JUPITER shows statin benefits for low-risk patients

Medical Tribune December 2008 P1 & 13

David Brill

Rosuvastatin can dramatically reduce the risk of death and major cardiovascular events among apparently healthy people, the highly-anticipated results of the JUPITER* study show.

The findings raise important questions about the indications of statins for primary prevention and should prompt a reassessment of current guidelines on risk assessment, one expert said.

JUPITER comprised 17,802 overtly healthy people with normal LDL cholesterol but elevated levels of high sensitivity C-reactive protein (hsCRP) – a group not currently indicated for statin treatment.

A 44 percent reduction in the incidence of the primary endpoint – comprising myocardial infarction (MI), stroke, cardiovascular death, arterial revascularization or unstable angina – was seen among those taking the drug compared to those on placebo (hazard ratio 0.56; P less than 0.00001).

Just 25 people would need to be treated with rosuvastatin to prevent one vascular event over a 5-year period, the researchers said.

The benefits of treatment were such that the trial was stopped a median of 1.9 years into the intended 4 year follow-up period.

"Despite evaluating a population with lipid levels widely considered to be optimal in almost all of our current guidelines, the relative benefit observed in JUPITER was greater than in almost all prior statin trials," said Professor Paul Ridker, the study’s principal investigator who presented the findings at a press conference during the recent annual Scientific Sessions of the American Heart Association.

"I think this is extremely reassuring for the statins as a class, and hopefully for the public at large who have been concerned about mortality benefits in this setting," he said.

Rosuvastatin reduced all-cause mortality risk by 20 percent and MI, stroke or cardiovascular death risk by 47 percent compared to placebo (hazard ratios 0.80 and 0.53; P=0.02 and P less than 0.00001, p=0.01).

The risk reductions were consistent across all subgroups regardless of gender, age, ethnicity, smoking status, BMI and Framingham risk score.

Statin therapy appears to have been safe, with no significant difference in serious adverse event rates between the groups. There was, however, an increase in the rate of physician-reported diabetes: 270 cases were recorded in the statin group and 216 in the placebo group (P=0.01).

Professor Andrew Tonkin, head of the cardiovascular research unit at Monash University, Melbourne, Australia, described the reduction in cardiovascular events in JUPITER as “extremely important.”

“I think that there will need to be a review of the guidelines for where CRP sits in risk assessment,” he said, adding that more information, such as the absolute risk reductions in subgroups and the cost effectiveness of treatment, is critically needed in order to establish the role of the marker as a screening tool for primary prevention.

Dr. Timothy Gardner, president of the American Heart Association, noted that the mechanisms for the risk reductions seen in JUPITER remain unclear.

“Statins lower both LDL cholesterol and hsCRP. Thus the findings presented today cannot determine whether lowering cholesterol, reducing inflammation, or a combination of both is responsible for the effects seen in this paper,” he said.

JUPITER, which was concurrently published in The New England Journal of Medicine, included men aged 50 or older and women aged 60 or older who had LDL cholesterol levels below 130mg/dl and hsCRP levels of 2.0mg/l or higher. Participants were non-diabetics with no history of cardiovascular disease. [2008 Nov 9; Epub ahead of print]

Rosuvastatin treatment (20mg daily) reduced LDL cholesterol levels by 50 percent and hsCRP by 37 percent.

Ridker, of Harvard Medical School, Boston, US, acknowledged that the study was too short to fully assess long-term safety, but noted that there is a large amount of data on statins as a whole and that they have been found to be “remarkably safe.” Despite the early conclusion, over 1,000 people in JUPITER were followed up for more than 4 years, he added.

“These drugs as a class are extraordinary. We want to give out a message that we want to continue with diet, exercise and smoking cessation but now we have very overwhelming evidence that this class of drugs, this method of lowering these surrogates [LDL cholesterol and hsCRP], fixes hard endpoints,” he said.

The JUPITER trial was supported by AstraZeneca.

