was liable to explode. In one of his early experiments Sobrero was badly scarred when a preparation exploded in his face. He is reported to have kept his discovery secret for a year before describing the chemical which he initially referred to as pyro-glycerine from the Greek meaning fire. Sobrero also reported that nitroglycerin had a sweet aromatic taste and when he placed a trace of it on his tongue it gave rise to a violent, pulsating headache, accompanied by weakness of the limbs. Sobrero counselled against producing nitroglycerine it because he considered it too dangerous to be of any practical use however his discovery was developed as an explosive by Alfred Nobel. Nobel combined liquid nitroglycerine with sand in tubes and invented “Dynamite”. He successfully patented this invention and became very wealthy. In 1888 a French newspaper mistook the death of his brother Ludvig for his, headlining his obituary "The merchant of death is dead” the article when on to say “Dr Alfred Nobel, who made his fortune by finding a way to kill the most people as ever before in the shortest time possible, died yesterday." Nobel became troubled by his posthumous reputation and he subsequently changed his will, bequeathing most of his fortune to the establishment of a series of prizes, so that no future obituary writer would have any doubt as to his yearning for peace and progress.” But what of the medical use of nitroglycerine. The physician William Murrell had observed the severe pounding headache after he touched the moist cork from a bottle of nitroglycerine to his tongue. A moment after he experience a violent pulsation in his head. Murrell decided to test the substance on a series of 35 individuals some of whom also received a placebo as a control in the experiment. He found those who took the nitroglycerine experienced same symptoms. It was obvious to Murrell that nitroglycerin produced impressive effect and together with other observations he thought the substance might be useful in treating patients with angina. He tested his theory by his experimental observation describing the case of William A in December 1877. Aged sixty-four William A complained of intense pain in the chest excited by the slightest exertion. Murrell ordered the patient to take 1% nitroglycerine solution in half an ounce of water three times a-day. One week later he reported that there had been a very great improvement with the attacks considerably reduced in frequency and when they did occur much less severe. He also found that if taken during an attack then it would reduce the length and severity and it had always succeeded. This is how nitroglycerine became the part of the standard treatment for angina. In later life Alfred Nobel himself suffered from angina. In 1890 his physician recommended nitroglycerine is a remedy but he declined it. In this letter to his assistant Ragnar Sohlman he wrote: 'My heart trouble will keep me here in Paris for another few days at least, until my doctors are in complete agreement about my immediate treatment. Isn't it the irony of fate that I have been prescribed nitroglycerine, to be taken internally! They call it Trinitrin, so as not to scare the chemist and the public.“ So the nitrovasodilators used to treat patients are high explosives. This is not a problem for patients because only a tiny amount of chemicals are present in medicines. But imagine you are manufacturing the substances then the amounts involved are much greater and therefore the risk of explosion very high. Although there are many different generic manufacturers of ISMO tablets all of them in the UK rely on one company Euticals to supply the API (active pharmaceutical ingredient) and this is where the current problem with the supply of ISMO lies. In November 2012 three workers at the Euticals plant in Wales were hospitalised following a chemical spill of isosorbide dinitrate. This led to an inspection by the Health and Safety Executive and a large amount of explosive isosorbide dinitrate was discovered - not surprising in a factory that was making the chemical which is a byproduct of the manufacture of ISMO. The factory was shut down so that the isosorbide dinitrate could be chemically treated before removal from the site and made safe. This resulted in the manaufacture of ISMO stopping and the UK production of this medication effectively ceasing without warning. Problems with toxicity of nitroglycerine in factory workers is not a new phenomenon. In the 1940's it was very common for munition workers to complain of monday morning headache because of the powerful vasodilator action of nitroglycerine which was absorbed from their skin when handling explosives. This effect wore off quite quickly during the working week due to tolerance developing. At the weekend the workers were resensitised and some even smeared nitroglycerine paste into their cap bands so that they would have a constant exposure and thus remain tolerent to the effects thus avoiding the monday morning headache. With regards to the current problems it is thought that the supply of ISMO will not re-start until