NSAID CV Risk Persists for at Least Five Years Post-MI

Three pieces from Medscape Sept.2012

1. Non-steroidal anti-inflammatory Drug and risk of heart attack

NSAID CV Risk Persists for at Least Five Years Post-MI

Sue Hughes

Sue Hughes

Authors and Disclosures

September 11, 2012 (Copenhagen, Denmark) — The latest study to investigate the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with a previous MI has found that the increased cardiovascular risk associated with these drugs persists for at least five years after the MI [1].
The study, published online in Circulation on September 10, 2012, was led by Dr Anne-Marie Schjerning Olsen (Copenhagen University Hospital Gentofte, Denmark).
She commented to heartwire: "We know that MI patients have an increased risk of a subsequent MI and that this decreases with time. We have also shown before that the risk of recurrent events is higher in patients taking an NSAID, but we have not known before how this risk varies with time. In this study, we show that the increased cardiovascular risk with an NSAID appears to remain constant with time after MI. In other words the risk appears to be similarly elevated at one year post-MI and five years post-MI.
"So NSAIDs are still dangerous to patients with a history of MI, even five years after their event. I would say there is no safe treatment window for these patients, and even short-term treatment with an NSAID is hazardous," Schjerning Olsen added.
She said many patients and doctors are unaware of this risk. "The American Heart Association issued guidelines in 2007 discouraging use of NSAIDs in patients with prior MI, but in our study 44% of the MI patients were still taking NSAIDs in 2009; the message has obviously not gotten through."
Better Education Needed
Noting that use of NSAIDs in Denmark has not declined at all since the cardiovascular hazards have been reported, either in MI patients or in the whole population, Schjerning Olsen called for better education, particularly of general practitioners, who tend to prescribe these drugs to many patients.
She suggested that the widespread availability of several NSAIDs without prescription is another factor that allows patients to believe these drugs are safe. "In Denmark, we only have low-dose ibuprofen available without prescription, and this is one of the safer ones regarding cardiovascular side effects, although it is associated with GI bleeding. But in many countries, several NSAIDs are available over the counter, including diclofenac, which had the highest cardiovascular risk in our study--even higher than rofecoxib [Vioxx, Merck], which has been withdrawn. Diclofenac should definitely not be available without a prescription for this reason."
For the study, Schjerning Olsen and her colleagues used national hospital and pharmacy registries in Denmark to identify 99 187 patients who had a first MI between 1997 and 2009 and track their NSAID use in subsequent years.
They found that 43 608 patients had had at least one prescription for an NSAID after the index MI, and these patients had a persistently increased risk of death and coronary death or nonfatal recurrent MI out to at least five years after the initial MI, which remained after adjustment for other factors.
Hazard Ratio (95% CI) of Death and CHD Death/MI in Patients Taking NSAIDs vs Those Not Taking NSAIDs
Time (y) / Death / CHD death/MI
1 / 1.59 (1.49–1.69) / 1.30 (1.22–1.39)
5 / 1.63 (1.52–1.74) / 1.41(1.28–1.55)
Of the individual NSAIDs used, diclofenac was associated with the highest risk of a cardiovascular event, with a hazard ratio of 2.07–2.73 over the five-year follow-up. The selective COX-2 inhibitors rofecoxib and celecoxib (Celebrex, Pfizer) were the next in line, with hazard ratios of 1.73–2.17 and 1.55–1.87, respectively.
As in previous studies, the current research found that naproxen was the NSAID with the lowest relative cardiovascular risk (HR 1.02–1.85). The authors write: "The results might indicate that naproxen should be preferred if NSAID treatment cannot be avoided." But they caution that, like ibuprofen, naproxen was associated with a high risk of gastrointestinal bleeding, which is associated with poor prognosis in MI patients. They therefore advocate "a very conservative approach to using NSAIDs among patients with MI."

