Robotic navigation set to guide arrhythmia treatment in SE Asia

Medical Tribune October 2009 P4
David Brill

Cardiac arrhythmia patients can be treated faster, more safely and with less radiation exposure, following the unveiling of a cutting-edge robotic system at the National Heart Centre Singapore (NHCS).

The technology allows electrophysiological catheter ablation to be done by remote control, using magnets to guide the catheter to its target with dexterity that cannot be achieved by hand.

Cardiologists direct proceedings from a computer workstation – sparing them from neck and back pain that can result from manual ablation procedures, which last up to 6 hours. Procedural time is expected to drop to 2-3 hours with the magnetic navigation system.

Twelve patients have already been treated with the system, which is the first of its kind in Southeast Asia.

“The robotic magnetic navigation system can allow us to safely map the heart to 1 to 2 mm accuracy and precision without the use of fluoroscopy,” said Dr. Teo Wee Siong, director of electrophysiology and pacing and senior consultant cardiologist at NHCS.

“This precision cannot be achieved by conventional ablation with our hands manually, no matter how skilled we are. This will definitely improve patient outcome and safety, especially in complex arrhythmia cases such as atrial fibrillation and ventricular tachycardia,” he said.

The procedure eliminates physician radiation exposure and lowers patient exposure by 40 percent compared with conventional ablation. The new catheters are also softer and more flexible than manually operated versions, thereby reducing the risk of damaging the heart walls from 2-3 percent to less than 1 percent.

The feasibility of magnetic navigation systems for catheter ablation was first demonstrated 7 years ago in dogs and pigs. [Circulation 2002;106:2980] The intervening years have seen the technology evolve and progress to human usage, with centers in the US, Italy and Germany among the first to report their results. Some procedural times were initially longer than conventional ablation, but have shortened with growing experience.

Most recently, the Texas Cardiac Arrhythmia Institute, US, reported success in 164 of 193 robotic catheter ablations (85 percent), compared to 159 of 197 manual ablations (81 percent). Mean exposure to fluoroscopy was slightly increased for the first 50 procedures performed with the robotic system (61.8 minutes versus 58.4 minutes for conventional ablation), but dropped to 44.5 minutes over subsequent procedures. [J Cardiovasc Electrophysiol 2009 Jul 28; Epub ahead of print]

NHCS sees around 300 patients each year requiring catheter ablation and an implantable cardioverter-defibrillator. It estimates that around 60 percent of cases could be treated with the new magnetic navigation system.

Aspirin ineffective for primary CVD prevention

Medical Tribune October 2009 P6

David Brill

Aspirin should not be used routinely for primary prevention of cardiovascular disease in people with asymptomatic atherosclerosis, results of a randomized trial suggest.

The Aspirin for Asymptomatic Atherosclerosis (AAA) study found that daily aspirin (100mg) did not significantly reduce vascular events compared to placebo, but increased rates of hemorrhage and gastrointestinal complications.

The trial involved 3,350 Scottish men and women aged 50 to 75 who had a low ankle brachial index (ABI; ≤ 0.95) – indicative of peripheral atherosclerosis. They were followed up for a mean of 8.2 years for primary outcomes of coronary events, stroke and revascularization.

A total of 357 study subjects experienced a vascular event: 181 in the aspirin group and 176 in the placebo group (hazard ratio 1.03, 95% CI 0.84 – 1.27). Secondary outcomes, including angina, transient ischemic attack and all-cause mortality, were also not significantly different between groups.

“There is no support for the routine use of aspirin for the prevention of vascular events in the context of ABI screening in the general population,” said study investigator Professor Gerald Fowkes of the University of Edinburgh, UK.

“It is possible that in the general population, aspirin could produce a smaller reduction in vascular events than this trial was powered to detect, but it is questionable whether such an effect, together with aspirin related morbidity, would justify the additional resources and health care requirements of an ABI screening program,” he said.

Fowkes noted that compliance is lower in the primary prevention setting, adding: “Whether aspirin is beneficial in clinical practice in a patient with a low ABI who was fully compliant with the medication is unknown, so our results cannot be extrapolated into that situation.”

Thirty four major hemorrhages occurred in the aspirin group and 20 in the placebo group (2 percent versus 1.2 percent; hazard ratio 1.71; 95% CI 0.99 – 2.97). There were 14 and eight cases, respectively, of gastrointestinal ulcers (0.8 versus 0.5 percent).

The efficacy of aspirin is well established for secondary prevention in patients with a history of cardiovascular disease, but the risk-benefit ratio for primary prevention in low-risk individuals remains less clear. A recent meta-analysis of six primary prevention trials found that aspirin reduced rates of serious vascular events by 12 percent, but increased major gastrointestinal and extracranial bleeds. [Lancet 2009;373:1849-60]

Recent studies have also questioned the use of aspirin for primary prevention in diabetic patients – a common practice which is advocated in international guidelines. [BMJ 2008;337:a1840]

New biomarker tests could slash heart attack diagnosis time

Medical Tribune October 2009 P7
David Brill

New-generation tests can rapidly accelerate the diagnosis of acute myocardial infarction (MI) – saving time, improving convenience and reducing costs in the emergency department, studies show.

High-sensitivity cardiac troponin assays can now rule MI in or out in patients presenting within the first hours of chest pain onset, thereby removing the delays associated with conventional tests and allowing for earlier transfer and treatment.

Testing for stress marker copeptin, meanwhile, can exclude MI with 99 percent certainty, thus saving many patients from unnecessary further testing.

Professor Christian Müller, reviewing the data, said that the new tests could answer an unmet clinical need in the assessment of chest pain, since current troponin tests have an undetectable “blind interval” of 3-4 hours after the onset of MI. Even if patients follow recommendations and present within 2 hours of chest pain, the test will be negative and electrocardiography monitoring will be required for 6 to 8 hours.

“The current-generation troponin tests are important but have important limitations in [making an] early diagnosis. There seem to be two approaches to solve this problem: either use troponin in combination with copeptin, or perhaps the approach now favored by many is the use of sensitive troponin assays,” said Müller, of the University Hospital Basel, Switzerland.

The new troponin assays were tested in two European multicenter trials, published recently in the New England Journal of Medicine. [2009;361:858-67; 2009;361:868-77]

German investigators tested 1,818 consecutive patients at admission and 3 and 6 hours later. Diagnostic accuracy at admission was higher with a sensitive troponin I test, as compared to a conventional troponin T test (area under the receiver-operated-characteristic curve [AUC] 0.96 versus 0.85). The new test had a clinical sensitivity of 90.7 percent and specificity of 90.2 percent, with accuracy unaffected by the time of chest pain onset.

The second study, led by Müller and colleagues, involved 718 consecutive patients – 123 of whom were ultimately diagnosed with acute MI. Four high-sensitivity assays were tested: all were superior to a conventional test (AUCs 0.95 – 0.96 versus 0.90) when performed at presentation. The difference was most marked in patients presenting within 3 hours of chest pain onset (AUCs 0.92 – 0.94 versus 0.76).

