The debate over whether patients with 3 vessel coronary artery disease should be treated with multi-vessel stenting (PCI) or coronary bypass surgery (CABG) has raged for the last decade. Stenting only needed to be as good as surgery for it to become the treatment of choice since the procedure is less invasive and the recovery time quicker. Comparison of the two forms of treatment has been difficult because stents have been constantly improved meaning that every trial was out of date compared to currently available technology at the time the results were published. This week the final 5 year results of the SYNTAX trial were published in the Lancet. This trial randomised 1800 patients to stents or surgery. The average age of the patients was 65 years, 75% were men and 25% diabetic. The combined end point included all-cause mortality, stroke, myocardial infarction and repeat revascularisation. The results showed that 26·9% in the CABG group and 37·3% in the PCI group reached that endpoint (p<0·0001). Myocardial infarction was higher in the PCI group (9.7% vs 3·8%; p<0·0001), as was the need for repeat revascularisation (25·9% vs 13.7%; p<0·0001). All-cause death and stroke were not different. So what can we learn from this trial. First the CABG group appear to get continued benefit as time went on. One explanation for this is that since CABG bypasses, any disease progressing in the artery proximal to the insertion point of the bypass graft remains treated which is not the case if a stent has been implanted. This may not be the whole explanation since CABG did not show a benefit over PCI in the left main stem treatment group although there were only 222 patients in this group. Second, SYNTAX acknowledged that not all 3 vessel disease is the same with some patients have discrete, simple lesions and others having very complex disease. Embedded in this trial was a scoring system (www.syntaxscore.com) which allowed a measure of the severity of the coronary artery disease. Treatment of low score (22 or less) or an isolated left main stem stenosis with CABG did not appear to confer an advantage over stents. In contrast an intermediate or high SYNTAX score predicted a significantly worse outcome if treated with stents rather than CABG. The results indicate that patients with simple three vessel disease could reasonably be treated with stents rather than surgery although it is important to remember that the analysis of subgroups in clinical trials is only hypothesis generating. The subgroups do not have enough patients in them to be adequately powered to draw definitive conclusions. Calculation of the SYNTAX Score gives the cardiologist an estimate of the severity of disease and helps feed into the decision making process regarding the best means of revascularisation. The other issue is that of patient choice. More patients randomised to CABG withdrew from the trial compared to PCI. Faced with a decision regarding what treatment to have the patient will have views and these need to be informed by a discussion of the best available evidence. If a patient understands that stents may have a less good outcome they may still decide to have this treatment because it is less invasive than CABG. The SYNTAX trial also leaves open the question of how to manage much older patients where the risk of stroke and mortality is greater. Many patients we currently see are in their late 70s or 80s, often with severe coronary disease and they may be less included to undergo CABG. Also most of the participants in SYNTAX were male and therefore it is difficult to know whether the outcomes for women would be the same. The SYNTAX trial is an important landmark to inform how we should manage severe coronary artery disease. However we need to remember that as cardiologists we treat individual people and the results of the clinical trials present results from pooled groups of patients may not always be representative of the patient in front of us. Coronary artery bypass graft surgery versus percutaneous coronary intervention in patients with three-vessel disease and left main coronary disease: 5-year follow-up of the randomised, clinical SYNTAX trial
