October 28th, 2013
Selections from Richard Lehman’s Literature Review: October 28th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint this selection from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.
NEJM 24 Oct 2013 Vol 369
Thrombus Aspiration During STEMI (pg. 1587): This Swedish trial compared thrombus aspiration during myocardial infarction with conventional percutaneous intervention. It was based on the national comprehensive Swedish Coronary Angiography and Angioplasty Registry (SCAAR). “All 29 PCI centers in Sweden as well as 1 in Iceland and 1 in Denmark participated in the trial. During the study period, 11,709 patients with STEMI in Sweden and Iceland underwent PCI and were registered in SCAAR. Of these, 7012 were enrolled in the trial. An additional 247 patients were enrolled from the center in Denmark, for a total of 7259 patients…None of the patients who underwent randomization were lost to follow-up with respect to the primary end point.” How about that? From start to finish the trial took less than three years, and it proves conclusively that aspirating clot at the time of PCI for ST elevation MI makes no difference to mortality.
JAMA 23/30 Oct 2013 Vol 310
Effect of Statin Therapy on Mortality in Patients with Ventilator-Associated Pneumonia (pg. 1692): Statins do a great deal more than just lower cholesterol, and for all we know they prevent cardiovascular disease by an entirely different mechanism, though the degree to which they do is proportional to their lowering effect on LDL-C. In particular they show strong evidence of having an anti-inflammatory action, and some studies have suggested that they can reduce mortality in sepsis. In this trial, patients in 26 French ICUs with ventilator-associated pneumonia were randomized to simvastatin 60mg or placebo. By the time the trial had recruited 300 patients, it was stopped for futility. Statins are wonderful drugs, but they do not reduce mortality in this situation.
Association Between Influenza Vaccination and CV Outcomes in High-Risk Patients (pg. 1711): I move among sceptics, and I am not entirely convinced that influenza vaccination does anything much, but this meta-analysis suggests that it may reduce cardiovascular events in high-risk individuals. “A large, adequately powered, multicenter trial is warranted to address these findings and assess individual cardiovascular end points.” Yes indeed: and it could be done in a single flu season in the whole UK if we could just harness the same national database methods as that Swedish trial of thrombectomy in MI.
Linagliptin for Patients Aged 70 Years or Older with Type 2 Diabetes Inadequately Controlled with Common Antidiabetes Treatments: A Randomised, Double-Blind, Placebo-Controlled Trial (pg. 1413): You can tell what’s coming, can’t you? Yes, “inadequately controlled” here means a HbA1c greater than 7%: and linagliptin reduces this over 24 weeks with a “safety profile similar to placebo.” Fewer than 10% of participants had an initial HbA1c level above 9%, which is where I would say it may be rational to discuss adding treatment in this age group. The reporting of this Boehringer Ingelheim funded study reads very smoothly, as well it might: five of the six authors are employees of the company, while the sixth and principal author “has received honoraria for lectures and advisory work from Boehringer Ingelheim (the manufacturer of linagliptin).” Yes, and the accompanying editorial salves The Lancet’s conscience in accepting this paper by gently mentioning its defects while going on to bang a drum for the concept of “frailty” as a missing element in this study. The more I read about “frailty,” the more I’m convinced that it is just one more misleading label, aimed more at extending the academic literature than at helping patients. But that is another matter. Just file this paper as one more example of advertising unnecessary treatment under the guise of a randomized trial.
BMJ 26 Oct 2013 Vol 347
Should People at Low Risk of CVD Take a Statin? Statins for all? Yes, I would say, statins for all who really want them after full discussion of the harms and benefits. Just what these are is a matter for debate, and this article presents one side of that debate, pointing out possible under-reporting of harms and overstating of benefits to people at low risk. But I would have to go to the primary literature to be sure, because these authors clearly have a definite view on the message they think should be conveyed to “patients”. Yet having a risk of cardiovascular disease does not make anyone a patient: everyone has some risk, and we are talking here about free individuals. To consider that we as doctors should be “gatekeepers” in this situation is an affront to human rights. What we badly need is a better tool to share decision-making with those who come to us for advice on this issue, and James McCormack has recently come up with a very good and flexible web-based one. I’m going to spend a few days seeing if I can finesse it and perhaps develop an even simpler guide on one side of printed paper.
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These are nice selections from Richard Lehman’s literature review.
The last selection, in particular, caught my attention as I was reading through these.
The authors walk us through the well-known Cholesterol Treatment Trialists (CTT) meta-analysis, with heavy emphasis on what they believe to be limitations in the study (and the Cochrane 2013 recommendations).
