Statins could boost prostate health, studies show

Medical Tribune July 2009 P4

David Brill

Evidence is growing to suggest that statins could help to maintain a healthy prostate – protecting against both benign and malignant disease.

Recent studies have found that statins lowered the risk of developing prostate cancer, reduced the aggressiveness of cancers, and reduced the risk of cancer recurrence after surgery.

Other reports have suggested that the drugs can protect against lower urinary tract (LUT) symptoms, benign prostatic hyperplasia (BPH) and even erectile dysfunction.

Researchers, however, are urging caution, saying that further studies are needed before firm conclusions can be drawn.

Six key studies were presented recently at the annual meeting of the American Urological Association (AUA) in Chicago, US. Three come from a single cohort of 2,447 men aged 40 to 79, who have been followed since 1990 by researchers at the Mayo Clinic, Minnesota, US.

The first study found that men who were taking statins were three times less likely to develop prostate cancer than non-users. Just 6 percent of statin users developed cancer over a median of 14.1 years of follow-up – a considerable reduction compared to the US national average, which sees around 17 percent of all men diagnosed with prostate cancer in their lifetime.

The second study, which included only 1,480 of the men, found that statins reduced the risk of erectile dysfunction in those aged over 60. This apparent protective effect increased over time – men who had been taking statins for 9 years or more were 64 percent less likely to develop the condition than men not taking statins, whereas those taking statins for less than 3 years were equally as likely.

A third analysis of the Mayo Clinic cohort, meanwhile, reported that statin users had a 57 percent reduction in risk of developing BPH, and a 63 percent risk reduction for developing LUT problems.

"If you are taking a statin for a heart condition or to lower cholesterol, these studies suggest that statins could have other benefits," said one of the study authors Dr. Jennifer St. Sauver, an epidemiologist at the Mayo Clinic. "However, it's very clear we need more information before men are advised to start taking statins for their urological health."

The fourth study presented at the AUA meeting found that men taking statins at the time of radical prostatectomy for prostate cancer were 30 percent less likely to have a recurrence. They also had lower prostate-specific antigen levels than non-users, and were more likely to have T1-stage disease. The study included 1,325 men, of whom 237 were taking statins at the time of surgery.

“Our findings suggest that statins may slow prostate cancer progression after radical prostatectomy," said study author Dr. Robert Hamilton, of the University of Toronto, Canada.

“Although the results of these studies are exciting, they need to be confirmed,” he added. “At this point we cannot say with confidence that statins reduce the risk of prostate cancer recurrence after radical prostatectomy."

The fifth study, led by Johns Hopkins University, US, found that prostate cancer was less aggressive in statin users than non-users. Of 1,282 men who underwent radical prostatectomy over 5 years, the 418 who were taking statins had lower tumor volume, lower prevalence of positive surgical margins, and lower percentage of cancer in their prostatectomy specimens.

The final study, meanwhile, suggests that statins might exert their beneficial effects by reducing inflammation within prostate tumors. Researchers from Duke University Medical Center, US, examined specimens from 254 men who had undergone radical prostatectomy, and found that inflammation was reduced by 72 percent in statin users compared to non-users.

Despite the positive results presented at the AUA, not all studies have shown benefits of statins of prostate cancer outcomes. One paper published earlier this year found that statin usage had no effect on progression-free survival after radiotherapy for prostate cancer. [Urology 2009 Jan;73(1):158-62. Epub 2008 Aug 22]

Some researchers have even suggested that statins could actually increase prostate cancer, and have called for further attention to be given to the issue. [Cancer Epidemiol Biomarkers Prev 2008 Feb;17(2):459]

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

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.

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.

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

hsCRP: A new player on the cardiovascular risk stratification stage

Medical Tribune January 2009 P2&3

Dr. Jacques Genest, director of cardiology and Novartis Chair in Medicine at McGill University, Montreal, Canada, addresses the emerging role of high-sensitivity C-reactive protein in predicting cardiovascular risk.

High-sensitivity C-reactive protein (hsCRP) represents a new paradigm in the assessment of cardiovascular risk. It is set to become the first new biomarker for 30 years to be incorporated into routine clinical practice alongside traditional tests such as blood pressure and cholesterol. Guidelines across the world are under review, and it is only a matter of time before hsCRP becomes an integral tool in the risk stratification armory of the primary care physician.

The recent Justification for the Use of Statins in Prevention (JUPITER) trial showed that treating patients who had elevated hsCRP in the absence of other risk factors could significantly reduce the incidence of major cardiovascular events. After a median of 1.9 years of follow-up, the occurrence of cardiovascular death, myocardial infarction, stroke, arterial revascularization or hospitalization for angina was reduced by 44 percent in those treated with rosuvastatin (20mg daily). [N Engl J Med 2008 Nov 20;359(21):2195-207]

These results do not justify testing everyone for hsCRP, but rather suggest that the test will be of great benefit for patients who occupy the grey area between low and high risk. A high hsCRP score can push a debatable case over the treatment threshold while a low score, conversely, can confirm that the patient does not require treatment. Those already deemed to be at high-risk should receive treatment regardless of hsCRP, so the test will add little prognostic value in these patients, while at the other end of the scale there is not sufficient evidence to support routine hsCRP testing in young, healthy people with no other risk factors.