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When a person has a heart attack they often ask why it happened? This is a normal reaction because if you understand why an illness occured then it might be possible to take action to prevent it from occurring again or progressing. Apart from the traditional cardiac risk factors such as age, male gender, smoking, high blood pressure, diabetes and high cholesterol, patients often ask me if job stress has been involved. The Whitehall study performed in the 1980s showed that chronic work stress was associated with increased risk of coronary heart disease especially in men under 50 years old. This was also seen in the INTERHEART study which found that stress at work was associated with more than twice the risk of heart attack. The Womens Health Study also confirmed that the effect of stress on heart disease was not limited to men. Last October The Lancet published a large, individual patient-level meta-analysis of 197473 European men and women without pre-existing coronary heart disease to try and investigate the effect of job strain on development of coronary heart disease. In the study 15% of partipants reported job strain which might be seen as a relatively low overall level of stress. The study assessed both the demands placed on the workers and the degree of control they had over their work. Four groups were identified. Low job strain (low demands/high control), passive (low demands/low control), active (high demands/high control) and high strain (high demands/low control). Compared to the low job strain group, the high control/high demands group did not have increased risk of coornary heart disease. In contrast those workers with low demand/low control jobs had increased risk and the risk was even higher in those with doing jobs with high demands and low control. These results indicate that it is the degree of control a worker has over the demands placed on him or her that determines whether the job increases the risk of coronary disease. A high work pace is not necessarily a stressor if the worker has control. A difficult task might be seen as a challenge rather than being excessively strenuous. Much of this work was carried out in industrial settings and the modern world of work is different and other factors such as the effort-reward imbalance model and job insecurity are likely to be of major importance in the future. So when a person asks: Did stress cause my heart attack? More than a simple yes or no answer is required. You need to understand what job they have been doing and at what level. Getting an idea of the degree of control the individual had to regulate the demands of the job is critical in understanding the role of stress in heart disease. Job Strain and Coronary Heart Disease - Lancet Whitehall Study - Stress & Health Study Job Strain, Job Insecurity, and Incident Cardiovascular Disease in the Women’s Health Study: Results from a 10-Year Prospective Study INTERHEART Study Every day about 400 millions searches are done using the Google search engine. Many of these searches are looking for health information and for every one the search terms, location of the computer and the time of search are stored. This data can be explored freely using Google Trends but can these trends tell us anything useful about disease patterns and do they have any potential to improve healthcare?
When a patient is admitted to St George's Hospital for a daycase cardiac procedure the chances are they will spend part of the day on James Hope Ward. Situated on the first floor of Atkinson Morley Wing this busy ward sees a constant stream of patients admitted for coronary angiograms, angioplasty or cardioversion. Whilst recovering they might wonder who was James Hope, and what was his connection to cardiology and St George's Hospital? James Hope was born near Manchester in 1801. His name was never associated with a disease or syndrome or the naming of a physical sign but his skill was to take a new invention, the stethoscope, and to demonstrate its value in the diagnosis of diseases of the heart. After studying for five years in Edinburgh he undertook further study in London, Paris and Milan beofre being appointed as assistant physician to St George's Hospital at Hyde Park Corner. Over the next 5 years he saw over 20,000 patients that we admitted and a further 15,000 outpatients. He was appointed to the staff of the hospital as physician in 1839 at the age of 38. James Hope’s major contribution to cardiology was to understand the origin of the sounds heard when examining the heart. Laennec, the inventor of the stethoscope, thought that the first heart sound was due to the contraction of the ventricles and the second sound due to contraction of the atria. Hope conducted experiments on the exposed heart of a stunned donkey and correlated the sounds with the movement of the beating heart. He used a dissecting hook to block the aortic valve from closing and found that he was able to eradicate the second heart sound correctly concluding that the second heart sound was due to the closure of the aortic valve. Like many new inventions many doctors were afraid of using the stethoscope. To aid this in July 1838 James Hope hosted a public demonstration on the use of the stethoscope. This was described in the London Medical Gazette: "The following experiment... affords demonstrative proof that the diagnosis in question, usually supposed to require years of experience, may be efficiently taught in the brief space of ten minutes; and I communicate it to you in the hope