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

ADA, EASD offer practical new guidance on diabetes treatment

Medical Tribune December 2008 P4
David Brill

An updated treatment algorithm has been released which promises to help guide primary care physicians through the ever-expanding field of treatments for type 2 diabetes.

The consensus statement, produced jointly by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD), places a strong emphasis on early treatment and the maintenance of HbA1c levels below 7 percent.

Metformin therapy plus lifestyle intervention is recommended from diagnosis for all patients, with further medications to be added promptly if targets are not achieved.

The statement also makes new differentiations within drug class
– advocating pioglitazone over rosiglitazone and dropping glybenclamide and chlorpropamide from the list of recommended sulfonylureas.

"We’ve seen absolutely that if you do not keep glucose levels within reasonable bounds you will reap a harvest of microvascular disease," said Professor Rury Holman, one of the authors of the algorithm.

"The tide is changing. The view that complications are inevitable is no longer true. They will occur even in the best controlled-people but the risk can be substantially reduced, and therefore I think we have a duty of care to minimize HbA1c to the extent that we can," he said.

Holman, head of the Diabetes Trials Unit at The Oxford Centre for Diabetes, Endocrinology and Metabolism, UK, said that the new algorithm is "not a prescription" to be followed in all cases but rather an evidence-based starting point for primary care doctors, who should still seek specialist advice where appropriate.

He also stressed the need to adopt a more cautious approach to HbA1c lowering in patients with a long-standing history of disease, noting that physicians should weigh up the relative risks and benefits before attempting to push HbA1c levels below 7 percent.

The latest version of the ADA/ EASD treatment algorithm, first issued in 2006, was published online recently in the journals Diabetes Care and Diabetologia. The document will continue to be updated as and when new data become available, Holman said.

For cases where the initial metformin approach is unsuccessful, the algorithm divides the subsequent intensification of therapy into two tiers according to how well validated the medications are considered to be. Tier 1 sees the addition of either sulfonylurea or basal insulin, progressing to initiation or intensification of insulin therapy. Tier 2 recommends pioglitazone or the glucagon-like peptide-1 agonist exenatide, before moving on to sulfonylurea or basal insulin.

Besides the algorithm, the consensus statement also contains a literature review on the relative merits of the different medications, and guidance on the titration of metformin and the initiation and adjustment of insulin regimens.

Dr. Kevin Tan, vice president of the Diabetic Society of Singapore, agreed that doctors now have a duty to initiate early, intensive glycemic control and said that incorporating the new algorithm would help them to focus on the older, better-established drugs and view the newer options as alternatives to be used where necessary.

Aspirin ineffective for primary cardiovascular protection in diabetics

Medical Tribune December 2008 P4
David Brill

Aspirin is of no benefit for the primary prevention of cardiovascular events in diabetics, new randomized trial data suggest.

The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) study found that neither aspirin nor antioxidants reduced the incidence of cardiovascular events among 1,276 diabetic adults with asymptomatic peripheral arterial disease.

The findings of the study, which conflict with international guidelines, demonstrate that the medical community has extended its practices beyond the existing evidence base, the study’s lead researcher said.

"We do know that aspirin and antiplatelet agents are useful for secondary prevention in diabetes," said Professor Jill Belch of the Institute of Cardiovascular Research at the University of Dundee, UK.

"The trouble is, we have been guilty of therapeutic greed and we’ve extrapolated these findings back into primary prevention without any evidence.

"Although aspirin is a relatively safe drug we shouldn’t lose sight of the fact that it does have potential side effects … if something doesn’t benefit you, and has the potential to do harm, then the net effect is negative and perhaps we should wait until the evidence is available before writing our guidelines."

Belch said that the use of aspirin for primary cardiovascular prevention in diabetes is "endemic worldwide," yet the data from the POPADAD trial and other studies do not offer convincing support for the practice.

Doctors should instead focus strongly on getting patients’ lipid levels and blood pressure on target using statins and antihypertensive agents, she said, noting that aspirin can cause gastrointestinal bleeding and is one of the most common causes of drug-related hospitalizations.

