Some Studies That I like to Quote - a
song designed to get you thinking about the problem with strictly
following cardiovascular guidelines/target shooting and NOT using
evidence to help you and your patient make decisions. The lab coat logos
are from top drug companies, top Rx medications and top guideline
producers. Guidelines are useful but make sure you know the evidence or
lack thereof.
LYRICS -- if anybody wants the evidence/studies referred to in this video please email me at james.mccormack@ubc.ca
Guidelines made me feel so happy I could die
I told my patients it was good enough
To lower glucose make them unconscious
I put my 95 year-olds on a statin
I should have known all along that this was wrong
100 over 60 made them fall, they really fall
Stopping salt and fat did not make sense
I really should have looked at evidence
I didn't know that half of guidelines were just opinion
You say I need an RCT
One that actually shows a difference in a real outcome
I'm supposed to know the NNT, and discuss it with my patients
Are you kidding me?
Don't know what a p-value is
You say I need a Cochrane review to help me find some numbers
I hear some surrogates were wrong
And now I need some studies I'm supposed to quote
Now I need some studies I'm supposed to quote
Now I need some studies I'm supposed to quote
Now and then I think of all the things you had me measure
You had me thinking there was always something that was wrong
All that fibre was an adventure
Now I'm passing wicker furniture Beta-blockers made me feel real slow
And now you telling me about some studies that you need to quote
But now I'm reading RCTs
You get a 1% reduction from a low dose statin
I know now that an A1C of less than 8 is good enough as long as you don't pee
Forget about your CRP
Just don't eat like a great fat pig and go get some activity
I think that I can help you now
I finally have some studies that I like to quote
Some studies
(That I like to quote)
Some studies
(Now I have some studies that I like to quote)
Some studies
(That I like to quote)
Some studies
(Now I have some studies that I like to quote)
(That I like to quote)
(That I like to quote)
(That I like to quote)
(Some studies)
Image via Wikipedia Fuente: Enrique Gavilan Via: Lista MEDFAM-APS España El JAMA acaba de publicar un artículo de análisis, que adjunto, intentando discutir las consecuencias que puede tener el reciente informe de expertos norteamericanos sobre detección precoz de hipercolesterolemia en niños y adolescentes (éste: http://www.nhlbi.nih.gov/guidelines/cvd_ped/summary.htm#chap9).
Sólo se salvan los bebés; a partir de los 2 añitos el sólo hecho de que tengas un padre con un infarto antes de los 55 años hace que te lleves como mínimo 2 pinchazos para medir la LDL. Y a partir de los 9 años, cribado universal...
La consecuencia lógica es que se prescriban estatinas a partir de la conjunción de dos astros y unos LDL de entre 130-160. Me quedo frío.
Y todo ello, por la simple aplicación de, de nuevo, silogismos fisiopatológicos y sin la más mínima evidencia, según el artículo del JAMA, de que esta estrategia aporte más beneficios que riesgos. Salvo por el uso indebido, una vez más, de variables surrogadas, como el LDL.
Vale la pena leer el artículo, vale la pena...
Cuando sale este tema de los colesteroles en los niños siempre me acuerdo de la anécdota que Petr Skranabek nos cuenta sobre la pequeña Ariel y el helado furtivo. Vale la pena leerlo...
I'm a little late reading the June 19th 2010 Lancet, but was intrigued to find letters in response to the meta-analysis by Sattar et al. looking at whether statin therapy increases the risk of diabetes.
I had previously written about this well-performed meta-analysis, and also written about some unfair ways that people use to try to attack randomized trials, and these letters provide an interesting (at least to me) intersection between these posts.
Letters in academic scientific journals are sociologically revealing. There's typically a polite veneer on even the most vicious attacks. Letters written to European medical journals have a somewhat different feel from those to American medical journals, and letters to the Lancet often seem to have a sneering tone that would be unusual to find in the NEJM or JAMA. One letter about the meta-analysis objects that the results cease to be statistically significant when diabetes diagnosed only by physician report are excluded, and secondly that the results involved a post-hoc analysis of the data, with the warning that we might fall victim to the logical fallacy, "Post hoc ergo propter hoc".
Are these fair objections?