that, through the medium of your valuable journal, it may by encouraging the diffident proof subservient to the progress of medical science." Sadly James Hope career was cut short by tuberculosis and he died in 1841. He was one of the first physicians interested in cardiology and is remembered for his important contributions to the science of cardiology. His memory lives on for all those staff and patients who come into contact with James Hope ward. Hope J. (1833). A treatise on the diseases of the heart and great vessels: comprising a new view of the physiology of the heart's action according to which the physical signs are explained. It is the ultimate accolade for an inventor or manufacturer when their name becomes part of the language or is used as a verb to describe a action. Examples include Hoover, Xerox and Google. In cardiology the stent, which is used to treat patients with narrowed coronary arteries shares this unique position as a noun and a verb but where did the word stent come from and why are stents called stents? Mosby's medical dictionary defines a stent as "1. a compound used in making dental impressions and medical molds. 2. a mold or device made of stent, used in anchoring skin grafts and for supporting body parts and cavities during grafting of vessels and tubes of the body during surgical anastomosis." In 1856 Dr Charles Stent invented a material made of natural latex mixed with stearine, talc and red dye which resulted in a stable flexible material which could be used to make dental molds. Some years later the famous plastic surgeon Harold Gillies in his 1920 book Plastic Surgery of the Face, wrote "The dental composition used for this purpose is that put forward by Stent, and a mold composed of it, is known us a "Stent." This is probably the first use of Stent's name as a noun. The use of the word stent to describe a scaffold in the vascular system was by Dr Charles Dotter who in 1983 published his report on "Transluminal expandable nitinol coil stent grafting." The first coronary stent was implanted in 1986 by Jacques Puel in Toulouse and together with Ulrich Sigwart they were been credited with developing the concept of the coronary stent. This device is now used in more than 80% of angioplasty procedures and provides a scaffold for the local delivery of drugs to the artery to prevent re-narrowing at the site of implantation. Syndrome X is the name used by cardiologists to describe patients who have typical symptoms of angina, an abnormal exercise ECG but apparantly normal unobstructed coronary arteries. The cause of the syndrome is much debated and many theories as to its aetiology abound. Most of the research focus has been on the coronary microvessels which are believed to have impaired function with an inability to dilate appropately. Clinically these vessels are difficult to assess since the microcirculation of the heart cannot be easily imaged or measured using standard investigations. Almost 50 years after the first description of Syndrome X still it remains somewhat enigmatic. Even the name suggests an element of mystery reminiscent of the "X files" used to refer unsolved cases in the popular television drama of the same name. So why and who named it Syndrome X in the first place? By the late 1960's, with the introduction of selective coronary angiography, it was becoming apparent that not all patients with angina had narrowed coronary arteries. Indeed nowerdays we recognise that ~40% of patients having a coronary angiogram will have no signficant obstruction to blood flow. In 1967 Likoff published a paper in the New England Journal of Medicine reporting "The Paradox of Normal Selective Coronary Arteriograms in Patients Considered to Have Unmistakable Coronary Heart Disease". This paper described 15 pre-menopausal women with smooth coronary arteries but typical cardiac sounding chest pain and an abnormal ECG during bicycle exercise. Once the observation was made further research was performed to try and understand the mechanisms involved. In 1973 Arbogast and Bourassa published a paper examining heart function during atrial pacing in patients with angina and normal coronary angiograms. These patients were referred to as "group X" and they were compared to people with narrowed coronary arteries who were referred to as "group C". These authors showed that rapid pacing of the heart resulted in reduction in cardiac function in patients with coronary disease but paradoxically an enhancement the patients in group X. This observation provoked much debate then and is still difficult to understand because abnormalities of heart function usually go hand-in-hand with reductions in coronary blood flow. The observations with "group X" led to the label of syndrome X being used in the accompanying editoral by Harvey Kemp to describe these patients. This spread though the medical literature and now there are over 1200 papers and articles published on cardiac syndrome X. Likoff W, Segal BL, Kasparian H. Paradox of normal selective coronary arteriograms in patients considered to have unmistakable coronary heart disease.N Engl J Med. 1967 May 11;276(19):1063-6 Arbogast R, Bourassa MG. Myocardial function during atrial pacing in patients with angina pectoris and normal coronary arteriograms. Comparison with patients having significant coronary artery disease.Am J Cardiol. 