2.Pertussin Vaccine effectiveness wanes every year

From Medscape Medical News

Pertussis Vaccine Protection Wanes 42% Every Year

JenniLaidman
Authors and Disclosures

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September 12, 2012 — The odds of acquiring pertussis increase 42% every year after children receive the fifth dose of the diphtheria-tetanus-acellular pertussis (DTaP) vaccine, leading to increasing outbreaks of whooping cough in immunized children, according to a study published in the September 13 issue of the New England Journal of Medicine.
Nicola P. Klein, MD, PhD, codirector of the Kaiser Permanente Vaccine Study Center, Oakland, California, and colleagues compared 3 groups of children who had been vaccinated against pertussis at between 47 and 84 months of age. In this case-control study, a group of 277 children aged 4 to 12 years tested positive for pertussis, using a polymerase chain reaction (PCR) assay. Another group of 3318 children were PCR-negative for whooping cough, and a third group of 6086 children served as matched control patients.
The study, which took place in California from 2006 to 2011, encompassed a large pertussis outbreak in 2010, the state's largest pertussis outbreak since 1958.
The research showed that children who were PCR-positive were more likely to have received their fifth DTaP vaccine earlier than those who were negative (P <.001), and earlier than matched control patients (P = .005) of the same sex, age, and ethnicity who attended the same medical clinic.
"Comparison with PCR-negative controls yielded an odds ratio of 1.42 (95% confidence interval [CI], 1.21 to 1.66), indicating that after the fifth dose of DTaP, the odds of acquiring pertussis increased by an average of 42% per year," the authors write. They adjusted the analysis for calendar time, age, sex, race, ethnicity, and medical service area. A secondary analysis comparing PCR-positive children to the matched control children brought a similar outcome, the authors state.
The study suggests that the acellular pertussis vaccine, which replaced the whole-cell vaccine in the 1990s, is associated with increasing numbers of pertussis outbreaks. Whole-cell vaccine fell into disfavor with rising concerns about its association with severe reactions such as convulsions (1 case per 1750 doses administered, according to a report by the Centers for Disease Control and Prevention [CDC]); rarely, acute encephalopathy (0 - 10.5 cases per 1 million doses administered, according to the CDC); and, some conclude, lasting brain damage.
"Our findings highlight the need to develop new pertussis-containing vaccines that will provide long-lasting immunity," the authors write.
New Pertussis Vaccine Not on the Horizon "Anytime Soon"
However, such a vaccine is unlikely to turn up anytime soon, Michael Pichichero, MD, professor in pediatrics, University of Rochester Medical Center, New York, told Medscape Medical News. Dr.Pichichero was not involved with the study.
"I doubt we will see such products soon on the market, since I am aware of no human trials involving new products that are underway," Dr.Pichichero wrote in an email correspondence. The solution to waning vaccine efficacy is far simpler than the expensive development of a new vaccine, he noted: "A DTaP booster with current products sooner than 11 [to] 12 years of age should suffice."
The study found that older children were more likely to be in the PCR-positive group. Among 6-year-olds tested, 4.5% were PCR-positive for pertussis; among 8-year-olds, 12.2% were PCR-positive; and among 10-year-olds, 18.5% were PCR-positive.
The time since the fifth dose of DTaP was significantly longer for PCR-positive children compared with PCR-negative control patients: 1699 days for PCR-positive children (95% CI, 1627 - 1772) and 1028 days for PCR-negative control patients (95% CI, 1003 - 1053; P < .001 for the difference in time between the 2 groups).
Pertussis cases in the study were of mild to moderate severity, and there were no hospitalizations or deaths.
Before introduction of whole-cell pertussis vaccination, "up to 270,000 cases of Bordetella pertussis yearly were diagnosed in the United States annually," leading to up to 10,000 deaths a year, usually in infants. Vaccination drove down the number of infections, with that number reaching its lowest point in 1976, but since the 1980s, outbreaks have occurred every 3 to 5 years, with each one worse than the last, despite widespread vaccine coverage.
In a pertussis outbreak that took place during the study period, children aged 8 to 11 years who had received the full 5-dose series had the highest incidence of pertussis.
The researchers note that the incidence of pertussis in their study was highest among children between 8 and 11 years old who had received all 5-doses of the DTaP series. They explain that this suggests "that the waning efficacy of the fifth dose among school-age children played a key role in both allowing and sustaining the recent pertussis outbreak." In addition, the current study showed a dip in pertussis incidence among children aged 12 to 15 years.
Together, these observations were "surprising because it is not until children reach their teenage years that they are usually considered to be a reservoir for pertussis, and teenagers have been disproportionately affected in previous pertussis outbreaks," the authors write. They remark, however, that the 12- to 15-year-olds were likely to have received whole-cell vaccination as infants
Herd Immunity, or Lack Thereof, Another Influential Factor
Dr.Pichichero, who said that in his experience, whole-cell vaccine can lead to significant reactions, held that low immunization levels might play the most important role in any pertussis outbreak. "I also note that the study was conducted in California, a state with a disproportionate share of the population of parents who refuse vaccines or construct their own vaccine schedule by requesting delays in vaccination," Dr.Pichichero noted.
"Pertussis is controlled to a significant degree by herd immunity.... Due to the vaccine practices of too many parents in California and the well-intentioned but misguided cooperation by healthcare providers, it may also be that the California pertussis outbreaks are due in part also to the lack of sufficient herd immunity to provide population protection," he concluded.
Kaiser Permanente, the institution employing the study authors, has grants or pending grants with GlaxoSmithKline, Sanofi Pasteur, Pfizer, Merck, and Novartis. One coauthor is a vaccine safety fellow with the CDC. Dr.Pichichero has led trials evaluating various DTaP products and combinations of DTaP vaccines with other vaccines, such as hepatitis B and polio. He has served as a consultant to Sanofi Pasteur, unrelated to DTaP. His institution has received funding from GlaxoSmithKline for vaccine studies unrelated to DTaP.
New Engl J Med. 2012;367:1012-1019.