Diagnosing diabetes by physician report rather than blood glucose measurement is likely to lead to misclassification: some patients will be classified as having diabetes who don't, and some who have diabetes will be missed. In an RCT, though, misclassification like this will almost certainly be random as well, leading to random misclassification bias. Bias of this sort is toward the null hypothesis (no difference between the groups), as you can convince yourself of if you imagine that the classification is perfectly random such that there is no relation between the classification and diabetes. Under such perfect misclassification, the two groups would have equal numbers of patients classified as having diabetes and there would be no difference between treatment and control. In a meta-analysis that found higher rates of diabetes in patients receiving statins, misclassification bias can be expected to have somewhat reduced the true effect, not to have created an effect out of thin air.
The second objection might be called the "post-hoc-ergo-propter-hoc-fallacy fallacy". The actual fallacy is, of course, a way of saying that just because B follows A, you should not conclude that A caused B. This question of causality is central to epidemiologic research and one of the primary reasons for performing randomized trials, which have particular strengths when arguing for causality. The fallacy has nothing to do with performing post hoc analyses of trials. (To be fair, it's possible the letter writer understood this and was being humorous when writing of this fallacy.) The main problem with a post hoc analysis of a randomized trial is that it often involves multiple comparisons/data dredging, where statistical blips are likely to confuse the issue of what is a true effect. As discussed in my earlier post, a prime issue preceding this meta-analysis was whether JUPITER had found just such a random blip or detected a real problem. The meta-analysis' reason for being performed was primarily to answer this question, and in such a setting there is nothing at all concerning about going back to previously conducted RCTs and performing post hoc analyses looking for diabetes effects. No data dredging was involved, and the analysis should not be looked at askance simply for being post hoc. Revealingly, the meta-analysis found an increased risk of diabetes even when data from JUPITER were excluded.
A second letter complained that the analysis would have been better had it been carried out using hazard ratios rather than odds ratios. While this would likely be true, such an analysis was not possible given the information available to the authors, and it is hard to imagine why an OR analysis would have shown statins to be causing diabetes if it were not true. The same letter also re-raised the possibility that statins appeared to be causing people to have more diabetes by keeping them alive longer to develop diabetes. However, the authors had already addressed this in their meta-analysis and reiterated in their response to the letters that differences in survival were much too small to produce such an effect.
A third letter mis-states the definition of a type I error on its way to arguing that the meta-analysis should have used 99% confidence intervals (p-value cutoff of 0.01) for some reason that was not made terribly clear, but seemed related to concerns that a very large meta-analysis would be more likely to detect a spurious result. It is true that given the enormous N in the analysis, it was possible to find a statistically significant difference in diabetes rates that is likely of little clinical significance, but this has nothing to do with the truth or falsehood of the result itself. The letter also argues that the result is biologically implausible, though it does not seem implausible that a medication could increase diabetes rates during the time of a randomized trial, if only by raising blood sugars in patients near the margin between insulin resistance and diabetes.
A fourth letter suggests that the "diabetes" found in the study might be different in terms of patient-important outcomes than the clinical condition we think of as diabetes. That is, statins might be raising blood sugars in a way that is harmless. While this is possible, it's interesting that when a drug class raises blood sugar people are willing to argue it might be harmless, but when a drug class lowers blood sugar there's a tendency (at least for the manufacturer) to argue that blood sugar control is an excellent surrogate for clinical outcomes. The author of the letter suggests an analysis that might have been done to sort out this issue, which the authors of the meta-analysis correctly point out would not have answered the question.
There were a few other replies to the article, which I have not detailed. Overall, though, this is a fairly typical picture of what happens when someone publishes a trial that conflicts with conventional beliefs, such as "statins are good". This occurs even when the conflict is quite minor -- the meta-analysis merely shows a small increase in diabetes that would be heavily outweighed by cardiovascular benefit in anyone who would be appropriately treated with a statin.
There is no guarantee that the meta-analysis by Sattar et al. is correct about statins and diabetes, but none of the letters published by Lancet raise a sensible reason to think that the post-analysis state of knowledge should change: it is now far more likely than not that statins cause a small increase in diabetes risk. Our response to a meta-analysis like this should be to congratulate the authors on a job well done, while recognizing the possibilities for errors and chance to disrupt the conclusions. It should not be to search high and low for far-fetched flaws that would allow us to discard the inconvenient likelihood that a new statin side-effect has been detected.
el riesgo de padecer una cardiopatía isquémica, pero no lo elimina del todo. Los niveles bajos de colesterolHDL se asocian a un mayor riesgo de desarrollar esta enfermedad, por lo que se cree que los tratamientos capaces de aumentar estos niveles podrían conseguir reducciones adicionales del riesgo. Los inhibidores de la proteína transferidora de ésteres de colesterol (cholesteryl ester transfer protein - CETP) aumentan los niveles de HDL y algunos disminuyen también los de LDL.