She stressed, however, that aspirin remains a vital drug for secondary prevention, and urged doctors to reassure patients with established cardiovascular disease about the need to continue taking the drug.

Patients in the POPADAD trial were followed up for a median of 6.7 years. Of the 638 primary events that occurred during the study, 116 were among patients taking aspirin and 117 among those taking placebo or antioxidants alone. [BMJ 2008 Oct 16;337:a1840]

Patients in the study were aged over 40 with either type 1 or type 2 diabetes but no symptoms of cardiovascular disease, and had an ankle brachial pressure index of 0.99 or lower. Aspirin was given at a dosage of 100 mg once daily.

Further research is needed to confirm whether primary prevention could be achieved using a different aspirin dosing schedule or an alternative antiplatelet agent, Belch added.

The American Heart Association and American Diabetes Association jointly recommend that aspirin (75 – 162 mg/day) be used for primary prevention in diabetics at increased cardiovascular risk, including those aged over 40. [Circulation 2007 Jan 2;115(1):114-26]

There are similar recommendations in Asia. For example, guidelines from the Ministry of Health, Singapore, advocate aspirin (75 – 100 mg/day) for all type 2 diabetics over the age of 45, or those with dyslipidemia, hypertension or preexisting cardiovascular disease.

The POPADAD study is now the seventh well-controlled trial to show that aspirin is ineffective for this purpose, according to Professor William Hiatt from the University of Colorado Denver School of Medicine, US.

"Although aspirin is cheap and universally available, practitioners and authors of guidelines need to heed the evidence that aspirin should be prescribed only in patients with established symptomatic cardiovascular disease," he wrote in an accompanying editorial. [BMJ 2008;337:a1806]

Study brings new hope for acute ischemic stroke treatment

Medical Tribune December 2008 P6
David Brill

The window of opportunity for treating acute ischemic stroke (AIS) is set to widen, bringing hope to previously untreatable patients, a stroke expert said recently.

The recently published European Cooperative Acute Stroke Study (ECASS) III, showed that thrombolysis with alteplase can reduce the long-term disability risk, when given up to 4.5 hours after symptom onset.

Present guidelines limit the use of alteplase to a window of 3 hours post-stroke, but less than 2 percent of patients currently receive the treatment.

Dr. Lee Kim En, head of the department of neurology at the National Neuroscience Institute in Singapore, said at a recent press conference that the ECASS III data are convincing and it is "just a matter of time" until international approval is gained and guidelines adjusted accordingly.

"More patients will benefit from this extension of the window," he said, noting that treatment within 3 hours is typically very difficult to achieve since patients rarely arrive at hospital within this timeframe.

"Alteplase is the only proven therapy for AIS, which is why we are working very hard to extend the benefits to the other 98 percent of patients."

ECASS III randomized 821 AIS patients who presented during the extended post-stroke window to receive either alteplase or placebo. [N Engl J Med 2008 Sep 25;359(13):1317-29]
A favorable outcome at 90 days, as defined by a score of 0 or 1 on the modified Rankin scale for stroke disability, was reported for 52.4 percent of patients in the treatment group compared to 45.2 percent in the placebo group (odds ratio 1.34; P=0.04).

Alteplase increased the risk of intracranial hemorrhage, which affected 27 percent of patients in the treatment group compared with 17.6 percent in the placebo group (P=0.001). Mortality, however, was not significantly different between the groups, suggesting that the increased risk was outweighed by the overall benefits of treatment, according to Lee.

He added that it remains important to treat stroke as quickly as possible, and that the study findings should not be seen as an excuse to delay this process.

"Time is brain – every minute counts here. Having more time does not mean you can take more time… if you can give treatment within a minute of coming through the door that’s the best thing to do."

The new protocol is already being introduced at Tan Tock Seng Hospital, Singapore, which treats around 2,000 AIS patients each year. At present just 20 to 25 of these receive alteplase, Lee said.

While the hospital is working hard to accelerate its internal processing of AIS patients, increasing public awareness of stroke symptoms will also be an important step towards improving outcomes, he said.

