November 12th, 2012
Selections from Richard Lehman’s Literature Review: November 12th
Richard Lehman, BM, BCh, MRCGP
CardioExchange is pleased to reprint selections 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.
JAMA 7 Nov 2012 Vol 308
Multivitamins in the Prevention of CVD in Men (pg. 1751): Vitamins are vital amines; you need them to stay healthy; therefore the more you take, the healthier you will be. It’s amazing how pervasive this delusion is: it led even Linus Pauling, three times Nobel prizewinner, to make an ass of himself. And it sells billions of dollars’ worth of useless tablets. Did I really see a two-storey emporium called Ye Olde Vitamin Shoppe in New York City, or had someone slipped some absinthe into my Starbucks? Anyway, you are a doctor, so you should know better than to take this rubbish: here is the Physicians Health Study II. “Among this population of US male physicians, taking a daily multivitamin did not reduce major cardiovascular events, MI, stroke, and CVD mortality after more than a decade of treatment and follow-up.” Antioxidants, antischmocksidants.
Platelet Function During Extended Prasugrel and Clopidogrel Therapy for ACS Treated Without Revascularization: Of course there are sound mechanistic reasons why antioxidants should prevent cardiovascular disease; it is entirely perverse that that they don’t. And there are sound mechanistic reasons why prasugrel should lead to better outcomes than clopidogrel when used with aspirin to prevent ischaemic outcomes following ACS without ST-elevation. In the TRILOGY ACS trial, patients who had not undergone revascularization had their platelet reactivity measured, and sure enough prasugrel was uniformly more effective than clopidogrel at inactivating platelets. But O perversity! “Among those in the platelet substudy, no significant differences existed between prasugrel vs clopidogrel in the occurrence of the primary efficacy end point through 30 months and no significant association existed between platelet reactivity and occurrence of ischemic outcomes.” Sound mechanistic reasons count for nothing in real life, yet again.
NEJM 8 Nov 2012 Vol 367
Statin Use and Reduced Cancer Mortality (pg. 1792): “Statin use in patients with cancer is associated with reduced cancer-related mortality. This suggests a need for trials of statins in patients with cancer.” Denmark stars again: the investigators assessed mortality among patients from the entire Danish population who had received a diagnosis of cancer between 1995 and 2007, with follow-up until December 31, 2009. They found a 15% reduction in overall mortality in people with 13 types of cancer taking statins of any kind and any dose, driven by a reduction in cancer-related mortality. So their conclusion is absolutely spot-on: we need trials of statins in cancer.
Ann Intern Med 6 Nov 2012
Comparative Effectiveness of Sulfonylurea vs. Metformin Monotherapy on Cardiovascular Events in Type 2 Diabetes (pg. 601): After the fall of the Roman Empire, the developed world entered centuries of intellectual darkness marked by minimal scientific progress, a period often called the “Dark Ages.” After many centuries, progress resumed and eventually accelerated during the Renaissance. In a similar fashion, knowledge about the comparative effectiveness of drugs to treat type 2 diabetes is finally beginning to emerge from 40 years of stagnation. This period of darkness and the current reawakening provide critically important lessons for contemporary medicine about the use of surrogate end points in drug development, regulatory oversight, and the hazards associated with reliance on commercial funding for pivotal clinical trials. OK, that’s the standard Lehman rant about diabetes trials. But it wasn’t written by me: there should be quotation marks around those opening sentences, which were actually written by Steve Nissen. That’s slightly ironic, given how much commercial funding he has received for conducting pivotal trials: but his editorial is still well worth reading. He is commenting on a large cohort study which compares the effects of sulfonylureas and metformin on CVD outcomes (acute myocardial infarction and stroke) or death. It’s nothing so ground-breaking as a randomized trial, and it simply confirms that use of sulfonylureas compared with metformin for initial treatment of diabetes was associated with an increased hazard of CVD events or death, of about 20%. It doesn’t tell us if metformin is beneficial, or sulfonylureas are harmful, or a bit of both. And these drug classes appeared half a century ago…
4 Responses to “Selections from Richard Lehman’s Literature Review: November 12th”
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Hopefully a trial with the aim to evaluate the effect of statin treatment on cancer patients may never be performed, because several cohort, case-control studies, statin trials and animal experiments have shown that statin treatment is carcinogenic, not carcinoprotective.
In the case-control studies the authors have compare cancer patients with matched controls and they found that a significant higher number of the former were or had been on statin treatment, and these patients´ cancers were also more aggressive.