In an earlier study, Müller and colleagues tested 487 potential MI patients for copeptin, the C-terminal section of the vasopressin prohormone, which denotes endogenous stress. Combination with a conventional troponin T test yielded an AUC of 0.97, compared to 0.86 for the troponin test alone (P<0.001). Low levels of both copeptin (<14 pmol/l) and troponin T (≤0.01 μg/l) correctly excluded MI in the majority of cases (sensitivity 98.8 percent; negative predictive value 99.7 percent). [J Am Coll Cardiol 2009;54:60-8]

ESC offers guidance on syncope workup

Medical Tribune October 2009 P9

David Brill

The European Society of Cardiology has updated its guidelines to facilitate the diagnosis and management of syncope – a common clinical challenge for GPs and specialists alike.

A novel diagnostic workflow promotes early risk stratification – enabling prompt treatment for those who need it and avoiding unnecessary therapy for those who don’t.

New emphasis is also placed on prolonged monitoring for patients with benign but recurrent syncope, which can adversely affect quality of life.

The guidelines reflect a multidisciplinary collaboration and have been endorsed by leading European and American societies, ranging from emergency medicine to geriatrics and neurology.

The authors recommend that initial evaluation be performed to divide patients into syncope or non-syncopal loss of consciousness. Genuine cases of syncope should then be divided into certain and uncertain diagnosis – with risk stratification performed for the latter.

“In the vast majority of the population the cause of syncope is something very benign and it has no consequences for the patient. But in some, syncope can be the herald of a severe cardiac arrhythmia or even the first manifestation of a future sudden death, so it is important to recognize in which patients it is severe and in which patients it is benign,” said task force chairman Professor Angel Moya, of the University Hospital Vall d’Hebron in Barcelona, Spain.

The authors have also revised the definition of syncope itself, such that reduced cerebral blood flow is now a prerequisite for diagnosis. They define syncope as: “a transient loss of consciousness due to transient global cerebral hypoperfusion characterized by rapid onset, short duration and spontaneous complete recovery.”

“Without this diagnostic addition the definition of syncope becomes wide enough to include other disorders such as epileptic seizures and concussion. In fact [it] would be nothing more than ‘loss of consciousness,’ irrespective of mechanism and duration,” said Moya.

Syncope is a common problem, thought to affect up to 50 percent of people at least once in their lifetime. The three most common types identified in the guidelines are reflex syncope, orthostatic hypotension and cardiac syncope.

Reflex syncope results from an alteration of the cardiovascular reflexes that control circulation, leading to hypotension and reduced cerebral blood flow. Orthostatic hypertension is typically a recurring event resulting from circulatory abnormalities, which may also cause other symptoms such as dizziness and palpitations. Cardiac syncope is more serious, and is usually a sign of an underlying arrhythmia which should be treated.

The new guidelines – developed in collaboration with the European Heart Rhythm Association, the Heart Failure Association and the Heart Rhythm Society – were published online in the European Heart Journal. [2009 Aug 27; Epub ahead of print]

Experts back healthy lifestyle in battle against CVD

Medical Tribune October 2009 SFV
David Brill

The drive to promote healthy living is gathering fresh momentum, with the publication of two major new studies suggesting substantial potential to tackle cardiovascular disease at a population-wide level.

Fourteen-year follow-up of over 83,000 healthy women in the Nurses’ Health Study showed that those who ate well, exercised and had lower BMI were considerably less likely to develop hypertension – the leading preventable contributor to death in women.

The Physicians’ Health Study, meanwhile, reported that keeping healthy significantly reduced the risk of developing heart failure over 22 years in a cohort of some 21,000 men. Those who followed at least four out of six healthy habits had a 10.1 percent lifetime risk of developing heart failure, compared to 21.2 percent for men who followed none of the six.

Both Asian and international experts are calling for a renewed focus on public health promotion in light of the data.

Dr. Goh Ping Ping, medical director of the Singapore Heart Foundation and chief of cardiology at Changi General Hospital, said that a lot of work remains to be done at the community level and urged doctors to “take a very proactive role”, particularly with opportunistic screening.

“Even if a patient comes in for a medical problem that is not directly related to the heart or to hypertension, [doctors] could also take the opportunity to check their blood pressure, or educate them on these very simple lifestyle principles,” she said, adding that further educational materials should be kept on hand for such cases.

An editorial accompanying the two papers noted that the “powerful simplicity” of the message begs a rethink on the very concept of lifestyle, which is often perceived to be an individual choice. Rather, it is an interaction between personal and societal factors that defines the approach to cardiovascular disease prevention, according to Dr. Véronique Roger of the Mayo Clinic, Minnesota, US. [JAMA 2009;302:437-439]

“The studies … underscore that healthy lifestyle will help prevent cardiovascular disease and greatly enhance health, which is a compelling reminder that health is the shared responsibility of individuals and communities. This in turn implies that public health policies and clinical care must join forces to achieve effective disease prevention,” she wrote.

The Nurses’ Health Study enrolled 83,882 women aged 27 to 44 in 1991, and followed them up until 2005. [JAMA 2009;302:401-11]

BMI, exercise, alcohol intake, adherence to the Dietary Approaches to Stop Hypertension (DASH) diet, use of non-narcotic analgesics and folic acid supplementation were all independently associated to risk of developing hypertension. Women who scored well on all six factors had a hazard ratio of just 0.22 (95% CI 0.10 – 0.51) for incident hypertension. Such healthy livers, however, comprised just 0.3 percent of the population.

The Physicians’ Health Study involved 20,900 men with a mean age of 53.6 at enrollment in 1982, with follow-up until 2008 (mean 22.4 years). [JAMA 2009;302:394-400]

Six lifestyle factors were also assessed: smoking, exercise, body weight, alcohol intake, consumption of fruits and vegetables, and consumption of breakfast cereals. Again, all factors were independently and jointly linked to an increased risk of heart failure.

Singapore’s Health Promotion Board welcomed the studies as “good evidence as to the importance of a healthy lifestyle,” given their size and robust data.

“A large proportion of chronic disease amongst the Asian population can be attributed to lifestyles, i.e. eating habits and lack of physical activity,” said Dr. Shyamala Thilagaratnam, director of the Healthy Ageing Division. “Therefore encouraging Singaporeans to lead a healthy lifestyle is likely to be useful in reducing the burden of chronic disease. Singaporean and other Southeast Asian doctors should use this as good evidence to promote the adoption of a healthy lifestyle amongst their patients.”

Goh added that it is important to adapt the messages of the studies to match local cultures and habits.

“Our dietary patterns are quite different – they talk about cereals for breakfast but that probably doesn’t apply too well here. It’s probably more about telling people not to have nasi lemak or roti prata, for example, and to substitute with something else,” she said.

No benefit to excessive BP lowering, study says

Medical Tribune September 2009 P14
David Brill

Lower is not necessarily better when it comes to blood pressure (BP), a recent systematic review has found.

The analysis of seven randomized trials concluded that there was no clinical benefit to lowering BP beyond a currently recommended target of 140/90 to 160/100 mmHg.

