TWICE DAILY ASPIRIN MAY BE BETTER FOR DIABETICS

Twice-daily aspirin administration, but not a once-daily doubling of the dose, appears to provide good inhibition of platelet cyclooxygenase (COX)-1 in diabetic patients who have rapid recovery of COX-1 activity and might enhance cardiovascular protection, Francesco Zaccardi, MD, a diabetology fellow at Catholic University of Sacred Heart in Rome, Italy, reported here at the European Association for the Study of Diabetes (EASD) 47th Annual Meeting.
Aspirin is currently recommended for cardiovascular protection for patients with type 2 diabetes mellitus, regardless of prior vascular events. But primary prevention trials have failed to demonstrate its efficacy in this population, possibly because of incomplete platelet inhibition. Italian researchers, led by Dr. Zaccardi, investigated glycemic control and other factors as possible reasons for the incomplete inhibition of thromboxane A₂ by low-dose aspirin over 24 hours. Thromboxane A₂, a product of COX-1 activity, is prothrombotic.
The investigators recruited 100 patients with type 2 diabetes who were taking 100 mg of aspirin daily. They measured thromboxane B₂, the hydrolysis product of thromboxane A₂ and a marker of platelet COX-1 activity, every 3 hours, between 12 and 24 hours after an observed aspirin administration, to assess the kinetics of recovery of COX-1 activity. In addition, a subset of 46 patients underwent 24-hour continuous glucose monitoring. Of them, the 33 patients with the steepest slopes of recovery of COX-1 activity were randomly assigned to receive aspirin 100 mg daily (n = 11), 200 mg daily (n = 11), or 100 mg twice daily for 28 days (n = 11). Recovery of COX-1 activity was determined on day 29 during the 12- to 24-hour dosing period.
The researchers found that COX-1 activity showed linear kinetics with large variability among individuals in the slope of recovery of enzyme activity. For the patients in the lowest tertile of recovery of activity, serum thromboxane B₂ increased in the 12- to 24-hour period by 0.02 ng/mL per hour (range, 0.01 to 0.03 ng/mL per hour), compared with an increase of 0.14 ng/mL per hour (range, 0.11 to 0.20 ng/mL per hour) for the tertile with the fastest recovery.
Independent predictors of the slope of thromboxane B₂ recovery were mean platelet volume (MPV) (P < .0001), higher body mass index (BMI) (P = .007), and age (P = .049). None of the parameters studied in continuous glucose monitoring (e.g., mean 24-hour glycemic value, mean amplitude of glycemic excursions), nor glycated hemoglobin or fasting glucose level, predicted the slope of recovery of thromboxane B₂.
In the cohort with the steepest slopes of return of COX-1 activity, the subjects taking 100 mg of aspirin twice daily showed complete normalization of the slope of platelet COX-1 activity; the administration of 200 mg daily did not have such an effect. Compared with 100 mg once daily, the once-daily administration of 200 mg of aspirin reduced the slope of the recovery line by 55%, and 100 mg of aspirin twice daily reduced the slope by 88% (P < .05 for each vs 100 mg once daily).
Considering the predictive effect of MPV, Dr. Zaccardi surmised that the interindividual variability in the return of COX-1 activity probably reflects abnormal megakaryopoiesis associated with type 2 diabetes. Furthermore, BMI might affect the pharmacokinetics after aspirin dosing. He concluded that twice-daily aspirin administration can overcome the inadequate thromboxane B₂ inhibition seen with once-daily dosing. He advised performing larger, randomized clinical trials to test the safety and effectiveness of this approach.
Since it is not feasible to measure COX-1 activity or thromboxane B₂ in routine clinical practice, Dr. Zaccardi told Medscape Medical News that in the future, we will likely "have to focus more attention on BMI, on age, and on MPV, because it's very easy to measure BMI and to obtain the value of MPV from a single blood analysis."
In summary, he said that an important finding of the study is that "one third of type 2 diabetic patients are poor responders to aspirin, and probably they need twice-daily administration of aspirin." He speculated that the one third of patients who are poor responders to aspirin might have diluted out an effect in the other two thirds in primary prevention trials, possibly accounting for the failure of those trials to show efficacy.