the summer of this year and so currently patients who were receiving ISMO are being offered alternative formulations which still contain the same basic ingredient but in a slow release formulation. Powerpoint Presentation on the History of Nitroglycerine as a Treatment for Angina The study of ancient medical history usually relies on documents and objects as sources. Ancient Egyptian medicine is unique because in addition to the ten medical papyri which date from 1550 BCE and objects and tomb drawings historians and biologists have had unparalleled access to human preserved material in the form of mummified remains. ![]() In the 19th century it was not uncommon for people to be invited to the "unrolling" of a mummy brought back from excavations in the middle east. More recently multi-disciplinary teams have come together to investigated mummies in museum collections and from newly excavated sites using non-invasive and tissue sparing techniques such as CT scanning, endoscopy and molecular biology. This has allowed the study of wrapped mummies and allowed these remains to be preserved intact. This work has led to some fascinating insights into the types of diseases present in our ancient ancestors who live over 4000 years ago. For the cardiologist coronary artery disease and atheroscleorsis are often thought of as 20th century problems caused by diet, smoking habits, exercise patterns and lifestyle. It is often said that if we were able to get back to a more primitive diet and to have the daily exercise of the ancient hunter-gatherers then heart disease would be a thing of the past. We also think of hardening of the arteries (so called calcification) as a problem of the elderly person with coronary artery disease, not seen commonly in middle aged individuals. So it is of great interest to see the publication of the HORUS study which has looked for evidence of vascular disease in 137 mummies from around the world (ancient Egypt, ancient Peru, the Ancestral Puebloans of southwest America and the Unangan of the Aleutian Islands). Using whole body CT scanning atherosclerosis was identifed by looking for the presence of calcified plaque in the wall of an artery. Atherosclerosis was noted in just over a third of mummies and in 4% of coronary arteries. This does not seem like a high proportion in the coronary arteries but we have to bear in mind that the average age of the mummies at death was 38 years. Although we commonly assume atherosclerosis to be a modern disease it was certainly present in pre-modern human beings and this raises significant questions about the basic predisposition and also the influences of lifestyle on the development of the atherosclerosis. Coronary artery disease. Sagittal 3D-volume rendered (A) and sagittal oblique 3D volume rendered (B) CT reconstruction of two mummies with coronary calcifications. (A) Coronary calcifications in the mummy of a Unangan woman (mummy 133) aged 47–51 years who lived in the late 19th century CE and was found on Kagamil Island of the Aleutian Islands. (B) Coronary artery calcifications in the mummy of Ahmose-Meritamun (mummy 35), an Egyptian princess aged 40–45 years who lived about 1580–1550 BCE and was found near modern day Luxor. RCA=right coronary artery. CE=common era. BCE=before common era ![]() Atherosclerosis across 4000 years of human history: the Horus study of four ancient populations. AR David: Disease in Mummies: The contribution of new technologies. Lancet Professor Rosalie David, Manchester University ![]() I like spironolactone, it is a great drug for the treatment of resistant hypertension and it has excellent evidence for treatment of poor left ventricular function and heart failure. So this week I read with interest the results of the Aldo-HF trial published in JAMA. This trial asked whether, in patients with heart failure and normal ejection fraction (HFNEF), addition of spironolactone improves echocardiographic measures of diastolic function and/or maximum exercise capacity measured by cardiopulmonary exercise testing. The results are stunningly unimpressive, which must come as a disappointment for the investigators after all the hard work of setting up and performing the trial and for cardiologists still trying to manage this difficult condition. The trial showed a small decrease in an echo measure of diastolic function known as E/E' which is regarded as a surrogate marker for left ventricular filling pressure/left atrial pressure. In spironolactone treated patients E/E' fell from 12.7± 3.6 to 12.1± 3.7 compared to a small increase in placebo group (12.8±4.4 to 13.6±4.3). Those of us practicing echocardiography realise this change is of no clinical signficance and within the day to day variability seen when performing echo. Importantly there was no change in symptoms (NYHA class) or VO2 max in the spironolactone patients. This supports the idea that the echocardiographic changes may be statistically significant but are not clinically significant. Was there anything positive from this trial? It does confirm the place of spironolactone as an effective antihypertensive agent. The