1973 Sep 7;32(3):257-63. Kemp HG Jr. Syndrome X revisited. J Am Coll Cardiol. 1991 Feb;17(2):507-8. Topological structure of C-reactive protein C reactive protein (CRP) is one of the most widely performed blood tests in patients admitted to hospital. Alongside a full blood count, kidney and liver function test CRP levels give an indication of possible bacterial infection or inflammation. Sometimes, especially in the elderly, it may be the only laboratory test indicating a patient is seriously ill. When discussing CRP on ward rounds one question I commonly ask is: "So what does the "C" in CRP stand for?" Most medical staff will have ordered and interpreted this test dozens of time but they won't have thought about this question. Often answers such as "complement" or even "cardiac" are suggested but neither is correct. The discovery of CRP dates back to 1930 when William Tillett and Thomas Francis, working at the Rockefeller Institute, published a paper in the Journal of Experimental Medicine entitled: "Serological reaction in pneumonia with a non-protein somatic fraction of the pneumococcus." They were investigating the Pneumococcus, a bacteria responsible for pneumonia, meningitis and other serious infections. The pneumococcus was known to contain two distinct constituents. One was present in the bacterial capsule and the other a nucleoprotein in the cell body. Tillett and Francis identified a third chemically distinct, non-protein somatic fraction which was heat and acid soluble. They designated this "Fraction C". Their key discovery was that if sera from patients with bacterial infections was mixed with the C-fraction of the pneumococcus an immediate precipitation was observed. Time course of CRP reaction as patient recovers They went on to show that the precipitation still occured when a patients serum was highly diluted and that reaction appeared promptly following the onset of the illness and disappeared quickly in the recovery phase. In their first paper they called this C-reactive substance but in later showed it to be a protein and renamed C-reaction protein. CRP is widely used today and is useful for assessing patients with suspected infections. In cardiology CRP is valuable in monitoring the response to antibiotic treatment in patients with infective endocarditis. It is also increased in patients with acute coronary syndromes predicting risk of death, cardiac rupture and recurrent myocardial infarction. More recent evidence has also emerged that CRP might have a role in predicting people at increased risk of heart disease. The precise biological role of CRP is still debated and it is unclear 80 years after its discovery whether it is a marker of disease or an immune mediator but whatever its role it is certainly a very valuable biomarker in everyday clinical practice. Tillett WS, Francis T. Serological reactions in pneumonia with a non-protein somatic fraction of pneumococcus. J Exp Med. 1930 Sep 30;52(4):561-71. Colchicum autumnale Colchicine from the autumn crocus (Colchicum autumnale) has been used in medicine for 2000 years. It is mentioned in the Ebers papyrus dating from ~1550BC and it was recognised as a treatment for gout in Dioscorides's De Materia Medica in the first century. Colchicine has shown beneficial effects in treatment of familial Mediterranean fever and recurrent pericarditis. More recent studies have investigated whether colchicine decreases atrial fibrillation after ablation and this week a new trial in JACC has shown that colchicine reduces cardiovascular events in patients with chronic stable angina. In stable coornary artery disease a previous study showed that colchicine 0.5mg twice daily reduced CRP levels by 60%; interesting but hardly proof of a beneficial clinical effect. A clinical trial published in JACC this week has taken this one step forward and investigated the effects of colchicine in patients with stable angiographically proven coronary artery disease. The Low Dose Colchicine (LoDoCo) study investigated 532 patients randomized to open label colchicine (0.5mg per day) treatment or no colchicine for two years. After a 3 year median follow-up the primary outcome (acute coronary syndrome, out-of-hospital cardiac arrest, or noncardioembolic ischemic stroke) occurred in 16% of placebo versus 5.3% of colchicine treated patients (67% significant RRR; NNT 11). The primary endpoint