With twice-daily dosing, compliance could be a problem. A slow-release formulation of 200 mg of aspirin could be helpful, but does not now exist, Dr. Zaccardi said. Session cochair Michael Cummings, MD, professor of diabetes and endocrinology in Portsmouth, United Kingdom, said he doubts that adding 1 more pill a day for an elderly type 2 diabetic patient on multiple medications already would present much of an additional problem.
He noted that guidelines in the United States and in Europe focus on using once-daily aspirin, so the study is intriguing for its use of twice-daily dosing, which has not been studied previously. "The implications of the study could be that a simple change to the way that we dose aspirin at the moment — [twice-daily] dosing — could lead to different clinical outcomes, and could perhaps have more pronounced cardiovascular benefits than we're seeing with once-daily aspirin," he said, "particularly in patients with type 2 diabetes."
Dr. Cummings noted that it is becoming increasingly apparent that how and when drugs are administered can change outcomes. As an example, he cited recent work showing that nighttime dosing of antihypertension drugs is probably better than taking them in the morning.
Dr. Cummings advised that future trials of aspirin in people with type 2 diabetes will need to look at cardiovascular outcomes, not just mechanisms of platelet inhibition. Dr. Zaccardi agreed, and said that in light of current good regimens for glycemic, cholesterol, and blood pressure control, "what we have to improve is the problem of [platelet] aggregation in diabetic patients. It is probable that this study could represent a solution...[to] the reduced ability of aspirin to block COX-1."

MASTECTOMY OFFERS NO SURVIVAL ADVANTAGE IN YOUNG WOMEN

Lumpectomy with adjuvant radiation and mastectomy provide "equivalent" overall and disease-specific survival in young women with early breast cancer, according to a new study presented at a press conference today in advance of the start of the 2011 Breast Cancer Symposium.
Young women "should not choose a mastectomy based on the assumption of improved survival," said lead investigator Usama Mahmood, MD, who was at the University of Maryland in Baltimore when the study was undertaken.
"Young age alone does not mandate mastectomy," commented Andrew Seidman, MD, from Memorial Sloan-Kettering Cancer Center in New York City, who moderated the press briefing. His comments related to this study and another reported at the briefing, which found similar rates of local recurrence with the 2 competing surgical approaches.
Using the Surveillance, Epidemiology, and End Results (SEER) database, Dr. Mahmood and colleagues reviewed outcomes among 14,760 women aged 20 to 39 years who were diagnosed with early-stage breast cancer (T1-2, N0-1, M0) between 1990 and 2007.
The women underwent breast-conserving therapy (45%; lumpectomy and radiation treatment) or mastectomy (55%). Everyone in the breast conservation group received adjuvant radiation, but only 17% of the mastectomy group received radiation.
A multivariable analysis that included tumor characteristics found that breast-conserving therapy resulted in similar overall survival (hazard ratio [HR], 0.93; P = .16) and breast cancer–specific survival (HR, 0.93; P = .26) as mastectomy, said Dr. Mahmood, who is now a fellow in radiation oncology at the University of Texas M.D. Anderson Cancer Center in Houston.
Median follow-up duration was 5.7 years.
A matched-pair analysis involving a subset of 4644 of the patients confirmed no difference in overall survival and disease-specific survival, he also said. The patients were matched according to specific factors such as tumor size, tumor grade, and number of positive nodes.
In this analysis, at 5, 10, and 15 years, the overall survival rates for the breast conservation group were 92.5%, 83.5%, and 77%, respectively. For patients who underwent mastectomy, overall survival rates were 91.9%, 83.6%, and 79.1%, respectively. Breast cancer–specific survival rates were also similar between the 2 groups of women, said Dr. Mahmood.
The study's importance is, in part, due to other research findings, suggested Dr. Mahmood. A series of studies presented in the 1980s comparing breast-conserving therapy and mastectomy found equivalent survival among women with early breast cancer. But the number of young women in those studies was small, he said.
Other research has not encouraged the use of breast-conserving therapy in young women, he suggested.
"Previous studies have shown that young women with breast cancer treated with breast-conservation therapy experience higher local recurrence rates," he said. However, those findings were challenged by another study presented at the press conference. The combination of 2 new studies "should make us question that mastectomy is the only option for young women with breast cancer," said Dr. Seidman, who added the caveat that BRCA status is also a key to decision-making in young women.
