\u00a0They all sound good at first. A decade later they don\u2019t sound so good.<\/p>\n
Human recombinant activated protein C (HR APC; drotrecogin alfa; Xigris) addresses the pathophysiology of sepsis. It is low in sepsis and associated with death. Replacing it should work. So a randomized trial was done in 2001 (http:\/\/bit.ly\/vQ0f5B<\/a>) showing that it decreased mortality (from 31% to 25% at 28 days) with a small increase in serious bleeding (2 to 3.5%, p=0.06). In the US, the FDA approved it.\u00a0 Subsequently a retrospective study finds substantial bleeding risk. Then 2011 brings a similarly sized trial (n=1696) finds no mortality benefit and it is withdrawn from the market (http:\/\/1.usa.gov\/vwQXtc<\/a>).<\/p>\n \u00a0Nesiritide is a vasodilator that addresses the pathophysiology of heart failure. It should work. So a randomized trial was done showing improvements in physiological parameters and dyspnea at 3 hours (http:\/\/bit.ly\/sl1yRi<\/a>). Another trial found similar improvements in symptoms (http:\/\/1.usa.gov\/vjYReu<\/a>). In the US, the FDA approved it in 2001. In 2011, a much larger trial (n=7141) found no effect on dyspnea or heart failure rehospitalization, and a doubling of hypotension (http:\/\/bit.ly\/sW5oRV).<\/p>\n \u00a0So even if they don\u2019t work at least they cost money and cause harm\u2026<\/p>\n \u00a0What happened? In both cases these were \u201cpivotal\u201d trials\u2014single studies after which governmental approval followed and changed clinical practice. In the case of APC, the early trial was stopped prematurely for benefit.\u00a0 We know this risks overestimation of benefits.\u00a0 In the case of nesiritide, an early (small) trial did not find (or look for) important clinical outcomes. The second one did.<\/p>\n \u00a0In retrospect the drugs should not have been approved or used widely.\u00a0 The evidence was insufficient. Maybe these were just mistakes, and now the lessons regarding appropriate interpretation of evidence have been learned.\u00a0 But I don\u2019t think so.<\/p>\n \u00a0I am not sure we will ever learn. Why? Because of how we are wired and how we understand things.\u00a0 First, we want to help.\u00a0 We want treatments that work, particularly for bad common diseases like sepsis and heart failure. Second, we find new treatments that can fix the physiology that has gone awry. We believe they will work and we take any supporting evidence we can get. Once we have it, we are not easily dissuaded (for examples see last blog re breast and prostate cancer screening (http:\/\/bit.ly\/tk4i1j<\/a>), or consider the evidence that shows intensive glucose control has little if any benefit but plenty of risk (http:\/\/bit.ly\/w3nqx6<\/a>), and evidence that finds the risk of pre-hypertension cannot be identified yet treatment is recommended (http:\/\/bit.ly\/va9w9w<\/a>).<\/p>\n \u00a0We become confident that we know what works, and when facts conflict with our expectations we ignore them (see a superb discussion re: the Surety of Fools by Daniel Kahneman who coined the term \u201cthe illusion of validity\u201d (http:\/\/nyti.ms\/t6qihi<\/a>).<\/p>\n \u00a0Lets see how the latest information on bisphosphonates, drugs that decrease fracture but are now known to also increase fractures is handled\u2026(see EBM online http:\/\/bit.ly\/rGi5cg<\/a>)<\/p>\n","protected":false},"excerpt":{"rendered":" \u00a0They all sound good at first. A decade later they don\u2019t sound so good. Human recombinant activated protein C (HR APC; drotrecogin alfa; Xigris) addresses the pathophysiology of sepsis. It is low in sepsis and associated with death. Replacing it should work. So a randomized trial was done in 2001 (http:\/\/bit.ly\/vQ0f5B) showing that it decreased […]<\/p>\n