Objetivo
Estudiar la seguridad y los efectos sobre las lipoproteínas del tratamiento con anacetrapib en pacientes con antecedentes de cardiopatía isquémica o alto riesgo de desarrollarla.
Se invittó a participar en el estudio DEFINE (Details of the Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib) a personas de 18-80 años con antecedentes de cardiopatía isquémica conocida o con alto riesgo de desarrollarla (riesgo estimado mediante las tablas de Framingham >20% a los 10 años), en tratamiento con estatinas con o sin otros tratamientos hipolipemiantes, y niveles de colesterol LDL de 50-100 mg/dL, colesterol HDL <60 mg/dL y triglicéridos ≤400 mg/dL. Se excluyó a los pacientes con insuficiencia cardíaca, un episodio agudo de cardiopatía isquémica o de AVC en los últimos 3 meses, con afectos de hepatopatías o nefropatías crónicas o en tratamiento con anticoagulantes orales.
Los participantes fueron distribuidos aleatoriamente y a doble ciego a tomar con la comida 100 mg/d de anacetrapib o placebo. Se decidió retirar del estudio a los pacientes que presentasen niveles de colesterol LDL <25 mg/dL en dos determinaciones consecutivas. Las variables de resultado principales fueron el porcentaje en la reducción del colesterol LDL a las 24 semanas de tratamiento y los efectos adversos (PA, hepáticos, musculares, electrolitos, eventos cardiovasculares y muertes por cualquier causa). Las variables secundarias fueron los niveles del colesterol LDL a las 76 semanas y de colesterol HDL, no HDL y las apolipoproteínas B y A-I a las 24 y 76 semanas.
Resultados
Se invittó a participar en el estudio DEFINE (Details of the Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib) a personas de 18-80 años con antecedentes de cardiopatía isquémica conocida o con alto riesgo de desarrollarla (riesgo estimado mediante las tablas de Framingham >20% a los 10 años), en tratamiento con estatinas con o sin otros tratamientos hipolipemiantes, y niveles de colesterol LDL de 50-100 mg/dL, colesterol HDL <60 mg/dL y triglicéridos ≤400 mg/dL. Se excluyó a los pacientes con insuficiencia cardíaca, un episodio agudo de cardiopatía isquémica o de AVC en los últimos 3 meses, con afectos de hepatopatías o nefropatías crónicas o en tratamiento con anticoagulantes orales.
Los participantes fueron distribuidos aleatoriamente y a doble ciego a tomar con la comida 100 mg/d de anacetrapib o placebo. Se decidió retirar del estudio a los pacientes que presentasen niveles de colesterol LDL <25 mg/dL en dos determinaciones consecutivas. Las variables de resultado principales fueron el porcentaje en la reducción del colesterol LDL a las 24 semanas de tratamiento y los efectos adversos (PA, hepáticos, musculares, electrolitos, eventos cardiovasculares y muertes por cualquier causa). Las variables secundarias fueron los niveles del colesterol LDL a las 76 semanas y de colesterol HDL, no HDL y las apolipoproteínas B y A-I a las 24 y 76 semanas.
Resultados
Participaron en el estudio 1.623 pacientes (fig. 1). Las características iniciales de los individuos asignados a los dos grupos eran parecidas. La edad media era de 62 años, el 77% eran varones y el 55% tenían antecedentes de cardiopatía isquémica. La media de colesterol LDL fue de 82 mg/dL y el del HDL, de 40,5 mg/dL.
Figura 1. Flujo de los participantes.
Se excluyeron 142 (17,6%) del grupo de tratamiento activo y 1 (0,1%) del grupo placebo por presentar niveles de colesterol LDL <25 mg/dL. Por lo demás, aproximadamente un 15% de los asignados al tratamiento activo y un 17% de los asignados al placebo interrumpieron el tratamiento por otros motivos. Al final del estudio se dispuso de los datos de más del 99% de los participantes.
A las 24 semanas, el colesterol LDL se redujo en un 40% y el HDL aumentó un 138% más en el grupo intervención que en el grupo placebo (figura 2).