The new study "serves as a reminder that women should be counseled appropriately about their treatment options," said Dr. Mahmood.
"The data is the data"
The factors included in the multivariate analysis included year of diagnosis, age, race/ethnicity, tumor grade, progesterone receptor status, tumor size, and lymph node status, noted the study authors. Patients had no more than 3 positive nodes, added Dr. Mahmood.
These are standard factors to consider when assessing breast cancer, suggested Dr. Seidman.
The new analysis did not include a number of factors that might also be used to make treatment decisions in the clinic, he further suggested. For instance, there are biological and luminal subtypes, as well the oncotype recurrence score, all of which may help clinicians and patients in their decision-making, he said.
"But most of us don't think about using that information as a decisive factor in the decision to undergo mastectomy or breast conservation therapy," Dr. Seidman said about these more recently identified breast cancer characteristics and newer tests.
Magnetic resonance imaging (MRI) may or may not have an important role to play in this decision-making process, he suggested. It is used to evaluate breast cancer in the preoperative setting to "better select" patients for the type of surgery, he said.
However, whether or not the use of MRI confers a survival advantage is "not settled," according to Dr. Seidman. "There is an epidemic of breast MRI," he said, quoting his colleague Monica Morrow, MD, from Memorial-Sloan Kettering Cancer Center.
"The data is the data," he said about the study, suggesting that any equivocations about the results and any missing factors in the analysis were not merited.
The investigators have disclosed no relevant financial relationships.

STATINS-A GOOD MEDICINE

Long-term results of the Anglo-Scandinavian Cardiac Outcomes--Lipid-Lowering Arm (ASCOT-LLA) study, eight years after the trial officially stopped, showed that treatment with 10 mg of atorvastatin (Lipitor, Pfizer) reduced all-cause mortality compared with placebo, mainly through a reduction in noncardiovascular deaths [1].
Presenting the results at a hot-line session today at the European Society of Cardiology (ESC) 2011 Congress, investigators observed that reductions in the risk of death from respiratory illness and infection contributed to the overall reduction in all-cause mortality. "The numbers are large, the data are convincing, but we have no definitive explanation to date for the hypothesized legacy effect of atorvastatin on noncardiovascular-death risk reduction," said lead investigator Dr Peter Sever (Imperial College, London, UK).
The study was published online August 28, 2011 in the European Heart Journal to coincide with the ESC presentation.
Chair of the hot-line session, Dr George Parcharidis (Aristotle University of Thessaloniki, Greece), asked, somewhat tongue-in-cheek, whether the data were sufficiently strong to support prescribing all young adults a statin for long-term treatment in the hope of reducing all-cause mortality. "They say that one swallow does not make a summer, and I would never advocate atorvastatin to young people on the basis of these findings," responded Sever. "But what these findings do demand is a prospective study in patients at high risk for infection to determine whether the presence of a statin could reduce serious sepsis or death from serious infectious illness."
ASCOT-LLA and the Long-Term Effects of Atorvastatin
The results of ASCOT-LLA were first presented and simultaneously published online in theLancet in 2003 [2]. As reported by heartwire , lipid lowering with atorvastatin resulted in a significant 36% reduction in the primary end point of fatal coronary heart disease and nonfatal MI after a median follow-up of 3.3 years. At the time the study was stopped, there was a nonsignificant trend toward reduction in all-cause mortality. Upon completion of ASCOT-LLA, investigators continued to collect mortality data and evaluated the mortality outcomes in participants originally randomized to atorvastatin or placebo in the ASCOT-LLA arm for a median of 11 years.
At the end of the extended follow-up, all-cause mortality was significantly reduced by 14% (hazard ratio [HR] 0.86; 95% CI 0.76–0.98), and noncardiovascular mortality was significantly reduced by 15% (HR 0.85; 95% CI 0.73–0.99). There was no difference in death from cardiovascular causes.
Looking more closely at deaths from noncardiovascular causes, investigators found that deaths due to cancer were not statistically significant between those treated with atorvastatin vs placebo. There was, however, a significant 36% reduction in deaths due to infection and respiratory illness (HR 0.64; 95% CI 0.42–0.97), driven primarily by deaths due to infection.