Patients treated to lower targets did achieve significantly lower BPs (-4/-3 mmHg), but there were no differences in total mortality, major cardiovascular events, myocardial infarction or stroke rates compared to those treated to standard targets.

The review included data from a total of 22,089 patients, who had taken part in trials targeting various different diastolic BPs below 85 mmHg. No suitable trials of low systolic BP targets were identified. [Cochrane Database Syst Rev 2009;(3):CD004349]

“At present there is no evidence from randomized trials to support aiming for a BP target lower than 140/90 in the general population of patients with elevated blood pressure,” said lead author Dr. Jose Arguedas, of the University of Costa Rica, Costa Rica.

“Our research included patients with diabetes or chronic renal disease, and the evidence was slightly less robust for those subgroups of patients. We intend to carry out separate systematic reviews for those subgroups, especially because guidelines recommend even lower blood pressure targets for them,” he added.

There were also no significant differences in the incidence of congestive heart failure (relative risk [RR] 0.88, 95% CI 0.59 – 1.32) and end-stage renal disease (RR 1.01, 95% CI 0.81 – 1.27) between patients treated to low, as compared to standard, targets.

The full picture remains unclear with regard to safety, the authors note, since six of the seven trials did not provide complete information on serious adverse events and withdrawals.

Excessive BP lowering could cause unnecessary cost and inconvenience to patients, as well exposing them to a potential increased risk of adverse events if the number of antihypertensive medications is increased, they add.

New CV risk score could replace Framingham in UK

Medical Tribune August 2009 P13

David Brill

The long-established rules for cardiovascular risk assessment could be overhauled in the UK, following calls for the Framingham risk score to be abandoned in favor of a newer model.

An independent analysis found the QRISK score to be superior to Framingham on all measures – identifying a higher proportion of people who went on to develop cardiovascular disease.

The findings prompted a resounding endorsement of QRISK in a British Medical Journal editorial, recommending its routine adoption. Reports have since emerged that QRISK is under review at the UK National Institute for Health and Clinical Excellence (NICE), and is set to be integrated into software packages used by GPs.

University of Oxford statisticians validated QRISK using an independent cohort of 1.07 million patients from 274 UK general practices. There were 43,990 cardiovascular events over a median of 4.9 years’ follow-up. [BMJ 2009 Jul 7;339:b2584]

QRISK under-predicted cardiovascular risk by 12 percent (13 percent for men and 10 percent for women) but was considerably more accurate than the Anderson Framingham algorithm, which overestimated risk by 23 percent (32 percent for men and 10 percent for women).

“We believe this formula has the potential to save many thousands of lives, by helping clinicians to more accurately predict those at risk of developing cardiovascular disease – the nation’s biggest killer,” said Professor Julia Hippisley-Cox of the University of Nottingham, who led the team which developed the QRISK score.

“It will arm doctors with all the information they need to decide how best to target patients with preventative measures such as lifestyle advice and cholesterol-lowering treatments. We are delighted to receive another strong endorsement of the value of QRISK in assessing the risk of heart disease in the UK population,” she said.

QRISK includes most of the traditional risk factors seen in the Framingham equations but also includes family history, social deprivation, body mass index and use of antihypertensive treatments. It was first developed and validated in 2007, using data from 1.28 million patients from 318 UK general practices. [BMJ 2007 Jul 21;335(7611):136]

Further refinements to the model – QRISK2 – were published last year to include ethnicity and other conditions such as type 2 diabetes, hypertension, atrial fibrillation, renal disease and rheumatoid arthritis. The updated version, however, has yet to receive independent validation. [BMJ 2008 Jun 28;336(7659):1475-82]

The external validation of the original QRISK was commissioned by the UK Department of Health to compare the model against the Anderson Framingham algorithm, which is presently recommended by NICE as the basis for deciding on whether to prescribe statins.

The incidence rate of cardiovascular events was 30.5 per 1,000 person years among men who were classed as high risk by QRISK, compared to 23.7 per 1,000 person years among men classed as high risk by the Anderson Framingham score. In high-risk women, the incidence rates were 26.7 per 1,000 person years for those identified with QRISK, and 22.2 per 1,000 person years for those identified by Anderson Framingham.

Despite the improvements with QRISK, the data provide “a sobering message about the current state of cardiovascular risk prediction,” according to the authors of the accompanying editorial. Increased usage, improved data collection and further refinements to the system could however increase the accuracy of risk prediction in future, wrote Professor Rod Jackson of the University of Auckland, New Zealand, and colleagues. [BMJ 2009 Jul 7;339:b2673]

Laughter: The best medicine for cardiovascular disease?

Medical Tribune June 2009 P3
David Brill

Watching comedy shows can improve cardiovascular risk factors, researchers have reported in the journal Psychosomatic Medicine.

The study of 18 healthy people found that arterial stiffness and central hemodynamics improved after watching a 30-minute section from the movie Naked Gun. Cortisol and von Willebrand factor levels also decreased with laughter, reported the team from Athens Medical School, Greece.

Watching stressful scenes, however, had the opposite effect: carotid-femoral pulse wave velocity increased after watching a 30-minute clip from Saving Private Ryan. Stressful viewing also lowered interleukin-6 levels, but did not affect fibrinogen or soluble CD40 ligand levels. [Psychosom Med 2009 Feb 27]

Fatty fish and fish oils could lower HF risk in men

Medical Tribune June 2009 P5
David Brill

Moderate consumption of fatty fish and marine omega-3 fatty acids may help to protect against heart failure (HF), a study of Swedish men has found.

Eating fatty fish once a week reduced the chances of developing HF over 6 years by 12 percent, while consuming around 0.3 grams a day of marine omega-3 fatty acids reduced the risk by 33 percent (adjusted hazard ratios 0.88, 95 percent CI 0.68 – 1.13; and 0.67, 05 percent CI 0.50 – 0.90).

The apparent protective effect did not grow stronger with increasing consumption, however. Eating more than moderate amounts, in fact, restored HF risk almost to that of men who did not consume any fatty fish or marine omega-3 fatty acids.

The researchers conducted food questionnaires in 39,367 men aged 45 to 75, and followed them up in inpatient and cause-of-death registries from 1998 to 2004. A total of 597 men developed HF in this time, 34 of whom died. [Eur Heart J 2009 Apr 21; Epub ahead of print]

“Our study shows that a moderate intake of fatty fish and marine omega-3 fatty acids is associated with lower rates of HF in men, but that the men did not gain a greater benefit by eating more of these foods,” said lead author Dr. Emily Levitan, a cardiology research fellow at Harvard Medical School, US.

“This study reinforces the current recommendations for moderate consumption of fatty fish. For example, the Swedish National Food Administration recommends consuming fish two to three times per week, with one of those portions being fatty fish. Similarly, the American Heart Association recommends eating fish, preferably fatty fish, twice a week,” she said.