Figura 2. Evolución de los niveles de colesterol LDL y HDL.
Los pacientes asignados al tratamiento con anacetrapib presentaron también cambios favorables en el colesterol no-HDL, los triglicéridos, las apolipoproteínas A y B y la lipoproteína(a) (fig. 3). Todos estos cambios se mantuvieron a las 76 semanas.
Figura 3. Cambio en el perfil lipídico respecto a los valores iniciales a las 24 semanas.
No se apreciaron diferencias estadísticamente significativas en la proporción de pacientes que tuvieron que interrumpir el tratamiento por efectos indeseables, en el porcentaje de pacientes que presentaron síntomas musculares, ni en la mayor parte de los parámetros analíticos monitorizados, con dos excepciones: menos pacientes en el grupo intervención que en el grupo placebo experimentaron elevaciones importantes de las transaminasas y los niveles de sodio disminuyeron algo más en los pacientes asignados al grupo placebo que en el grupo intervención.
Aunque no se encontraron diferencias estadísticamente significativas, se dieron menos eventos cardiovasculares en el grupo de tratamiento activo que en el grupo placebo, sobre todo a expensas de eventos coronarios no mortales. En cambio se dieron más muertes cardiovasculares y por todas las causas (tabla 1).
Tabla 1. Eventos cardiovasculares y mortalidad en los dos grupos (en %) (diferencias sin significación estadística).
Anacetrapib
Placebo
Eventos cardiovasculares mayores
2,0
2,6
Muertes de causa cardiovascular
0,5
0,1
IAM no mortal
0,7
1,1
Ingreso por angina inestable
0,1
0,7
AVC no mortal
0,6
0,6
Muertes totales
1,4
1,0
Conclusiones
Los autores concluyen que el tratamiento con anacetrapib tiene efectos muy potentes sobre el colesterol HDL y LDL, con un perfil de afectos adversos aceptable y sin los efectos adversos cardiovasculares que se observaron con el torcetrapib.
Conflictos de interés
Financiado por Merck.
Comentario
Hasta ahora, el tratamiento sobre el perfil lipídico se ha basado en intentar disminuir el nivel de colesterol LDL mediante las estatinas. Este enfoque ha demostrado su eficacia en la prevención cardiovascular primaria y secundaria. Sin embargo, un porcentaje elevado de pacientes en tratamiento hipolipemiante presentan nuevos eventos (lo que se incluye en el concepto de "riesgo cardiovascular residual").
Para intentar reducir este riesgo se han propuesto nuevos abordajes, como los tratamientos para elevar el colesterol HDL. Entre los fármacos capaces de conseguirlo se encuentran los inhibidores de la proteína transferidora de ésteres de colesterol. Se ha descartado la utilización del primer fármaco de este grupo que se probó en humanos, el torcetrapib, dado que en un ensayo clínico de 12 meses se detectó un incremento en la mortalidad por todas las causas y en el número de eventos cardiovasculares, al parecer ligado al hiperaldosteronismo detectado en el que en el grupo de tratamiento activo.
En estudios preclínicos, el anacetrapib había demostrado aumentar de forma importante los niveles de colesterol HDL y disminuir de forma significativa los del LDL sin que se detectasen efectos apreciables sobre la PA. En esta publicación, se detallan los resultados observados en un ensayo clínico a medio plazo. Los efectos sobre el colesterol HDL y el LDL son similares a la de los estudios previos, el fármaco se toleró razonablemente bien y no se detectaron indicios de hiperaldosteronismo. Sin embargo, a pesar de que no era el objetivo del estudio, se apreció una tendencia no significativa estadísticamente a una mayor mortalidad cardiovascular y total, por lo que es necesario disponer de estudios más amplios antes de poder decidir su utilidad en la clínica.
Bibliografía
Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJP, Komajda M et al. Effects of Torcetrapib in Patients at High Risk for Coronary Events. N Engl J Med 2007; 357: 2109-222. R TC (s) PDF (s)
Krishna R, Anderson MS, Bergman AJ, Jin B, Fallon M, Cote J et al. Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies. Lancet 2007; 370: 1907-1914. R TC (s) PDF (s)
Chapman MJ, Le Goff W, Guerin M, Kontush A. Cholesteryl ester transfer protein: at the heart of the action of lipid-modulating therapy with statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors. Eur Heart J 2010; 31: 149-164. R TC PDF
