3 ms·

This is a really good question. I'll list a few in no particular order: From my perspective, cardiology for a while was misunderstanding the contribution made

by et2o 8y ago

This is a really good question. I'll list a few in no particular order: From my perspective, cardiology for a while was misunderstanding the contribution made to CVD from exogenous cholesterol (what you eat) vs. endogenous cholesterol (what your body makes/transports around). Initially there was a lot of focus on reducing dietary cholesterol. This isn't "Wrong" with a capital "W", but emerging evidence seems to indicate that dietary cholesterol doesn't play as big of a result as a person's endogenous cholesterol processes. However, it's still good to eat a lower cholesterol diet. A lot of the resistance to LDL-C evidence comes from people who want patients to eat less refined sugar. This is 100% a great idea; refined sugar is bad for you metabolically for a number of reasons. However, it's not an either-or proposition and I can't understand why people keep making this case. Finally, I think we are still working out the role chronic inflammatory processes play in cardiovascular disease. They are an important component of the atherosclerotic process and one of the three main "knobs" we have available to twist with medication (the major other ones being blood pressure via antihypertensives and LDL via statins/PCSK9is). However, our typical anti-inflammatory drugs don't really work for cardiovascular disease yet the most common ones work on the COX pathway, which (I don't want to get into it, but it's pretty well studied) in chronic use actually causes increased risk for things like heart attack via upregulation of various prostaglandins that you don't want upregulated. There's some really interesting work on monoclonal antibodies targeting different inflammatory pathways that seems promising, but it's (1) still a ways in the future and (2) seems to be less powerful (so far) than is managing BP and LDL. Edit: Also, if you had asked me five years ago, I'd say that the evidence for the pleiotropic effects of statins (e.g., effects of statins on things other than LDL cholesterol) were pretty interesting. And they were, 5 years ago! However, a lot of good evidence has come out since then showing that most of the effects of statins can be attributed by their action on LDL. It seems like the pleiotropic effects of statin therapy are getting less and less significant as we study them more. For me, this emerging evidence was actually kind of disappointing as I had been planning a few studies to look at statin pleiotropy.

AstralStorm 8y ago
Actually I've dug out a recent (2016) analysis that actually reasonably strongly suggests mechanism different from direct lipid lowering effects. See thread above. More importantly, PCSK9 inhibitors have not shown clear mortality benefits in best analysis we have and they're much more specific to cholesterol... https://www.ncbi.nlm.nih.gov/pubmed/29223954 https://www.ncbi.nlm.nih.gov/pubmed/29223954 And yes, this is after and including the big trials. There are some benefits shown, but they do not translate to mortality endpoint, despite not translating to obvious other controlled morbidity. It looks like an odd and unexpected result, but partly predicted by studies correlating higher total cholesterol with lifespan. Everyone would like it to be as simple as turning down LDL-C knob and fixing the world. Unfortunately, reality is apparently not as accomodating. We truly do not know the exact mechanisms.
- et2o 8y ago
  Again, this paper does not support what you're saying it does at all. You are either misreading or intentionally distorting what it says. 1) Patients had a baseline cholesterol of 106 mg/dL. So already pretty good control of lipids. This implies they were already on intensive statin therapy, and so the effect of PCSK9is can be only incremental improvements. Given that you say PCSK9is are more specific to cholesterol (although this is debatable), we can thus probably attribute most of the effect to reduction in LDL. 2) I quote: Treatment with a PCSK9 inhibitor was associated with a lower rate of a) myocardial infarction (2.3% versus 3.6%; odds ratio [OR]: 0.72 [95% confidence interval (CI), 0.64-0.81]; P<0.001) b) stroke (1.0% versus 1.4%; OR: 0.80 [95% CI, 0.67-0.96]; P=0.02) c) coronary revascularization (4.2% versus 5.8%; OR: 0.78 [95% CI, 0.71-0.86]; P<0.001). d) All cause mortality was only marginally significant: all-cause mortality (OR: 0.71 [95% CI, 0.47-1.09]; P=0.12). This does not mean PCSK9is don't reduce mortality, it just means that we haven't followed enough people for long enough. Again, you have to understand how null hypothesis testing works to interpret this statement. The reason that they reduces MI and Stroke without the same effect on reducing all-cause mortality is that we treat MI and Stroke pretty well typically, so you usually don't die from them. The event rate for these is higher, which means if you run a trial for them as the outcome instead of all-cause mortality you can use fewer patients and get it done faster and cheaper, which is ultimately good for patients. However, we obviously know that MI and Stroke are associated with increased risk death. Furthermore, you can die from a lot of other reasons than cardiovascular disease, which makes the trial require even more people to separate out the signal. No one is arguing that PCSK9 inhibitors are a magic bullet (well maybe someone is, but not most people), but they are clearly pretty good even when added to already-pretty-good therapy.
  - AstralStorm 8y ago
    This is an interesting definition of marginal significance, with P=0.12 (more than double the standard 0.05) and 10%+ OR overlap. You seem to be focusing on OR means too much. Absolute risk adjustments are surprisingly low considering certain predictions. I agree with the conclusion that 106 mg/dL mean could've reduced the power of the experiment. I also agree that a good followup is relevant and important. It could change results a lot, including the initial positive results. However, in the meantime, we have no way to actually evaluate the risks and are essentially making educated guesses. Note that the patients treated were on average 60 years old. This reduces followup time considerably but also reduces potential effect size. The results are mostly based on ODYSSEY LONG TERM and FOURIER trials. The former verified PCSK9i alongside high dose statin therapy. The latter used a monotherapy in some cases but not defined the subgroup. FOURIER alone is quite damning. ODYSSEY LONG TERM does not consider mortality endpoints. Such interesting tidbits like "In terms of individual outcomes, evolocumab had no observed effect on cardiovascular mortality, and hence P values for other outcomes should be considered exploratory." The inhibitors in question were allegedly not mainly tested here as an adjunct to statin therapy or replacement for resistant cases, but it so happened anyway. You're supposed to be comparing it to current best known treatment which is statins, which is a very valid comparison. Any other comparison would only be of educational value but should be done regardless. It is even more suspect that it was not done but instead it was used as an adjunct. Not even canadian cross design was used...