Omega-3 fatty acids, which are found in fish oil, have been previously shown to reduce blood pressure, triglycerides and platelet aggregation, and to benefit heart rate and endothelial function. Consumption of fatty fish, such as salmon, herring and mackerel, has also been shown to confer cardiovascular benefits: one such study found that moderate consumption reduced the risk of coronary death by 36 percent and total mortality by 17 percent. [JAMA 2006 Oct 18;296(15):1885-99]

The reason for the U-shaped association between consumption and HF risk in the present study is unclear, said Levitan, although she speculated that men with poor health may be eating more fish in an attempt to improve their wellbeing.

“It will be important to replicate these findings in other populations, particularly those including women, as our study was conducted in men only,” she added.

Omega-3 fatty acids may also have a protective effect against age-related macular degeneration (AMD), a recent study of elderly Australians suggests. One serving of fish per week reduced AMD risk by 31 percent, with a similar magnitude observed for consumption of long-chain omega-3 polyunsaturated fatty acids. [Arch Ophthalmol 2009 May;127(5):656-65]

The OMEGA (Randomized trial of omega-3 fatty acids on top of modern therapy after acute myocardial infarction) trial, however, found that daily consumption of omega-3 fatty acids had no benefit for preventing sudden cardiac death after acute myocardial infarction, in a cohort of 3,851 patients with 1-year follow-up. The results were presented recently at the Annual Scientific Session of the American College of Cardiology.

Study heralds dawn of the cardiovascular polypill

Medical Tribune May 2009 P1&6

David Brill

A five-drug combination tablet could cut the risk of coronary heart disease by more than 60 percent and nearly halve the risk of stroke, results of the first major ‘polypill’ trial suggest.

The Indian Polycap Study (TIPS) found that combining the medications did not hinder their potency – offering effective blood pressure (BP) and lipid control with a simple once-daily capsule.

The study paves the way for further trials to see whether the pill improves clinical outcomes on a wide scale, say the researchers.

The Polycap formulation used in TIPS contains low doses of aspirin (100 mg), simvastatin (20 mg), thiazide (12.5 mg), atenolol (50 mg) and ramipril (5 mg).

It was tested in a double-blind randomized controlled trial of 2,053 people aged 45 to 80 who had one existing risk factor but no history of cardiovascular disease (CVD).

Lead researcher Dr. Salim Yusuf stressed the need for further trials but called the potential to lower CVD risk with a single pill “a huge step in the management of patients.” He said that the Polycap has “definite” applicability for secondary prevention, and would lower costs and improve compliance in CVD patients who are already taking the individual drugs.

“The big question … is whether you take the whole world at large, over a certain age group, don’t measure anything, and then give them all a polypill. I will withhold judgment on whether that’s the right thing to do or not right now,” he said at a press conference.

TIPS was presented at the 58th Annual Scientific Session of the American College of Cardiology and published online in The Lancet. [2009 Mar 30; Epub ahead of print]

The study, carried out at 50 centers in India, comprised nine groups: 412 patients took the Polycap, while around 200 each were assigned to one of eight different permutations of the drugs alone and in combination.

After 12 weeks of Polycap therapy, mean systolic and diastolic BPs decreased by 7.4 mmHg and 5.6 mmHg, respectively, as compared to people taking no BP-lowering drugs. This magnitude was similar to that achieved with three BP-lowering drugs, either with or without aspirin.

LDL cholesterol was reduced by 0.70 mmol/L in Polycap users – a slightly lesser reduction than with simvastatin alone (0.83 mmol/L; P=0.04) but still highly significant compared to people who did not take a statin (P less than 0.0001).

The Polycap, manufactured by Cadila Pharmaceuticals, India, was well tolerated: discontinuation rates were similar to other treatment groups and largely attributable to social reasons.

The projected risk reductions for taking the Polycap were 62 percent for coronary heart disease events and 48 percent for stroke. These were calculated using the methods of Drs. Wald and Law, who first proposed the polypill concept in a seminal British Medical Journal paper. [2003 Jun 28;326(7404):1419]

Yusuf, director of the Population Health Research Institute at McMaster University, Canada, said that clinical event-driven trials of polypills could be published within 6 months to a year.

He acknowledged concerns that polypills could promote the wrong message if marketed incorrectly, stressing that lifestyle modification is the “the crux and the fundamental basis of CVD prevention.” He rejected, however, the suggestion that widespread medication could be a difficult idea to promote.

“There’s something inherently repulsive to most of us to say we’re medicalizing the whole population. Just think of the millions of people in the world taking multivitamins with no evidence.

“The concept of taking a pill to improve your health is really not new – it is embedded in most cultures, whether it is Asian, Western or wherever else,” he said.

Guidelines grow but offer opinions, not evidence

Medical Tribune May 2009 P4
David Brill

The complexity of cardiology guidelines is growing but new recommendations are often unsupported by scientific evidence, a recent study has found.

The analysis of American College of Cardiology (ACC) / American Heart Association (AHA) clinical practice guidelines shows that the number of recommendations has risen considerably in the past 24 years.

The balance of recommendations, however, has shifted towards ‘class II’ – those that reflect a conflict of evidence or a divergence of opinion. The proportion of class I recommendations has remained largely unchanged.

Just 11 percent of all recommendations in the most recent guidelines are based on evidence level A. Almost half are based on level C – the lowest level – comprising expert opinion, case studies or standards of care.

The study, published in the Journal of the American Medical Association, was accompanied by an editorial calling for guidelines to be abolished unless the present system can be overhauled. [2009;301(8):831-41; 2009;301(8):868-9]

“Unfortunately, too many current guidelines have become marketing and opinion-based pieces, delivering directive rather than assistive statements,” wrote Drs. Terrence Shaneyfelt and Robert Centor from the University of Alabama, US.

“If all that can be produced are biased, minimally applicable consensus statements, perhaps guidelines should be avoided completely. Unless there is evidence of appropriate changes in the guideline process, clinicians and policy makers must reject calls for adherence to guidelines.”

Dr. Pierluigi Tricoci, lead author of the study, was more cautious in his response – acknowledging room for improvement with the format of guidelines but saying that they remain “important and useful” documents.

“The main message of our paper is that in cardiology, which we believe is one of the most advanced and evidence-based fields in medicine, we have a huge gap in knowledge,” said Tricoci, a cardiologist at Duke University, US. “In most situations that we find in clinical practice we don’t have enough supporting evidence that helps us make clinical decisions on what’s best for the patient.

“We hope that [this study] gives out the right message because we are not in a very good situation right now. Institutions and the government have to understand that there is a lot of research that is not well funded … we want to improve our current situation to close those gaps.”
Tricoci and colleagues reviewed 53 separate guidelines covering 22 topics. Excluding those which were never revised or updated, the number of recommendations has risen by 48 percent from the first to the latest editions of each document. The total number of recommendations rose from 1,330 in 1984 to 1,973 in 2008.

The levels of evidence vary widely between diseases. More than 20 percent of recommendations in heart failure and ST-segment elevation myocardial infarction guidelines, for example, have evidence level A. For valvular heart disease guidelines, however, just one of 320 recommendations is based on level A.