Physicians should begin, therefore, by performing a full and complete cardiovascular risk stratification including sex (until menopause in women), age, physical activity levels, diet, diabetic status, blood pressure and LDL, HDL and total cholesterol levels. For patients who are not obviously at high or very low risk, the physician should now routinely include an hsCRP test. Present evidence suggests that this strategy should be adopted in all men aged over 50 and women aged over 60 – the population that was successfully targeted for treatment in JUPITER. In my opinion, hsCRP will ultimately prove to be of use in men aged over 40 and all postmenopausal women, since these years often herald an increasingly sedentary lifestyle whereby the long-term outcome is likely to be heart disease or cancer. We await the support of local guidelines on this point, however, and at present physicians should exercise their own judgment as to the appropriate age for introducing hsCRP testing.

JUPITER treated patients with hsCRP levels of 2.0 mg/l or higher, and physicians may wish to adopt this level as their cut-point for deciding whether to initiate treatment. There is, however, strong epidemiological data and an ongoing argument in support of adopting a threshold of 3.0 mg/l or higher. This, again, will prove a matter for the guideline makers to decide and is likely to vary from country to country. For those with socialized medicine the cost implications of adopting the lower threshold will be considerable, and will prove an important factor in this decision.

Introducing routine hsCRP testing will undoubtedly increase the number of patients being treated with statins. We must not lose sight, however, of the continued importance of diet and lifestyle interventions, for which there is incontrovertible evidence in favor. Physicians should continue to press the message on five fronts: smoking cessation, quality of diet, quantity of diet, daily exercise, and serenity. The latter encompasses both stress management and levels of social interaction – both important prognostic factors in long-term mortality outcomes. Addressing these issues in a single consultation can be difficult – particularly when seeing the patient only once every 6 to 9 months – and I would recommend that GPs refer certain cases to a dietician and kinesiologist in order to improve motivation through more regular advice and feedback.

Many biomarkers have come and gone over the past 20 years of my research career but very few have proven to be clinically useful. Homocysteine, inflammatory factors, cell adhesion molecules, matrix metalloproteinases, and enzymes such as lipoprotein-associated phospholipase A2 have all failed or are still not ready for primetime use. These markers may predict disease but that does not mean that targeting them will automatically yield a reduction in hard clinical trial endpoints.

The journey towards hsCRP testing has been a long one but the marker has finally matched our ability to predict with our ability to prevent, while also asserting its independence from other risk factors. Guidelines will change in time, but in the face of the evidence from JUPITER physicians may decide not to wait. The time is right, in my opinion, to begin measuring hsCRP and implementing the appropriate strategies in the JUPITER-like patient while we await further international guidance. Unlike other biomarkers, hsCRP testing is here for good.

Dr. Genest is one of the investigators of the JUPITER trial and reports receiving consulting fees from AstraZeneca, Merck, Merck Frosst, Schering-Plough, Pfizer, Novartis, Resverlogix and Sanofi-Aventis.

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

Chinese rice extract could be superior to statins for coronary prevention

Medical Tribune August 2008 SFIX
David Brill

A compound extracted from red yeast rice can significantly reduce the risk of coronary events among patients with a history of myocardial infarction (MI), a randomized trial involving 4,870 Chinese patients has demonstrated.

The magnitude of the effect surpasses that previously reported for statin monotherapy, according to the authors of the study which was published in The American Journal of Cardiology.

Major coronary events occurred among 10.4 percent of patients who took placebo and 5.7 percent of those who took the extract – correlating to a relative decrease of 45 percent and an absolute decrease of 4.7 percent.

The compound, known as Xuezhikang (XZK), was also associated with a 30 percent reduction in risk of cardiovascular death and a 33 percent reduction for total mortality. The average treatment duration was 4.5 years.

“This study shows very clearly that the results exceed that which you would find with any of the statin studies done with patients that have average cholesterol levels,” said Dr. David Capuzzi, one of the authors of the trial, which was conducted at 65 hospitals across China.

“I think it’s very promising. I would be surprised, quite frankly, if this turned out not to be an excellent product.”

He added that the closest comparable study is the Cholesterol and Recurrent Events (CARE) trial, which demonstrated that taking pravastatin led to a 24 percent reduction in risk and an absolute difference of 3 percent. [N Engl J Med 1996 Oct 3;335(14):1001-9]

XZK, which is produced by the Beijing WBL Peking University Biotech Co. Ltd., contains lovastatin, lovastatin hydroxyl acid and ergosterol, among other components. Patients who took 600 mg of XZK orally twice a day also showed significant decreases in triglyceride and LDL cholesterol levels and increases in HDL cholesterol levels compared to those who took placebo.

Dr. Paul Chiam, an associate consultant in the Department of Cardiology at the National Heart Centre Singapore, said that XZK has the potential to become a useful drug for patients who need lipid lowering treatment.

“XZK appears to be at least as effective and perhaps more effective than conventional statins reported in previous studies.

“However, the population in this study was different from studies of statins in the literature, and only a direct randomized head-to-head comparison between XZK and a well established statin, such as simvastatin, would resolve the question whether XZK is indeed more effective,” he said.

Chiam added that although XZK appears to be well tolerated, longer-term safety data are still required. At present a statin would still be first choice for the majority of patients, he said.

Capuzzi, who is based at the Lankenau Institute for Medical Research in Pennsylvania, US, stressed that XZK is extracted from rice grown under controlled laboratory settings and that the results cannot necessarily be extrapolated to commercially-available red yeast rice which may contain unknown compounds.