was driven by the reduction in ACS events as you might expect. On the safety side there was an 11% drop out rate from the colchicine treated group due to adverse GI effects of the drug during the first 30 days of treatment. The mechanism of action of colchine in reducing ACS events is unclear and the authors postulate it is secondary to an anti-inflammatory effect reducing cytokines and certaining this trial provides some support for the paradigm that reducing inflammation is beneficial in ACS. However we are still a long way from being able to conclude that colchicine is a therapy for stable CHD patients. A larger double blind clinical trial is needed before it could enter clinical practice for this indication. But who would fund such a trial with with a drug that is generically available. This would seem like an ideal trial for an investigator led study funded from MRC/BHF or Wellcome. However it might just interest the Pharma and in this respect colchicine has history. In July 2009 the FDA officially announced that colchicine was effective in treating acute gout. But didn't we know that 1500 years ago! Well colchicine had never been officially approved by the FDA. Although the 1938 Food, Drug, and Cosmetic Act required new drugs be approved it allowed drugs already marketed to remain available. Colchicine was one of a number of drugs that the FDA never formally evaluated. In 2007 URL Pharma did studies with colchicine to investigate the drug's safety and efficacy in gout in a randomized controlled trial. On the basis of their results the FDA approved Colcrys (the URL brand of Colchicine) for treatment of acute gout. Because this was technically a new indication for the drug, the Hatch-Waxman Act authorized the FDA to give the company 3 years market exclusivity which led to the price of colchicine to rise 50-fold from 9 cents to $4.85 per tablet. Ample enough reward considering the trial only had 185 participants with. A appropriately powered trial of colchinine in stable coronary disease would require a considerably greater number of participants and long period of follow-up so the rewards to Pharma might not be enough to make this viable. So colchicine remains an interesting drug and 2 millenia after its discovery we are still learning new things about its pharmacology but whether it will enter the cardiologists arena for treatment of coronary artery disease remains to be determined. Low-Dose Colchicine for Secondary Prevention of Cardiovascular Disease. JACC 29 Jan 2013: Vol. 61, pp. 404-410. Incentives for Drug Development — The Curious Case of Colchicine. N Engl J Med 2010; 362:2045-2047 Non flowing limiting mid LAD stenosis Most patients who present with an acute coronary syndrome (ACS) undergo coronary angiography and the majority are then treated with percutaneous coronary intervention (PCI). The remaining patients either have coronary artery disease which is not suitable for revascularisation or have lesions which do not appear to be angiographically flow limiting. ACS is thought to arise following rupture or erosion of thin-cap fibroatheroma (TCFA) on vulnerable plaques. When the angiogram shows non-flow limiting, but irregular and hazy lesions, some cardiologists feel uncomfortable treating the patient with medication alone. There is often discussion in the catheter laboratory about whether a coronary stent should be deployed with the rationale that this might "seal" or stabilise" the plaque and reduce the chance of future cardiac events. Advanced imaging with intravascular ultrasound-virtual histology (IVUS-VH) or optical coherence tomography (OCT) may help to identify TCFAs but there is no evidence that treating such lesions with bare metal or drug eluting stents reduces furture coronary events. Any potential benefit of stent treatment needs to be balanced against the risk of procedural complication, re-stenosis and stent thrombosis. A recent trial has sought to address the question of how to treat the vulnerable plaque. The SECRITT study published in Eurointervention in December 2012 investigated the effects of a stenting vulnerable plaque. 23 patients with high risk IVUS-VH and OCT proven TCFA and a non-flow limiting lesion proven with quantitative coronary angiography and FFR by pressure wire were randomised to treatment with a nitinol self-expanding vShield stent. This device has ultrathin 56 micron struts designed to reduce vessel damage and encourage laminar flow. The stent is self expanding and this avoids the need to deploy using conventional high pressure balloons. Following randomisation patient received either the vShield stent (n=13) or standard medical therapy (n=10). The baseline stenosis in the vShield group was 33.2±13.5% and the FFR 0.93±0.06. At six-month follow-up vShield patients had 18.7±16.9% stenosis and FFR was unchanged. The fibrous cap thickness at baseline was 