The ACC and the AHA welcomed the study’s findings in a joint statement, calling it a “valuable and important message” about the need to invest more in research.

“There are gaps in the evidence base for patient care, gaps that could be eliminated if more clinical research were funded, especially comparative effectiveness research that specifically compares one kind of diagnostic procedure or treatment with another,” said ACC president Dr. Douglas Weaver.

“Improving our evidence base can lead to even greater improvements in treatment and in saving lives.”

Statin ‘reloading’ improves PCI outcomes

Medical Tribune May 2009 P8

David Brill

Topping up a patient’s statin levels before percutaneous coronary intervention (PCI) could improve outcomes in long-term statin users, a new study suggests.

The ARMYDA*-RECAPTURE trial found that “reloading” with high-dose atorvastatin before PCI reduced the relative risk of major adverse cardiac events by 48 percent at 30-day follow-up.

Treating seventeen patients with this strategy would prevent one such adverse event, the investigators reported.

The study, which involved 352 chronic statin users, extends the findings of the earlier ARMYDA trial which demonstrated the benefits of a statin loading dose in statin-naïve patients undergoing PCI.

“These findings may support a strategy of routine reload with high-dose atorvastatin early before intervention, even in the background of chronic therapy,” said lead investigator Dr. Germanio Di Sciascio, of the University of Rome, Italy.

“If confirmed by future studies, the results of ARMYDA-RECAPTURE may influence practice patterns, particularly for the acute care of non-ST elevation acute coronary syndromes [ACS].”

The researchers randomized 175 patients to placebo and 177 to atorvastatin reloading, which comprised an 80mg dose 12 hours before angiography, followed by a further 40mg dose 2 hours before.

Just 3.4 percent of statin-treated patients reached the primary endpoint – a composite of cardiovascular death, myocardial infarction and target vessel revascularization – as compared to 9.1 percent of those in the placebo group (P=0.045).

This effect was driven largely by patients who presented with ACS, rather than those presenting with stable angina. In a separate analysis of ACS patients alone, the relative risk reduction with atorvastatin was 87 percent and the number needed to treat was 9.

Atorvastatin reloading also significantly reduced the proportion of patients with elevation of creatine kinase-MB and troponin-I following PCI, and non-significantly reduced the proportion with elevated C-reactive protein. These findings suggest that a rapid LDL-independent effect may underlie the cardioprotective phenomenon, said Di Sciascio.

Dr. Robert Harrington, director of the Duke Clinical Research Institute, US, said that ARMYDA-RECAPTURE adds to the literature supporting early, intensive statin therapy both before and after ACS.

“The trial was very carefully done and it adds to the totality of the data. It is, however, small, and it does have borderline P values with very broad confidence intervals, suggesting a high degree of uncertainty as to the true estimate of effect.

“The limitations of the trial, I believe, warrant replication or validation before recommending widespread adoption of statin reloading,” he said. “Efforts to reduce periprocedural MI should absolutely explore options other than anti-thrombotic therapy, and inflammation certainly is a reasonable target.”

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*Atorvastatin for Reduction of Myocardial Damage during Angioplasty

Japanese CPR success could light the way for Asia

Medical Tribune May 2009 P10
David Brill

Japan’s “impressive” success at tackling out-of-hospital cardiac arrests could inspire other Asian countries to improve their own survival rates, according to the chairman of the Singapore Heart Foundation (SHF).

One-month survival after a witnessed ventricular fibrillation episode has risen from 15 to 31 percent since a program was implemented in Osaka in 1998, researchers reported recently in Circulation. [2009;119:728-734] Neurologically-intact 1-month survival has risen from 6 to 16 percent.

The initiative has also reduced delays in calling for medical services, initiating cardiopulmonary resuscitation (CPR), and delivering a first shock, the study shows.

In Singapore, just 2.7 percent of people currently survive following an out-of-hospital cardiac arrest (OHCA), according to the SHF, which launched its own CPR initiative last year.

“This is a very encouraging study because it inspires us to put more effort into CPR training and providing defibrillators,” said SHF chairman Associate Professor Terrance Chua.

“What is most impressive is that they were able to improve survival rates. Having this clear documentation is good for morale because otherwise you can commit a lot of resources without knowing how much benefit you are getting from it,” he said. “We really take our hats off to them for having done this in a prospective registry so that they can monitor the improvements.”

The Utstein Osaka Project focuses on a four-step “chain of survival,” comprising activation of emergency medical services, CPR, defibrillation and advanced life support measures given by healthcare providers. The survival benefits were driven largely by improvements in the first three links of the chain, suggesting that the program’s public education component has had a significant impact.

Some 120,000 citizens per year have been trained in conventional CPR since the introduction of the program in Osaka, covering an area with a population of 8.8 million.

“This study proves that improvement in the chain of survival results in increased survival from out-of-hospital cardiac arrest in the real world,” said Dr. Taku Iwami, an assistant professor at Kyoto University Health Service, who led the research.

“We need to increase the number of automated external defibrillators [AEDs] in public places as well as train people in not only CPR but in the use of AEDs,” he said. “In many areas of the world, there are serious delays in the use of CPR and AEDs. We hope this study encourages other emergency medical service systems to start or continue their efforts to improve based on objective data.”

The study included 42,873 OHCAs in which resuscitation was attempted, occurring from May 1998 to December 2006. The median time from collapse to call for medical attention dropped from 4 to 2 minutes, and the time from collapse to first CPR dropped from 9 to 7 minutes. Median time from collapse to first shock decreased from 19 to 9 minutes.

In Singapore the public response to learning CPR has so far been “pretty positive,” according to Chua, who noted that despite the improvements in Osaka’s survival rates the study still highlights that there is further room for improvement.

The SHF launched its 3A (Anyone, Anytime, Anywhere) program in November 2008. The project includes the provision of CPR kits which include a mannequin, DVD and other reference materials, all of which can be used at home with the intention of creating a ”multiplier effect” whereby CPR skills are passed on to friends and family.

Thailand and Indonesia have also expressed an interest in adopting similar programs, Chua said.

The SHF has already trained some 2,000 students from seven schools using the CPR kits, which are on sale at a subsidized price of S$20 for students and S$50 for corporations and communities.

Several commercial facilities, including Suntec City and VivoCity shopping centers, have already installed their own AEDs since the launch of the 3A program, according to Chua. Changi Airport has also backed the project, and is currently in the process of developing and implementing its own AED installation program.

A 2002 study from three airports in Chicago, US, reported that 11 out of 18 patients who arrested with ventricular fibrillation over a 2-year period were successfully resuscitated using AEDs. Ten were alive and neurologically intact a year later. Six of the 11 rescuers had never used an AED before, although three were medically trained. [N Engl J Med 2002 Oct 17;347(16):1242-7]

CRT holds promise for atrial fibrillation in heart failure

Medical Tribune April 2009 P9
David Brill

The benefits of cardiac resynchronization therapy (CRT) for heart failure could extend to those sicker patients who have atrial fibrillation (AF), according to a leading Hong Kong cardiologist.