BP difference in the spironolactone and placebo groups was 8/3mmHg. There was a small reduction in LV mass index noted (-6g/m2). The authors suggest this was independent of the blood pressure changes and they performed corrections for blood pressure to substantiate this conclusion. I am sceptical about this because other studies have shown that spironolactone reduces central aortic blood pressure significantly more than brachial blood pressure. Central aortic pressure is a more important determinant of afterload and hence a greater stimulus for alteration in LV mass. The other issue for comment, central to all trials of HFNEF, regards the type of patients included in the study. My typical HFNEF patient is an elderly lady with a long history of hypertension and often atrial fibrillation. The main symptoms are usually exertional shortness of breath and fatigue sometimes with ankle oedema. The BNP is often mildly raised and the echo usually shows a small cavity left ventricle with a dilated left atrium. In my experience these patients often respond to spironolactone at least in terms of an improvement in BP control and sometimes symptoms. The rapid rise in blood pressure and heart during exercise also seems to predict a group of more symptomatic patients. In the Aldo-HF trial 50% were female, only 4% had atrial fibrillation and the NT-proBNP at baseline was only 158. The Minnesota Living with Heart Failure score was 21 which is low and suggests that the patients in the clinical trial were mildly symptomatic at the start of the trial. So what is next for spironolactone? The Aldo-HF trial is disappointing but we need to await the results of the forthcoming TOPCAT study which is looking a spironolactone in over 3445 patients with HFNEF (EF>45%) and NTproBNP >360 or a previous admission to hospital with heart failure. This is likely to be a more severe group of patients than the Aldo-HF trial and the results are keenly awaited. The primary completion date is June 2013 so the results are likely to be reported at the AHA meeting this autumn. References The Miracle of Low Dose Spironolactone Laragh, Am J Hypertension 2001, 14:86-89 Effect of Spironolactone on Diastolic Function and Exercise Capacity in Patients With Heart Failure With Preserved Ejection Fraction: The Aldo-DHF Randomized Controlled Trial JAMA Spironolactone on central aortic blood pressure and LV mass in CKD TOPCAT Study Design ![]() In 1975 a simple ceremony was held at the Horton Hospital in Epsom. A plaque was unvieled commemorating the contribution made between 1925 and 1965 towards the "relief of suffering". The building housed the Mott Clinic also known as the Horton Malaria Laboratory. It was here, before the discovery of penicillin, that malaria infected mosquitos were used to treat patients with syphilis. In Vienna at the end of world war one Professor Wagner-Jauregg dicovered that malaria-induced fever was effective in the treatment of the syphilitic condiiton General Paralysis of the Insane (GPI). GPI was a serious problem affecting about 10% of patients in psychiatric hospitals and there was until that time no effective treatment. The malaria therapy was reported to result in over 80% of patients were free of disease progression. The treatment was introduced rapidly into England but there was lack of awareness of the lethal effects of certain species of human malaria parasites such as Plasmodium falciparum. Horton was chosen to treat these patients because after a pilot study at Cane Hill and Claybury hospitals they found that there was a high risk that malaria would spread between patients; Horton was ideal because of the fourteen bed isolation hospital and so to try and render the treatment as safe as possible the Mott Clinic and Horton Laboratory was established. Colonel S. P. James, was the first director and he found a strain of malaria in Madagasca that was safe for use in man. In May 1925, mosquitoes infected with this strain were taken to Horton and fed on two female patients.The function of the laboratory was to provide malaria parasites use in the treatment of GPI and this continued until penicillin made the treatment obsolete. Overall the clinic provided treatment for thousands of patients sufferering from GPI with more than 16,000 treated in Horton Hospital itself. A stream of publications appeared in scientific journals originating from the Horton Laboratory including the discovery of the exoerythrocytic parasite in the liver in man in 1948. The laboratory moved into the testing synthetic antimalarial drugs in conditions of maximum secrecy during the second world war. The laboratory closed in 1973 and its memorabilia and archives are held at the Wellcome Museum and the London School of Hygiene and Tropical Medicine. Epsom and Ewell Archives |
Dr Richard BogleThe opinions expressed in this blog are strictly those of the author and should not be construed as the opinion or policy of my employers nor recommendations for your care or anyone else's. Always seek professional guidance instead. Archives
August 2023
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