48±12µm increasing to 201±168µm. No dissections occured and there were no plaque ruptures with the VShield. There were no device-related major adverse cardiovascular events (MACE) events at six-month follow-up. In the control group of 5 patients the % diameter stenosis, FFR were unchange at 6 months and there was no significant difference in late loss between the Vshield and medical treated groups. SECRITT is proof of principle study which has demonstrated that passivation and sealing of TCFA with a vShield self-expanding nitinol device appears feasible and safe. Whether treatment of vulerable plaque with conventional stents would have the same results is unknown. A comparison of the VShield with conventional balloon expandable stents has shown conventional stents result in a high proportion tissue prolapse or intra-stent dissection visible with OCT which are less frequently seen with the VShield stent. However, these vessel-wall injuries were not associated with in-hospital clinical events and currently it is difficult to know if OCT-detectable acute vessel-wall injury after stenting is associated with untoward clinical safety events. A long-term, larger randomised study is needed to evaluate the efficacy of stenting the vulnerable plaque is needed, until we have that data intensive medical therapy remains the standard treatment for non-flow limiting lesion. SECRITT Trial Slide Set Comparison of Acute Vessel Wall Injury After Self-Expanding Stent and Conventional Balloon-Expandable Stent Implantation: A Study with Optical Coherence Tomography Today MSD announced that it will be withdrawing its nicotinic acid preparation called Tredaptive following announcement of results from the long awaitied HPS2-Thrive trial. Tredaptive is a combination of nicotinic acid with laropiprant which reduces flushing, the major side effect of the drug. HPS2-Thrive investigated whether, in patients already treated with statins, addition of tredaptive reduced major vascular events. The trial which followed patients for 4 years did not reach its primary endpoint. This result also follows the early termination of the AIM-HIGH trial in 2011 which investigated another nicotinic acid preparation called Niaspan. This trial was also negative. There is epidemiological data from the Framingham Study which showed that risk of cardiovascular disease increases by about 1% for every 1% increase in LDL cholesterol. Clinical trials with statins, which potently lower LDL, have consistently demonstrated reduction in cardiovascular endpoints when compared to placebo. However despite widespread treatment with statins some people still go on to have a heart attack or require coronary stents or bypass surgery leaving cardiologist to look for additional treatments to try and reduce risk and targetting patients with a low HDL has always been an attractive for cardiologists. We recognise that patients with recurrent cardiac events often have low levels of HDL (<1.1mmol/L). This is often seen in patients with type 2 diabetes and in South Indian Asians. People wiht low HDL often have raised triglycerides and small dense LDL particles which are highly atherogenic. There is good evidence from the Framingham Study that for a 1% increase in HDL there is a 3% reduction in the risk of cardiovascular disease. This led pharmaceutical companies to look search for new drugs which increase HDL also to re-examine old drugs (e.g. nicotinic acid) which also raising HDL. But there is a catch, we need to remember that Framingham was an epidemiological study which only looks at associations between risk factors. An association of increased HDL with reduced cardiovascular risk does not prove causality and raising HDL may not translate into reduced atherosclerosis and cardiovascular events. Nicotinic acid also known as vitamin B3 or niacin has been used for 50 years to raise levels of HDL. Early research in the Coronary Drug Project published in the 1970's suggested it might be effective but careful analysis of the study demonstrated only a very modest benefit in decreasing definite non-fatal recurrent myocardial infarction and did not decrease mortality. It was only in a long-term follow up study over 15 years (9 years after medication stopped) that a significant 11% difference in mortality was demonstrated. These results have not been repeated and were performed in non-statin treated patients so the results are not relevant for today's clinical practice. The results of the AIM-HIGH and HPS2-thrive trials are long awaited but clearly demonstrate no benefit of nicotinic acid. Perhaps its time for us to move on from regarding HDL as a target for pharmacological modification and simply use it as a marker of small dense LDL and increased cardiovascular disease risk. |
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
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