In the event that a stroke patient presents to their GP, the physician can also help by documenting the time of symptom onset and sending them straight to hospital, he added.

ECASS III was conducted between July 2003 and February 2008 at 30 sites across 19 European countries. Alteplase was given intravenously at a dosage of 0.9 mg per kg. The trial was sponsored by Boehringer- Ingelheim, which manufactures the drug.

Liver fat a predictor of ‘metabolically benign obesity’

Medical Tribune December 2008 P6
David Brill

Measuring the distribution of fat in the liver could help identify obese patients who are most in need of treatment, a new study suggests.

The researchers characterized a subset of people with "metabolically benign obesity," who, despite their increased weight, do not seem to be at high risk of diabetes and atherosclerosis.

These patients, comprising around a quarter of the obese subjects in the study, had comparable insulin sensitivity and carotid intima media thickness to normal-weight people.

Ectopic fat in the liver was the strongest predictor of this phenotype and could therefore be used for risk stratification of obese patients, according to lead author Professor Norbert Stefan.

"Clinicians are seeing so many obese people now that they really need to try and focus their resources on those who need treatment earliest. By identifying those who are not in such high need they can put them on more moderate treatment," said Stefan, who heads a research team at the University of Tübingen in Germany.

MRI scans showed that the benign obese group had on average 54 percent less fat accumulation in the liver than insulin-resistant obese subjects (4.3 percent vs. 9.5 percent). The presence of ectopic fat in skeletal muscle was also a determinant of insulin sensitivity.

By measuring visceral adiposity – a known predictor of type 2 diabetes and cardiovascular risk – researchers were able to differentiate between insulin-sensitive and insulin-resistant subjects in the normal-weight and overweight groups. However, visceral adiposity was a weak predictor among the obese.

Doctors should assess patients for all the classical risk factors for cardiovascular disease and diabetes and then consider using MRI to measure liver fat in those deemed to be at high risk, Stefan said. Liver enzymes and ultrasound can also help to provide an assessment, he added.

The study, published in The Archives of Internal Medicine, comprised 314 white subjects with an average age of 45. [2008 Aug 11;168:1609-16]

Stefan stressed the importance of putting out the right public health message regarding the study’s findings.

"This is the start – it identified an important new target but we still need to tell the metabolically healthy obese people that they can’t lean back and say ‘okay that’s it, I’m not at risk.’

"Every obese person needs treatment, even the metabolically benign, because we’re not sure whether the endpoints are that they have a lower risk of dying or developing disease," he said.

A second study, published in the same edition of the journal, looked at the association between cardiometabolic abnormalities and obesity in a cross-sectional sample of 5,440 US adults. The researchers found that 31.7 percent of obese people were metabolically healthy, while 23.5 percent of normal-weight people were in fact metabolically unhealthy. [Arch Intern Med 2008 Aug 11;168(15):1617-24]

Stefan’s research, meanwhile, is now looking at the parameters that regulate the accumulation of liver fat. A larger 2-year study involving 400 people is currently ongoing and is expected to be completed early next year, he said.

Pacemaker power: All in a heartbeat

Medical Tribune December 2008 P8
David Brill

Pacemakers could one day be powered by the beating of the heart, allowing for the development of more advanced features without the need for larger batteries, a British study suggests.

The team at Southampton University Hospital demonstrated that a prototype device, implanted into a pig, was able to successfully generate electricity solely from the contractions of the cardiac chambers.

At present the energy produced is just 17 percent of that needed to power a contemporary pacemaker but refinements of the model could increase this output to 100 percent, the researchers say.

“This study has proved the concept that it’s possible to harvest the energy of cardiac motion using a device that could be part of a standard pacemaker or ICD lead,” said Dr. Paul Roberts, a consultant electrophysiologist who led the study.

“We think that this study may represent a major advance in pacemaker and ICD technology. We don’t envisage that this would be a stand-alone device – we think that it would … augment current pacemaker and ICD batteries so in effect the heart would be continuing to charge the pacemaker battery.

“This may therefore allow for the development of additional device functions that had previously been limited by power constraints,” he said.