During the session, Sever noted there are emerging data on the effects of statins on infection, with preclinical studies showing statins modulate neutrophil function, reduce proinflammatory cytokine release, improve vascular function, have antithrombotic properties, and improve outcomes from pneumonia and sepsis. Results of other observational studies have suggested that prior statin use reduces mortality from sepsis. Despite these observations, Sever said that there is still the possibility of confounding bias in some of the observational studies that have shown a benefit of statins in pneumonia and sepsis and that caution should be used when interpreting such results until a randomized clinical trial is performed.
Serious Decision for Primary Prevention Patients
Dr Guy De Backer (University Hospital, Ghent, Belgium), the discussant who also wrote an editorial that accompanies the published study [3], said that the introduction of statins into primary prevention is a serious decision considering that asymptomatic patients would be advised to take a drug for the rest of their lives and the only treatment benefit would be that "nothing happens." Moreover, there is little long-term safety data. For these primary-prevention trials, the mean patient age is 55 to 66 years old and the median length of statin use is just under five years, and yet primary-prevention patients would likely be treated with a statin for 15 to 20 years.
For this reason, the long-term ASCOT-LLA study is welcome, said De Backer. In primary-prevention studies, the most important clinical outcome is total mortality and quality of life, he added. One of the reassuring results of ASCOT-LLA is that the results confirm the benefits observed in the Scandinavian Simvastatin Survival Study (4S) and West of Scotland Prevention Study (WOSCOPS). In 4S, WOSCOPS, and ASCOT-LLA, there were significant 15%, 12%, and 14% reductions in all-cause mortality, respectively--all achieving statistical significance. He added that data suggesting a therapeutic role for statins in the management of pneumonia and sepsis are supported by observational studies.
Still, De Backer, like Sever, urges caution in interpreting the findings, especially because there is no explanation for the long-term carryover effect of statins on all-cause mortality but not on cardiovascular mortality. The data are essentially a subgroup analysis, and the reduction in all-cause mortality might be the result of chance, De Backer added. Quoting Dr Peter Sleight (Oxford University, UK), De Backer said, "Subgroup analyses are fun to look at, but don't believe them."

ACTIVE SURVEILLANCE IN LOW RISK PROSTATE CANCER

There is now an "emerging consensus" that supports the use of initial active surveillance in low-risk prostate cancer, according to an essay published online August 8 in the Journal of Clinical Oncology.
At the same time, active surveillance is a "relatively uncommon management strategy," admit the essayists, led by Matthew Cooperberg, MD, from the University of California, San Francisco (UCSF).
Two related challenges have limited the widespread acceptance of active surveillance, say Dr. Cooperberg and his prominent coauthors, Peter Carroll, MD, also from UCSF, and Laurence Klotz, MD, from the University Toronto in Ontario, Canada.
In their essay on the "progress and promise" of active surveillance, the trio identify these 2 big challenges as problems in "defining eligibility" (i.e., who should be followed with active surveillance) and "identifying progression" (i.e., when this strategy should be stopped and replaced with active treatment).
They also introduce a host of other impediments to acceptance of the strategy, including economics. "Active surveillance is labor intensive and reimbursed relatively poorly," they write.
The essayists dramatically cite another retarding factor: patients. For some men, despite all educational efforts of a clinician, "the conversation about surveillance ends at the word cancer," they say.
Dr. Cooperberg and colleagues do not directly say that the practice of urology is at fault for the lack of uptake of active surveillance, but they allude to some responsibility, saying that "cultural biases in favor of aggressive treatment" might be at play.
The behavior of urologists is an important consideration, suggested a medical oncologist not involved with the essay.
"Urologists have been taught that the right way to treat cancer is to take it out," said Richard Lam, MD, from Prostate Oncology Specialists in Marina del Rey, California. This 3-physician practice, which treats about 1500 men with prostate cancer, is headed by medical director Mark Scholz, MD, author of Invasion of the Prostate Snatchers (2010, Other Press), a scathing indictment of the mainstream approach to prostate cancer.
Dr. Lam maintains that urologists "have not been taught to not take out prostate cancer."
"It's almost in their DNA to take it out," he told Medscape Medical News.
"Active surveillance is not a concept that they cannot grasp," said Dr. Lam about urologists. "The question is," he continued, "whether or not the basic principles [of active surveillance] are followed."
"There is very little likelihood that a cancer that is destined to be cured will not be cured if active surveillance is done," Dr. Lam asserts.