1. Acupuncture in chronic pain

From Medscape Medical NewsNeurology

Acupuncture Superior to Placebo, Usual Care for Chronic Pain

Pauline Anderson
Authors and Disclosures

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September 10, 2012 — Acupuncture is superior to both sham acupuncture and standard care for the treatment of different types of chronic pain, suggesting that the effects of acupuncture are more than just placebo effect, a new meta-analysis shows.
The analysis found that about 50% of patients who got acupuncture had improvement in pain compared with 30% who didn't get acupuncture and 42.5% who had sham acupuncture.
"In other words, 20% of patients were feeling better because they had acupuncture; about one third of those would only feel better if the right needles were put in the right points to the right depth, and two thirds of them would feel better getting any kind of acupuncture," lead study author Andrew J. Vickers, DPhil, attending research methodologist, Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, told Medscape Medical News.

Dr. Andrew J. Vickers
So in contrast to other interventions, for which the placebo effect is typically about one third of the effect of the treatment, "in acupuncture, it looks like it's two thirds," said Dr. Vickers. "That's quite a large benefit and that's what the patient will actually experience in real clinical practice," where the decision is not whether to have true or sham acupuncture but whether to get a referral for acupuncture or not.
The analysis is published online September 10 in Archives of Internal Medicine.
Individual Patient Data
The researchers searched MEDLINE, the Cochrane Collaboration Central Register of Controlled Trials, and the citation lists of systematic reviews for randomized, controlled trials (RCTs) that included at least 1 group receiving acupuncture needling and 1 group receiving sham acupuncture or no-acupuncture control.
Unlike previous investigators, researchers carried out an individual patient data meta-analysis of only high-quality randomized clinical trials. Such meta-analyses are superior to summary-data meta analyses because they enhance data quality, enable different forms of outcomes to be combined, and allow use of statistical techniques of increased precision, according to the authors.
This analysis included 29 RCTs with a total of 17,922 patients from the United States, the United Kingdom, Germany, Spain, and Sweden who had 1 of 4 indications: back or neck pain, shoulder pain, chronic headache, or osteoarthritis. Of the 29 studies, 18 with 14,597 patients compared acupuncture and no acupuncture, and 20 with 5230 patients compared acupuncture and sham acupuncture. All patients had access to analgesics and other standard treatments for pain.
Sham acupuncture included needles inserted superficially; needles that retract into the handle rather than penetrate the skin; and non-needle approaches, such as deactivated electrical stimulation or detuned laser. The usual care in no-acupuncture control groups also varied; for example, in 1 RCT, control group patients were merely advised to "avoid acupuncture." In some trials, both acupuncture and sham groups received a course of additional treatment, such as exercise.
The meta-analysis showed that acupuncture was statistically superior to control for all analyses (P < .001). The effect sizes among patients receiving acupuncture were 0.23, 0.16, and 0.15 standard deviations (SDs) lower than those among sham controls for back and neck pain, osteoarthritis, and chronic headache, respectively. Effect sizes were larger for the comparison between acupuncture and no-acupuncture control than for the comparison between acupuncture and sham.