Although more randomized controlled studies are needed, observational data so far appear to support the use of CRT for these patients said Dr. Jeffrey WH Fung, director of cardiac electrophysiology and pacing services at the Prince of Wales Hospital, Chinese University of Hong Kong.

Fung estimated that up to 30 percent of heart failure patients have AF, but noted that guidelines currently exclude this group from the class I indications for CRT. This top-level recommendation is presently reserved for those who are in sinus rhythm, while AF patients are grouped under class IIa indications – reflecting a lower level of evidence in support of the treatment.

Fung, however, pointed to a recent paper from the Multicentre Longitudinal Observational Study (MILOS) group – the largest study so far to address the use of CRT in AF patients. After a median of 34 months following CRT, all-cause and cardiac mortality were similar between the 243 AF patients and the 1,042 sinus rhythm patients. [Eur Heart J 2008 Jul;29(13):1644-52]

Further support for these findings comes from a meta-analysis of 5 observational studies involving 1,164 patients, which showed that AF and sinus rhythm patients had similar mortality 1 year after CRT initiation. Improvements in New York Heart Association functional class were also comparable for the two groups. [J Am Coll Cardiol 2008 Oct 7;52(15):1239-46]

“It seems that sinus rhythm and AF patients behave similarly after receiving CRT,” Fung summarized. He noted that sinus rhythm patients appear to fare better on quality of life measurements, but said that this finding is “consistent with other heart failure studies which show that AF patients are much sicker than those who remain in sinus rhythm, no matter what therapies they receive.”

Besides the clinical benefits, CRT also seems to offer comparable improvements between the two patient groups when it comes to echocardiographic parameters, he added.

The jury is still out, however, on whether AF patients should undergo atrio-ventricular junction (AVJ) ablation alongside CRT, said Fung. The MILOS study found that ablation improved survival compared to CRT alone but other studies have produced inconsistent results, he said, cautioning that AVJ ablation renders patients device-dependent for the rest of their lives and should not be done unless necessary.

“I think we need a properly randomized study to try to ascertain the merits of ablation or pharmacological rate control and understand which one is really preferred in patients with heart failure and permanent AF,” he said.

“We should try to maximize drugs and sometimes maybe if there is a very low percentage of pacing you may ask the patient to undergo AVJ ablation. But looking in our database it seems that most of the patients are doing fine with more than 90 percent pacing just with drugs,” he concluded.

Statin-associated adverse events under-appreciated, experts say

Medical Tribune April 2009 P11

David Brill

The potential hazards of taking statins may be under-appreciated by the medical community, with adverse reactions often overlooked and sometimes even dismissed, according to US researchers.

Attention has largely focused on the most commonly-reported issue of muscle problems but the full side effect profile is wider than typically thought, they warn.

Cognitive problems are the second most common reaction to statins, followed by peripheral neuropathy-type symptoms, such as numbness and burning, said Dr. Beatrice Golomb, an associate professor of medicine at the University of California, San Diego (UCSD).

Rarer reports have also linked statins to a range of other conditions including sexual dysfunction, glucose elevation and vision problems.

Golomb is head of the Statin Study Group at UCSD, which is currently conducting an observational study looking at the adverse effects of the drugs. She also recently co-authored a literature review which, with almost 900 references, she believes to be the most comprehensive look at the subject to date. [Am J Cardiovasc Drugs 2008;8(6):373-418]

“In clinical trials, adverse events look rare. But for those of us who see real-world patients they’re a really big problem,” she told Medical Tribune.

Golomb highlighted a French observational study reporting that 10.5 percent of patients experienced muscle symptoms, and a Danish population-based study which showed that current statin users had a roughly 16-fold increased risk of polyneuropathy compared to non-users. [Cardiovasc Drugs Ther 2005 Dec;19(6):403-14; Neurology 2002 May 14;58(9):1333-7] She noted, however, that adverse event rates vary between different studies and populations, making it difficult to provide definitive overall figures.

Meta-analyses, meanwhile, have yielded significant odds ratios of 1.4 and 1.44 for any adverse event on statins (the latter with intensive therapy), although both also recorded substantial clinical benefits. [Clin Ther 2006 Jan;28(1):26-35; Clin Ther 2007 Feb;29(2):253-60]

“I think there is a lack of awareness of these problems from physicians,” added Golomb, pointing to an earlier survey of 650 patients which found that doctors were “more likely to deny than affirm a connection” in cases of adverse statin reactions. [Drug Saf 2007;30(8):669-75]

“Even for patients who met literature criteria for probable or definite causality of their problems, the physicians denied the possibility of a connection about 50 percent of the time for each of the top three best known and most reported symptoms. And when we asked who initiated the conversation it was overwhelmingly the patients, even though it should be the physician who is aware of the connection of those specific symptoms to statins,” said Golomb.

Golomb believes that the most of the problems are class effects, and largely relate to the dose and potency of the statin rather than to any particular brand. Her literature review also notes that mitochondrial mechanisms are implicated in several adverse effects and proposes that this may be a common underlying factor behind a wide range of the problems.

She added that muscle problems occurring with statins are not always associated with a rise in creatine kinase levels, and that this can sometimes cause them to be overlooked.

Other academic authors have reached different conclusions about the risk profile of statins. The most recent such review paper in The Lancet, for example, concluded that statins are “a well-tolerated and extensively studied group of drugs.” [2007; 370:1781-90]

“With a few caveats, and while awaiting good-quality randomized data for the newer drugs, statins seem to be a remarkably safe group of drugs when used at their usual doses,” wrote Dr. Jane Armitage, of the University of Oxford, UK.

Golomb added, however, that the side effects reported so far could be just “the tip of the iceberg,” cautioning that even more problems could ultimately be shown to be related to statins.

“We’ve had reports from patients who have developed accelerated hearing loss or tinnitus with onset of statins. We don’t have data to demonstrate an association but that’s one of the domains in which I predict an association will likely be found in future,” she said.

Orbit of JUPITER extends to stroke prevention

Medical Tribune April 2009 P12
David Brill

The benefits of rosuvastatin for patients with elevated high sensitivity C-reactive protein (hsCRP) could include a reduction in the risk of stroke, according to new data from the JUPITER* trial.

The relative risk of any stroke was reduced by 48 percent among patients taking the drug, the study’s investigators reported recently at the International Stroke Conference in San Diego, US.

This finding appears to have been driven largely by a reduction in ischemic stroke rates – just 23 of the 8,901 patients in the treatment group experienced this outcome compared to 47 in the equally-sized placebo group (hazard ratio 0.49; P=0.004). Rates of hemorrhagic stroke, conversely, were not significantly different – six events occurred in the intervention group and nine in the placebo group (hazard ratio 0.67; P=0.44).

The new stroke data bring fresh fuel to the debate about the role of hsCRP in risk stratification and the use of statins for primary prevention – questions that have risen to prominence since the presentation of the original JUPITER study at the American Heart Association’s annual Scientific Sessions in November last year. [N Engl J Med 2008 Nov 20;359(21):2195-207]

“The bottom line is that we now have conclusive evidence for the efficacy of statins specifically for primary prevention of stroke,” said Dr. Robert Glynn of Brigham and Women’s Hospital in Boston, US, one of the JUPITER investigators who presented the latest findings.