However, this is a major concern, as Brantley Thrasher, MD, from the University of Kansas Medical Center in Kansas City, and a spokesperson for the American Urological Association, pointed out in a previous interview with Medscape Medical News.
"Once you know there is a cancer, you have to be very careful," Dr. Thrasher noted. If the patient opts for active surveillance but then is noncompliant with regular follow-up tests, and a metastatic prostate cancer is discovered after a few years, then there is danger — especially in the litigious environment of the United States — of a claim of medical negligence, because there might have been a window of opportunity for curative treatment that was missed, he explained.
Dr. Cooperberg and colleagues also cite "medicolegal" risks as a retardant to the uptake of active surveillance.
But Dr. Lam said that, with a patient who is carefully oriented to active surveillance, "we are not very concerned about lawsuits."
Patient Education Could Change Things
Dr. Lam said that the essay by Dr. Cooperberg and colleagues is "well balanced," and adds that he has admired and followed Dr. Klotz's pioneering work in active surveillance "for years."
But Dr. Lam emphasized the need for patient education about active surveillance, and said that he and his colleagues at Prostate Oncology Specialists work hard to educate patients.
Among the 1500 men with prostate cancer attending their practice, about 400 are on active surveillance.
"It takes a lot of time and empathy to communicate the concept that most prostate cancer is a slow growing disease that doesn't kill people," he said.
"Urologists don't do this," Dr. Lam said.
Education is the key to patient acceptance of active surveillance, he asserted. Foremost, patients need to know that active surveillance is "not a case of writing them off," said Dr. Lam, who provided an example of the kind of simple teaching he uses.
He explains to patients that one of the criteria for judging the appropriateness of active surveillance is the "amount" of cancer. Patients with low-risk cancer are told that as the amount increases, their risk increases. They are asked to think of low-risk prostate cancer as a "marble."
"People don't die of a cancer that is the size of a marble," he explains to patients. If it increases to the size of a "ping pong ball," they will continue to watch and biopsy it. And they take out the cancer that is "like a basketball."
One of the investigators in the Surveillance Therapy Against Radical Treatment (START) trial, the first-ever North American phase 3 trial comparing active surveillance and treatment, also suggested that education can shape patients' attitudes.
When enrolling men for START, Adam Kibel, MD, from the Washington University School of Medicine in St. Louis, Missouri, found that, once educated, "many patients end up being concerned about possibly being randomized to treatment."
Reflecting on "Reflexive" Treatment
Dr. Cooperberg and colleagues make numerous references to the fact that the current approach to the care of men with low-risk prostate cancer is in need of repair.
"In contemporary practice in the United States, diagnosis tends to lead to treatment; thus, as the proportion of prostate cancers diagnosed with low-risk characteristics has grown, overdiagnosis has been associated with high rates of overtreatment," they write.
Overdiagnosis and overtreatment are likely to increase with the American Urological Association's new recommendation to begin screening at age 40 years for most men, they suggest.
Autopsy series have shown that 30% of men in their 30s have histologic evidence of prostate cancer, Dr. Cooperberg and his coauthors point out. Thus, it is especially important that "reflexive treatment should be avoided for young men with low-risk disease, whose period of tumor latency may be prolonged."
In general, urologists need to stop offering surgery to everyone with prostate cancer, suggest the essayists. "Reflexive radical treatment of all new diagnoses is increasingly difficult to justify," they write.
There is evidence now that active surveillance is a sound initial strategy in low-risk prostate cancer. "The data to date are sufficient to conclude that most men with low-risk disease — and likely most with intermediate-risk disease and significant comorbidity — should be offered at least a trial of active surveillance," they write.
Who are the best candidates?
"The obvious candidate for active surveillance is an older man with low-risk prostate cancer," the essayists write. Dr. Lam pointed out that older men with comorbidities such as heart disease, who are less likely to be referred to surgery as a result, are especially obvious candidates.
The essayists concur and further qualify this point. "Cancer risk, comorbidity, and life expectancy should receive greater consideration than chronologic age per se in treatment decision making."
How to define risk progression in this setting is "equally challenging," say the essayists. "Overall, grade progression seems to be the most consistent driver of progression," they write. However, "none" of the end points used to measure progression is "entirely satisfactory."