In the CARE trial 12/286 women got breast cancer in the treatment group, but only 1/290 in the control group (p=0.002). In the PROSPER trial 245/289 got cancer in the treatment group, but only 199/2913 in the control group (p=0.02). In the SEAS trial 39/944 got cancer in the treatment group, but only 23/929 in the control group (p=0.05). In the two first simvastatin trials 4S and HPS 256/12454 in the treatment groups got non-melanoma skin cancer, but only 208/12459 in the control groups (p=0.028). In their paper Nielsen et al refer to two meta-analyses, which showed that statin treatment did not influence the incidence of cancer, but theses analyses are also biased, because after the publication of HPS no statin trial has recorded the number of non-melanoma cancer, the first cancer to be expected if statin treatment is carcinogenic.
A problem with analyzing statin side effects is that many patients stop the treatment during the trial. A better way is therefore to relate the number of side effects to the degree of cholesterol lowering, as did Matsuzaki et al. They gave 47294 hypercholesterolemic patients a low dose simvastatin and noted that six years later cancer mortality was three times higher among those whose cholesterol was lowered to <160 Mg/l compared with those whose cholesterol was normal or high.
Most likely it is not the statin drugs themselves, but the low cholesterol they achieve that is dangerous. At least nine cohort studies have shown that low cholesterol measured 10-30 years previously is a risk factor for cancer. Therefore Nielsen et al. have introduced a serious bias by comparing people on statin treatment, most of whom have lived most of their life with high cholesterol, with untreated people, whose cholesterol with all certainty must have been low. In accordance, cancer and total mortality was lowest in the group treated with the lowest statin dose.
A detailed description of the studies mentioned above with references is available (1). We have also given a detailed explanation to the carcinogenic effect of low cholesterol. In short: Since long it has been documented that the lipoproteins partake in the immune system by binding and inactivating all kinds of microorganisms and their toxic products, and about 20 % of all cancers are caused by microorganisms.
1. Ravnskov U, McCully KS, Rosch PJ. The statin-low cholesterol-cancer conundrum. QJM 2012;105:383-8.
Clearly those are uncomtrolled studies. Patients with cancers are notoriously difficult to follow and to study , properly. A better study would be to take a group of mice , bred todevelop some kind of cancer , and then give a group the statin as well as keeping a group a s controls. Three possiblilities remain . some will develop cancer earlier, some willdevelop cancer later and some will develop cancer at the same time a usual rate..Then cholesterol, diet , etc can be re analyzed. Live ill patients make poor subjects.
Let say we are interested in studying the ‘pleitropic’ effects of drug S on mortality for a variety of reasons. We have the extremely powerful instrument of a nationwide excellent registry both for drug prescription / use and mortality. Both in the universal cohort and in the nested case-controlled study the drug is associated with reduced mortality associated with cancer and increased mortality for cardiovascular reasons. One would suggest that the drug should be used in a clinical trial for cancer (as the authors of the paper propose) and proscribed for patients hith increased cardiovascular disease (something not suggested by the authors). Well, we know that that drug S is a statin, that has proven beyond doubt it reduces cardiovascular morbidity and mortality. Incidentally statins have not been associated with changes in cancer incidence e or mortality in RCT.
Yes statins are prescribed for people with increased CV risk, therefore there is an indication bias easy to explain. However, even in the adjusted evaluation of case-control study statins persisted in its association with increased CV mortality in a dose-dependent manner (!!!)
But also statin use is associated with increased health awareness (both by the patient (healthy-user effect) and the attending clinician). Indeed the paper shows that statin users had more frequently small size tumors as opposed to non-statin users. The authors try to adjust for this factor (but tumor size was missing in about 70% of non statin-users). Furthermore, chemo or radiotherapy data were missing in about 70$ of statin users vs 25% in non users.
To further complicate the relationship between statins & cancer mortality no dose-response was found. Both antiproliferative and proapoptotic effects (modulated by isoprenoid availability) and serum cholesterol are dose-dependent effects of statins.
Finaly important and simple data regarding cancer and mortality such as tobacco use are missing.
This paper adds a new potential benefit of statins in observational studies that repeatedly are refuted by further investigations.
In summary, the association of reduced cancer mortality and statins seems more likely the result of uncontrolled bias than a real drug effect.
Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature. 1990 Feb 1;343(6257):425–30.
Guijarro C, Blanco-Colio LM, Ortego M, Alonso C, Ortiz A, Plaza JJ, et al. 3-Hydroxy-3-methylglutaryl coenzyme a reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture. Circ. Res. 1998 Sep 7;83(5):490–500.
Smeeth L, Douglas I, Hall AJ, Hubbard R, Evans S. Effect of statins on a wide range of health outcomes: a cohort study validated by comparison with randomized trials. Br J Clin Pharmacol. 2009 Jan;67(1):99–109.
All that we have here is a statistical correlation in a retrospective study. All that such a study can do without exceeding the bounds of statistical inference is to suggest a relationship to be looked for in a future double-blind study. Correlation is almost never due to causation in these studies, because there are too many unknown variables.