LDL cholesterol is not typically considered as a risk factor for stroke in patients without established vascular disease, said Glynn, noting that CRP, however, has been shown to be a valid predictor of stroke risk. Statin therapy, which lowers levels of both biomarkers, could therefore be particularly beneficial for stroke prevention in patients with elevated CRP, he added.

The ARIC** study implicated hsCRP as a risk marker for stroke. The study, which involved 12,762 middle-aged men and women followed up for around 6 years, showed that those with an hsCRP level above 3 mg/L had an adjusted hazard ratio for ischemic stroke of 2.7 when compared to those with an hsCRP level below 1 mg/L. [Arch Intern Med 2005 Nov 28;165(21):2479-84]

The SPARCL*** study, meanwhile, demonstrated the benefits of atorvastatin (80 mg daily) for secondary stroke prevention in a population of 4,731 patients with a recent history of stroke or transient ischemic attack. After a median follow up of 4.9 years, overall stroke risk was reduced by 16 percent in the statin group compared to placebo (adjusted hazard ratio 0.84; P=0.03) with comparable mortality between the two groups. There was, however, an increase in the number of hemorrhagic strokes: 55 events occurred in the atorvastatin group and 33 in the placebo group. [N Engl J Med 2006 Aug 10;355(6):549-59]

The original JUPITER trial found that after a median of 1.9 years of follow up rosuvastatin (20 mg daily), as compared to placebo, reduced the relative risk of major cardiovascular events by 44 percent in a cohort of 17,802 overtly healthy subjects with baseline hsCRP levels above 2 mg/L and LDL cholesterol levels below 130 mg/dL (hazard ratio 0.56; P<0.00001). Over the course of the study hsCRP levels were reduced by 37 percent and LDL cholesterol levels by 50 percent. *JUPITER: Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin **ARIC: Atherosclerosis Risk in Communities *** SPARCL: Stroke Prevention by Aggressive Reduction in Cholesterol Levels

Declining heart attack severity drives drop in CHD deaths

Medical Tribune March 2009 P1
David Brill

A decrease in the severity of heart attacks is fuelling the decline in coronary heart disease (CHD) deaths in the US, new research suggests.

The study – an analysis of 10,285 myocardial infarction (MI) cases hospitalized over 15 years – showed significant declines across almost all indicators of severity.

This trend, which appears to be mirrored by data from some parts of Asia, was independent of either gender or ethnicity.

“This landmark study suggests that better prevention and better management in the hospital have contributed to the reduction in deaths,” said Dr. Merle Myerson, principal investigator of the Atherosclerosis Risk in Communities (ARIC) study, published in Circulation. [2009 Jan 19; Epub ahead of print]

“Better control of risk factors for heart disease, such as blood pressure and cholesterol, as well as improvements in hospital management, may lessen the severity if somebody has a heart attack,” he said.

The time between symptom onset and arrival at hospital remained constant throughout the study, period with only around a third of patients arriving at the hospital within 2 hours of an attack.

Dr. Adrian Low, a consultant at the National University Heart Centre Singapore, stressed the importance of raising public awareness in order to further improve MI outcomes.

“While this study is reassuring, it also emphasizes that we still have room for improvement. A significant percentage of patients still present late to us for treatment,” he said.

“We know that early presentation and appropriate management can result in better outcomes. This will only be achieved with enhanced public education and a better evaluation of how we can overcome our shortcomings,” he added.

The ARIC investigators reviewed MI discharge data from 1987 to 2002, taken from hospitals across four communities in North Carolina, Maryland, Mississippi and Minnesota. The analysis was limited to white and African-American patients, aged 35 to 74.

Previous studies had shown that CHD mortality in the US was dropping but that the incidence of MI remained unchanged – prompting the researchers to investigate whether declining MI severity might be the driving force behind the bigger-picture CHD effect.

In-hospital deaths from acute MI in Singapore have also dropped over a similar period, according to data from the National Heart Center, where overall inpatient mortality declined from 20.6 percent in 1988 to 14.7 percent in 2002. [Ann Acad Med Singapore 2007 Dec;36(12):974-9] A study published last year by the Singapore’s National University Hospital, meanwhile, showed that the use of evidence-based medications for MI has significantly reduced 1-year mortality in both elderly and young patients. [Am J Geriatr Cardiol 2008 Jan-Feb;17(1):21-6]

Low added that the ARIC study “reinforces our current understanding that cardiovascular risk factors, treated aggressively, can impact on subsequent development and outcome of acute MI,” but noted that there are several limitations to the research. The generalizability to other populations is not clear, nor is it known which specific measures led to the improved outcomes, he said. He also added that some of the severity indicators used by the researchers are proxies for disease severity, while more direct measures such as left ventricular ejection fraction were unavailable.

Twenty MI severity indicators were used in the ARIC study, including the proportion of cases having major ECG abnormalities. For ST-segment elevation, for example, the proportion of cases dropped by 1.9 percent per year (P = 0.002), while the percentage of cases with any major Q wave dropped by 4.5 percent per year (P<0.001).>

Nuisance bleeding prompts patients to drop clopidogrel

Medical Tribune March 2009 P18

David Brill

“Nuisance bleeding” is a common and under-recognized cause of clopidogrel cessation following drug-eluting stent implantation, according to a recent study.

Some eleven percent of patients who experienced nuisance bleeds stopped taking the drug, increasing their long-term risk of potentially fatal stent thrombosis, US investigators reported.

The American Journal of Cardiology study is the first to quantify the impact of superficial bleeding on clopidogrel compliance, the authors claim, noting that previous research has tended to focus on major and internal bleeding events. Nuisance bleeding included bleeds from minor cuts, easy bruising, ecchymosis and petechia. [2008 Dec 15;102(12):1614-7]

Dr. Ron Waksman, the study’s lead author, said that he was “alarmed” by the findings and called for better education of patients about the potential complications of prolonged antiplatelet therapy.

“Patients should be aware that they are going to experience this bleeding and that they should still adhere to the clopidogrel. We have to explain to them that having stent thrombosis could be life-threatening whereas nuisance bleeding is just a nuisance,” he said.

“This is one of the taxes that you pay if you get a drug-eluting stent. It’s something that is not usually captured in clinical trials so we don’t tend to care much about it but for patients it is a real issue,” he added.

Waksman and his colleagues followed up 2,360 patients who underwent successful sirolimus-eluting stent implantation at Washington Hospital Center (WHC), a tertiary referral hospital in the US, and were subsequently recommended for a minimum of 6 months of dual antiplatelet therapy.

After 36 months of clinical follow-up, 32.4 percent of patients had experienced some form of bleeding – 85.7 percent of which fell into the nuisance category. Of those who had nuisance bleeds, 11.1 percent stopped taking clopidogrel and 5 percent stopped taking aspirin.