by et2o 8y ago

AstralStorm 8y ago

Actually I've dug out a recent (2016) analysis that actually reasonably strongly suggests mechanism different from direct lipid lowering effects. See thread above. More importantly, PCSK9 inhibitors have not shown clear mortality benefits in best analysis we have and they're much more specific to cholesterol... https://www.ncbi.nlm.nih.gov/pubmed/29223954 https://www.ncbi.nlm.nih.gov/pubmed/29223954 And yes, this is after and including the big trials. There are some benefits shown, but they do not translate to mortality endpoint, despite not translating to obvious other controlled morbidity. It looks like an odd and unexpected result, but partly predicted by studies correlating higher total cholesterol with lifespan. Everyone would like it to be as simple as turning down LDL-C knob and fixing the world. Unfortunately, reality is apparently not as accomodating. We truly do not know the exact mechanisms.

et2o 8y ago
Again, this paper does not support what you're saying it does at all. You are either misreading or intentionally distorting what it says. 1) Patients had a baseline cholesterol of 106 mg/dL. So already pretty good control of lipids. This implies they were already on intensive statin therapy, and so the effect of PCSK9is can be only incremental improvements. Given that you say PCSK9is are more specific to cholesterol (although this is debatable), we can thus probably attribute most of the effect to reduction in LDL. 2) I quote: Treatment with a PCSK9 inhibitor was associated with a lower rate of a) myocardial infarction (2.3% versus 3.6%; odds ratio [OR]: 0.72 [95% confidence interval (CI), 0.64-0.81]; P<0.001) b) stroke (1.0% versus 1.4%; OR: 0.80 [95% CI, 0.67-0.96]; P=0.02) c) coronary revascularization (4.2% versus 5.8%; OR: 0.78 [95% CI, 0.71-0.86]; P<0.001). d) All cause mortality was only marginally significant: all-cause mortality (OR: 0.71 [95% CI, 0.47-1.09]; P=0.12). This does not mean PCSK9is don't reduce mortality, it just means that we haven't followed enough people for long enough. Again, you have to understand how null hypothesis testing works to interpret this statement. The reason that they reduces MI and Stroke without the same effect on reducing all-cause mortality is that we treat MI and Stroke pretty well typically, so you usually don't die from them. The event rate for these is higher, which means if you run a trial for them as the outcome instead of all-cause mortality you can use fewer patients and get it done faster and cheaper, which is ultimately good for patients. However, we obviously know that MI and Stroke are associated with increased risk death. Furthermore, you can die from a lot of other reasons than cardiovascular disease, which makes the trial require even more people to separate out the signal. No one is arguing that PCSK9 inhibitors are a magic bullet (well maybe someone is, but not most people), but they are clearly pretty good even when added to already-pretty-good therapy.
- AstralStorm 8y ago
  This is an interesting definition of marginal significance, with P=0.12 (more than double the standard 0.05) and 10%+ OR overlap. You seem to be focusing on OR means too much. Absolute risk adjustments are surprisingly low considering certain predictions. I agree with the conclusion that 106 mg/dL mean could've reduced the power of the experiment. I also agree that a good followup is relevant and important. It could change results a lot, including the initial positive results. However, in the meantime, we have no way to actually evaluate the risks and are essentially making educated guesses. Note that the patients treated were on average 60 years old. This reduces followup time considerably but also reduces potential effect size. The results are mostly based on ODYSSEY LONG TERM and FOURIER trials. The former verified PCSK9i alongside high dose statin therapy. The latter used a monotherapy in some cases but not defined the subgroup. FOURIER alone is quite damning. ODYSSEY LONG TERM does not consider mortality endpoints. Such interesting tidbits like "In terms of individual outcomes, evolocumab had no observed effect on cardiovascular mortality, and hence P values for other outcomes should be considered exploratory." The inhibitors in question were allegedly not mainly tested here as an adjunct to statin therapy or replacement for resistant cases, but it so happened anyway. You're supposed to be comparing it to current best known treatment which is statins, which is a very valid comparison. Any other comparison would only be of educational value but should be done regardless. It is even more suspect that it was not done but instead it was used as an adjunct. Not even canadian cross design was used...