Placebo hazards

New York Heart Association Class II or ni CHF and LVEF of 35% or less shock-only, single-lead ICD (829pts) (1) Conventional therapy for CHF plus placebo (847pts) (2) Conventional therapy plus amiodarone (845 pts) (3) Conventional therapy plus a conservatively programmed, shock only, single-lead-ICD (1) Median follow-up 45.5 months 244 deaths (29%) in the placebo group (2) 240 deaths (28%) in the amiodarone group similar risk of death as compared with placebo (hazard ratio, 1.06 97.5% confidence interval, 0.86-1.30 p = 0.53)... 

SCD-HeFT, a prospective NIH-sponsored, multicenter, randomized primary prevention trial enrolling high-risk, well treated. New Yoric Heart Association Functional Class II and HI heart failure patients tested the hypothesis that vamio-darone or ICD implant, compared to a placebo pill would improve survival. Patients with left ventricular ejection fractions < 0.35 were enrolled, and randomized to a placebo piU, amiodarone, or an ICD. Patients (n = 2,521) were followed for a median of 45.5 months. ICDs deaeased risk of death compared with placebo (hazard ratio, 0.77 p = 0.007). The curves deviated at 18 months. Amiodarone had a similar mortality outcome compared with placebo (hazard ratio, 1.06 p = 0.53) (Fig. 14.3). The absolute risk reduction at 5 years was 7.2%. 

The risk of potentially serious side effects should be enough to preclude the prescription of antidepressants for their placebo benefit, but this is not the only hazard associated with these medications. On 19 July 2006 the FDA issued a public-health advisory warning that, when taken in conjunction with other drugs that can affect serotonin levels, antidepressants can induce a life-threatening disorder called the serotonin syndrome .5 The serotonin syndrome is caused by an excess of serotonin in a person s body. 

No health hazards are known with the proper use of kava (Gruenwald et al. 1998). Kava has been approved by the German Commission E for treatment of anxiety and insomnia. In clinical studies of kava for anxiety, adverse effects were uncommon and did not differ across placebo and kava groups. There do not appear to be any studies published on the effects of acute overdosage with kava. Given its CNS depressant effects, it should not be taken with other similar drugs, including benzodiazepines, barbiturates. 

A hazard ratio of one corresponds to exactly equal treatments the hazard rate in the active group is exactly equal to the hazard rate in the placebo group. If we adopt the above convention and the event is death (or any other undesirable outcome) then a hazard ratio less than one is telling us that the active treatment is a better treatment. This is the situation we see in Figure 13.3. A hazard ratio greater than one is telling us that the active treatment is a poorer treatment. 

Each trial that is to be included in the meta-analysis will provide a measure of treatment effect (difference). For continuous data this could be the mean response on the active treatment minus the mean response in the placebo arm. Alternatively, for binary data the treatment effect could be captured by the difference in the cure rates, for example, or by the odds ratio. For survival data, the hazard ratio would often be the measure of treatment difference, but equally well it could be the difference in the two-year survival rates. 

FIG. 5-7. Relapse rate of schizophrenic patients after 4 months on active drug or placebo. Bottom panels present hazard rate per week. (Adapted from Davis JM, Janicak PG, Chang S, Klerman K. Recent advances in the pharmacologic treatment of the schizophrenic disorders. In Grinspoon L, ed. Psychiatry 1982. The American Psychiatric Association annual review. Washington, DC APPI Press, 1982 192.)... 

FIG. 5-9. Relapse rate of schizophrenic patients after 6 months on placebo. Bottom panel presents hazard rate per month. (Adapted from Davis JM, Janicak PG,... 

HAZP Placebo risk for dropout (hazard) PrLOWCOM Probability of low compliance... 

FIGURE 35.3 Results of the global SA from the zidovudine analog efficacy trial simulation displaying the mnltidimensional effect of parameter nncertainty on trial power (probabihty of snccess). Parameters displayed are placebo risk on the dropont hazard (HAZP) and maximnm dmg effect (ZDVSL) on the dropont hazard. 

Trial Drug Patient Population Primary End Point Results (%) Drug Placebo Adjusted Hazard Ratio p Value... 

---