Table. Effects of Acupuncture vs Sham or No Acupuncture in Chronic Pain
Indication / Studies (n) / Fixed Effects / P Value
Acupuncture vs sham
Neck and back pain / 8 / 0.37 / <.001
Osteoarthritis / 5 / 0.26 / <.001
Chronic headache / 4 / 0.15 / .31
Shoulder pain / 3 / 0.62 / .44
Acupuncture vs no acupuncture
Neck and back pain / 7 / 0.55 / <.001
Osteoarthritis / 6 / 0.57 / <.001
Chronic headache / 5 / 0.42 / <.001
Shoulder pain / 0 / No trials
The authors provided an example of what the effect sizes might mean in "real terms." A baseline pain score on a 0-100 scale for a typical RCT might be 60, and, given an SD of 25, follow-up scores might be 43 in a no-acupuncture group, 35 in a sham acupuncture group, and 30 in patients receiving true acupuncture.
"If responses were defined in terms of a pain reduction of 50% or more, response rates would be approximately 30%, 42.5%, and 50%, respectively," they write.
Sensitivity analyses showed that neither restricting the sham RCTs to those with low likelihood of unblinding nor adjusting for missing data had any substantive effect on the main estimates. Inclusion of summary data from RCTs for which raw data were not obtained or that were published recently also had little effect.
Repeating the meta-analyses excluding RCTs with a sample size of less than 100 had essentially no effect on the results, nor did an analysis examining the effects of pooling different end points measured at different periods of follow-up.
Acupuncture Type
The type of acupuncture didn't seem to make a difference to the results, said Dr. Vickers. "Some acupuncturists will tell you not to go to such and such a person because that person doesn't put the needles in the right way, or they don't use the right theories, or they're not as well trained, but the particular type of acupuncture you get doesn't seem to make a large difference."
Dr. Vickers and his colleagues are comparing 2 accepted approaches to acupuncture, Chinese and western. "At this point, we can only say that if there's a modest difference between doing real acupuncture and something that no one would think of as being acupuncture, then the difference between 2 bona fide types of acupuncture are unlikely to be large."
Some 3 million Americans receive acupuncture treatments every year, most for relief of chronic pain. A "good proportion" of those are referrals from doctors, said Dr. Vickers.
"Many doctors would be quite reasonably concerned about referring a patient for acupuncture for chronic pain due to a lack of evidence that it would benefit that patient," said Dr. Vickers. "A proportion of those doctors may read this paper and conclude that this evidence is sufficiently robust that they now believe that such a referral would in fact help."
Dr. Vickers noted that many patients with chronic pain are very well managed on medication. Patients who don't get sufficient relief from medication or have side effects from those drugs can choose from a wide variety of other treatments, including physical therapy, manipulation, and behavior therapy. "How exactly acupuncture should be used amongst those other options is actually not clearly understood right now."
Although this analysis didn't tackle the topic of cost-effectiveness, other research has generally found that acupuncture provides "bang for your buck," said Dr. Vickers. "Those studies have typically found that the health gain per dollar spent is well under the typical threshold."