While I appreciate their effort to bring more attention to potential understated adverse effects of statin therapy, I think they make some assumptions that may be problematic, thereby weakening their argument. First, they call to attention the discrepancy between two Cochrane reviews on the same topic that are two years apart, suggesting that the changes in conclusions are largely a result of the CTT meta-analysis. This seems inconsequential. Physicians, experts, and well-established investigators frequently revise their assessment of any number of topics – I believe this is the natural ebb and flow of medicine; in part, what makes medicine interesting and an ongoing challenge. Whether or not the Cochrane reviews changed is less important than what those changes are based on. This brings the authors to the crux of their narrative: flaws with CTT.
They continue their argument priming the reader with mortality as the ‘most’ hard endpoint of all – being less biased to confounded reporting, diagnosis, and the like. I would argue that this is a provincial take on the issue and perhaps misguided. Practically speaking, if you ask any cardiologist why they’ve started a statin on a patient, I would imagine the vast majority of us would answer: to prevent a recurrent MI. Of course, this is with the ultimate goal of increasing longevity over a lifetime. Refocusing on what’s relevant, the CTT meta-analysis shows a good reduction in major coronary events and coronary revascularization with statin therapy in the same low-risk groups that the authors address (RR 0.52-0.63). Indeed, they point out – rightfully so – that the number needed to treat is relatively high in this low-risk population. This, however, is expected with therapies applied to low-risk patients due to low event rates.
Third, they seem to overstate the adverse effects of statins. They put aside RCT data and replace it with NHANES data. Knowing the limitations of data acquired in RCTs, it still seems harsh to push all of this data aside. While NHANES may be useful for specific national level information – one has to remember that this is a survey, consisting largely of self-reported events that are open to biased reporting. Knowing that the most common adverse effect of statin therapy is myalgia – an exceptionally high-frequency nonspecific symptom in the general population – it is likely that NHANES numbers are overestimating true medication-related adverse effects. They state that “the prevalence of muscle pain in statin users is 50% greater than non-users [or] 100 times greater than reported in clinical trials.” I have to say that in my clinical practice, I have come across myalgias secondary to statin therapy only rarely, which by far matches the data from RCTs much better than those the authors favor in NHANES. A second component to this is management strategy. Perhaps some physicians see greater rates of adverse effects due to high dosing without a low threshold to change to a high-potency statin for further lipid reduction.
While I do believe that ongoing vigilance of potential statin-related adverse effects is important, I do not think it is excessive – even in the case of low-risk patients – which is the case the authors try to make. With that said, consideration of an individual’s 10-year risk is becoming far less relevant than their lifetime risk. Thinking of this collective risk, having an in-depth pros-cons discussion with each patient, and making a collaborative decision is likely the best approach in this subgroup. The goal here is to keep them event-free for the remainder of their life.
My main concern is if statin treatment or perhaps low cholesterol is carcinogenic, because there is much evidence in support of that. At least nine studies have shown that low cholesterol is associated with an increased risk of cancer 10-30 years later even after exclusion of cancer occurring during the first four years. In accordance, cancer increased significantly after statin treatment in the trials named CARE, PROSPER and SEAS.
Furthermore, the number of nonmelanoma skin cancer increased in the first two simvastatin trials 4S and HPS. The increase was not significant, but if the figures from both trials are calculated together, it becomes significant (p = 0.028). Meta-analyses of the statin trials have not shown an increase of cancer, but after the publication of HPS, authors of statin trials have not reported the number of this cancer category. This is a grave error because skin cancer is the first cancer type to be expected if statin treatment is carcinogenic. Lung cancer for instance does not appear even after ten years of heavy smoking. And there are more scary observations.
When Matsuzaki et al followed 47294 hypercholesterolemic patients on 5-10 mg simvastatin for 6 years, they found that the number of cancer deaths was more than three times higher in patients whose total cholesterol was <160 mg/dl at follow-up compared with those whose cholesterol was normal or high (P<0.001).
In a case–control study by Iwata et al .13.3% of patients with lymphoid malignancies had been treated with statins compared with 7.3% of control individuals with non-malignant diseases matched for age and sex (P<0.001).
In a retrospective study of 388 men with prostate cancer and 1552 matched
controls Chang et al. found an increasing cancer risk with increasing cumulative statin dose (p=0.007).
In a retrospective analysis of 1261 patients who had undergone radical prostatectomy, Ritch et al. found that those on statins were more likely to have an elevation of biochemical tests that suggested recurrent cancer (P< 0.05), and also a more aggressive cancer type than non-users (p<0.05),
Hoffman et al. found that of 83 patients with bladder cancer, the tumour became more aggressive in 53% of those who took statins, in contrast to only 18% for non-users (P=0.004).
In a review of experimental carcinogenicity in rodents, Newman and Hulley found that both fibrates and statins produced cancer after a short time at serum levels close to those achieved in clinical trials.
References to the studies i have mentioned above are present in our paper: Ravnskov U. Rosch PJ, McCully KS. The statin-low cholesterol-cancer conundrum. QJM 2012;105:383-8.
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