The so-called self-energizing implantable medical microsystem (SIMM) is presently hampered by the size of the lead, which has a maximum diameter of around 6mm. The researchers are now looking to bring this into line with current pacemakers by reducing the diameter to around 2 or 3 mm, Roberts said.

He added that it is likely to be several years before the device could be ready for use in humans.

The prototype, which has already attracted commercial interest and UK government funding, was inserted using the standard techniques for pacemaker implantation. The procedure was uneventful and took around 2 or 3 minutes, Roberts said.

The SIMM comprises two pressure-sensitive bladders placed in the right atrium and ventricle. As the heart contracts and relaxes the pressure pushes a magnet back and forth through the connecting lead, thereby generating electricity from a series of coils embedded in the lead.

At rest the system produced 4.3 μJ of energy and a voltage of 0.2 per heartbeat. The energy output increased to 9.6 μJ/beat during pharmacologically-induced tachycardia and dropped to 3.0 and 1.5 μJ/beat during bradycardia and atrial fibrillation, respectively.

Exercise beneficial for heart failure patients, experts say

Medical Tribune December 2008 P9
David Brill

Exercise training is safe and of great benefit to patients with heart failure (HF), experts concluded following the recent presentation of a new study.

HF-ACTION*, the largest-ever randomized trial to assess the effects of exercise in HF patients, was greeted as a success despite failing to meet its primary endpoint.

Participation in a structured exercise program produced a modest reduction in all-cause mortality or hospitalization, which only achieved significance after adjustment for prognostic factors (adjusted hazard ratio 0.89; P=0.03).

Exercise training also improved quality of life among HF patients, a substudy of the trial showed.

Discussing the findings of HF-ACTION, which involved 2,331 patients with an average age of 59, Professor Philip Poole-Wilson of Imperial College, London, UK, said that the data were "compelling" and had wide implications.

"They missed their primary endpoint and there are those who would say ‘well that’s the end of it, let’s go home.’ I think that would be a very wrong interpretation," he said.

"I think that this trial does support the use of exercise and will strengthen the guidelines for both primary care and for the treatment of HF.

"The one thing this trial does not show is what type of exercise to advocate, and I think we’re going to see a lot more studies in that area," he added.

HF-ACTION was conducted at 82 sites in Europe, Canada and the US, with patients followed up for an average of 2.5 years.

A 15 percent reduction in the risk of cardiovascular mortality and HF hospitalization – a secondary endpoint of the study – was also seen after adjustment (adjusted hazard ratio 0.85; P=0.03).

"The HF-ACTION study results support a structured exercise training program for patients with reduced left ventricular function and HF symptoms in addition to evidence-based therapy," said Professor Christopher O’Connor, the study’s principal investigator who presented the findings to the media.

He added that the additional benefits of exercise in HF-ACTION came on a background of excellent medical and device therapy – superior to that seen in any previous HF clinical trial population. More than 90 percent of the patients were on optimal medical therapy and around 40 percent had implantable cardioverter defibrillators, he said.

The exercise program comprised 36 supervised sessions, after which patients were given an exercise bike or treadmill for use at home and encouraged to undertake five weekly sessions of 40 minutes each.

After 3 months, 52 percent of patients were completing at least three such sessions per week. At one-year follow-up, just 25 percent of patients were completing the full five sessions each week.

O’Connor, director of the Heart Center at Duke University Medical Center, US, stressed that adherence is much harder to achieve in lifestyle intervention trials than drug trials, noting that by the conclusion of the study most patients were exercising for just 50 or 60 minutes per week.
Professor Mariell Jessup, a HF specialist from the University of Pennsylvania, said that for many years it was thought that the best treatment for HF was to go to bed and avoid exertion.

"Exercise in HF-ACTION was safe and it improved outcomes so it’s a very encouraging and positive trial. Now when patients come into the office you can say that you need to exercise and it’s perfectly safe for you to do so."


*HF-ACTION: Heart Failure – A Randomized Controlled Trial Investigating Outcomes of Exercise Training.