Around 70 percent of those who experienced nuisance bleeds did so on a daily basis, according to Waksman, who is associate director of the division of cardiology at the WHC. He noted that the aspirin dosage can be reduced for those who continue to experience inconvenient bleeding but stressed that clopidogrel should be maintained for at least a year.

Future research is directed at better understanding the mechanisms by which these drugs affect platelet inhibition, said Waksman, adding that this will help us to learn why some patients experience bleeding while others do not.

“It can go both ways: those who don’t bleed at all may be still at risk for stent thrombosis and may need a higher dose, while those who have nuisance bleeding may be too sensitive to the drug and could do well with half the dose,” he said.

Southeast Asia aligns with JUPITER

Medical Tribune February 2009 P9
(Indonesia / Philippines edition only)
David Brill

Experts in Southeast Asia are responding with cautious optimism to the landmark JUPITER* study, which dominated headlines at the recent American Heart Association conference in the US.

While there are several important messages to draw from the study doctors should not rush to incorporate the findings into routine practice, specialists from the region told Medical Tribune.

Local guidelines are not anticipated to change in the immediate future, they said.

JUPITER – a randomized controlled trial of 17,802 participants – demonstrated that rosuvastatin, as compared to placebo, significantly reduced major cardiovascular event rates in overtly healthy people with normal LDL-cholesterol but elevated high-sensitivity C-reactive protein (hsCRP) levels. [N Engl J Med 2008 Nov 20;359(21):2195-207] The study has moved hsCRP into the limelight and prompted some international experts to call for the biomarker to take a more prominent role in cardiovascular risk stratification.

Professor Cheuk-Man Yu, head of the division of cardiology at the Chinese University of Hong Kong, said that the reduction of cardiovascular events in the study was “highly encouraging” for both physicians and patients but noted that more research is still needed into the pathophysiological mechanisms that underlie the effect.

“It will be difficult to generalize this into routine practice without further understanding the relationship between lipid lowering, reduction of vascular inflammation and reducing atherosclerosis,” he said.

“I don’t think we fully understand the hsCRP story. From this study it does seem to be a very important mediator for underlying vascular disease but we still haven’t got the definite answer as to whether it is a stand-alone risk factor or just a manifestation of the accumulated conventional risk factors.”

hsCRP levels can be altered by a number of factors and may not be solely a marker of inflammation in vascular plaques, said Yu, noting that bacterial and viral infections, rheumatoid arthritis, tuberculosis and lupus erythematosus can all increase levels of the biomarker. These potential explanations would all need to be ruled out, and all conventional risk factors worked upon, before considering intervention on the basis of an elevated hsCRP alone, he said.

Associate Professor Terrance Chua, chairman of the Singapore Heart Foundation, said that he expects hsCRP testing to “take on a bigger role” in risk assessment, in light of the data from JUPITER.

“It would be useful in a situation where a patient is at intermediate risk and one is trying to make a decision whether or not to initiate lipid-lowering therapy. hsCRP may help to further refine the risk and cast the deciding vote on whether or not to start treatment in these patients. We will have to wait and see how the guidelines committee absorbs this information,” he said.

Chua also noted that the JUPITER results are consistent with those of previous statin trials and provide further reassurance as to the benefits of cholesterol-lowering therapy. He added, however, that it is important not to lose sight of the importance of non-pharmaceutical interventions such as diet.

“The great challenge is really to try to change lifestyle,” he said. “It’s a bigger challenge than taking a tablet but if we want to have a truly cost-effective way of dealing with the growing problem then changing lifestyle would obviously be more effective.”

Dato’ Seri Dr. Robaayah Zambahari, senior consultant cardiologist at the National Heart Institute in Kuala Lumpur, Malaysia, said that she believes strongly in the benefits of statins for secondary prevention but that the risk-to-benefit ratio will need to be reviewed before adopting a primary prevention strategy.

She added that JUPITER did not address the long-term safety of rosuvastatin since the trial was stopped after just 1.9 years.

-------------------------------------------------
*Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin

Journal editorials fuel unfounded brand-name bias

Medical Tribune Unpublished
David Brill

Medical opinion leaders are adding to unnecessary spending by promoting the misperception that generic cardiovascular drugs are inferior to brand-name versions, a recent study suggests.

In a thorough systematic review and meta-analysis comprising 47 studies, researchers from Harvard Medical School, US, found that generic cardiovascular drugs were equivalent to brand-name drugs in almost all clinical outcomes.

They also observed, however, that more than half of the relevant journal editorials and commentaries published over the same period expressed negative views about the substitution of these medications.

“Unfortunately, in general, generic drugs are relatively under-used because there are a lot of misperceptions out there that they might somehow be inferior to brand-name drugs,” said Dr. Aaron Kesselheim, lead author of the Journal of the American Medical Association paper. [2008 Dec 3;300(21):2514-26]

“The best way to combat these misperceptions is by looking at the data so that’s what we tried to do. There was no evidence that brand-name drugs are superior to generic drugs,” he said, adding that the study is the first to his knowledge to take such a comprehensive approach to summarizing the literature in this field.

The rising cost of brand-name drugs is not only creating a financial burden but also directly contributing to poor health outcomes, the researchers wrote, citing a study which found that the promotion of generic or preferred medications improved adherence. [Arch Intern Med 2006 Feb 13;166(3):332-7]

Kesselheim called on both the authors and publishers of editorials to take greater responsibility for ensuring that opinion pieces have a reasonable evidence base and present both sides of the argument when the data are conflicting.

“Doctors look to these journals as a source of medical information and that can influence a lot of prescribing practices. It seems that that the general message of a lot of these editorials was not in concert with what the data show,” he said.

The research did not address the reasons underlying these negative attitudes but Kesselheim speculated that physicians may have “fallen into the same cognitive trap” as patients, who tend to naturally associate the word generic with meaning lower quality.

“Another alternative is that some of the physicians who are writing these editorials might have financial relationships with brand-name drug companies that color their opinion of brand-name drugs as compared to generic drugs,” he added.

The meta-analysis included 38 randomized controlled trials (RCTs) and nine retrospective studies addressing the clinical equivalence of nine different cardiovascular drug subclasses. Only FDA-approved brand-name medications were assessed.

Clinical equivalence was observed in all seven RCTs of beta-blockers, five out of seven RCTs of calcium channel blockers and 10 out of 11 RCTs of diuretics. All of the remaining RCTs – covering statins, antiplatelets, alpha-blockers, angiotensin-converting enzyme inhibitors, class 1 antiarrhythmics and warfarin – demonstrated the clinical equivalence of generic medications.

“The implications are that physicians can feel confident prescribing generic drugs for their patients with cardiovascular disease when appropriate for their condition … and patients can be confident that they’ll be getting the same clinical effects that they might be getting with a brand-name drug,” said Kesselheim, who is an instructor in medicine at Harvard Medical School.

The literature review and content analysis included 43 editorials, 23 of which were deemed to have a negative stance towards generic drug substitution. Twelve articles were in favor of the practice and eight were neutral.