For the video version of this post, click here. Quitting smoking is really hard. It’s frustrating for smokers and for their doctors. And I need to come clean and admit that when varenicline (Chantix) came out I was excited to have one more weapon in my anti-smoking armamentarium. After all, the gums, lozenges, and patches didn’t seem to work very well, but here was this new drug – a pill – that initially boasted quit rates as high as 40%. Compare that to 8% with placebos.
Even compared to the nicotine patch, varenicline seemed better, with one study showing quit rates of 26% versus 20% at one year. Of course, patients had some interesting side-effects, but smoking must be worse than vivid nightmares, right?
Recent studies have suggested that combination nicotine replacement therapy, with a patch to give some basal nicotine and lozenges to curb cravings, might be the better strategy.
Now a study appearing in the Journal of the American Medical Association finally pits the drug against a fair competitor. Researchers randomized around 1000 smokers to treatment with 12 weeks of a nicotine patch alone, a patch plus lozenges, or varenicline. The big question was what percent of those would stay quit at 14 weeks after all interventions stopped.
And I’ll skip right to the punchline. Patch: 23%, Varenicline 24%, patch plus lozenge 27%. There were no statistically significant differences between any of these numbers. Out at 1 year? 20% stayed quit across the board. The winner appears to be… nobody.
To me, more interesting than the intervention results was the analysis of factors that would predispose to quitting. Some were no surprise – if someone else was smoking in the home, your chance of quitting was 22% instead of 27% in a smoke-free home. But there was a pretty large discrepancy in quit rates based on whether or not you smoked menthols. 30% of standard cigarette smokers stayed quit, compared to just 19% of minty cigarette smokers.
Now, we may be tempted to tell our patients – "use whatever you like". But maybe the guidepost should be their tolerance of adverse events – as these were significantly different between the treatment strategies. Hate itching, hives, and hiccups? Avoid the patch. Hate nausea, vomiting, and vivid dreams? Stay away from varenicline.
Actually, you know what's even easier? Stay away from cigarettes in the first place.
For the video version of this post, click here. Is there a breakthrough drug, that, unlike currently available medications for Alzheimers disease targets the disease itself, and not just the symptoms? Thats what various news outlets are reporting after the publication of a study in the Journal Alzheimers and Dementia evaluated the anti-amyloid antibody solanezumab.
But, in my opinion, this is flat out wrong. In fact, the incredibly dense article, which reads somewhat like a love letter to the FDA, could be a lesson in how to try to get your failed drug approved. Heres the story:
Eli Lilly ran two phase 3 trials of Solanezumab in patients with mild to moderate Alzheimers disease. This is pretty standard practice, as the FDA requires two independent randomized trials to grant a new drug approval. Expedition 1 failed to meet either of its two primary endpoints performance on the Alzheimers Disease Assessment Scale Cognitive Subscale or the Alzheimers Disease Cooperative Study Activities of Daily Living Inventory.
Of course, the study looked at tens of outcomes, and, in Expedition 1, it appeared that there was a significant improvement in a different cognitive scale. Expedition 2 was still going on, so they changed the primary outcome of Expedition 2 to be this new scale. Clever. But, swing and a miss in Expedition 2 this outcome was not significantly different between the groups.
But by combining the results of Expedition 1 and 2 and and this is starting to seem desperate frankly limiting the analysis to just those with mild Alzheimers at baseline they were able to finally demonstrate a statistically significant difference. This is not surprising, because the new endpoint was chosen based on the outcome of Expedition 1.
Now hopelessly out of the realm of quality trials, the company (and this paper is almost entirely authored by Lilly employees), performed whats called a delayed-start analysis. After Expedition 1 and 2, participants randomized to placebo could stay on and switch to solanezumab. So, the argument goes, you have an early-start group and a new delayed-start group. The argument they are trying to make is that, if the delayed-start group catches up to the performance of the early-start group, the drug is merely masking symptoms. If, instead, they fail to catch up, then the drug is fundamentally affecting the disease process itself.
The delayed start group didnt catch up, at least according to the incredibly broad definition of catch up used in this study. The authors conclusion? Our drug targets the disease itself. Cue press release and breathless excitement.
Listen, I really wish this were true. But the likelihood is that this drug just doesnt work - not in a way that will matter to patients at least. You can tweak the statistics, you can market it however you want, but the data is the data. The major lesson we learn from this paper is how modern clinical trial design allows for many ways out when your primary hypothesis isnt supported. Weve got to stay skeptical. And if staying skeptical doesnt work try some other outcome maybe the FDA will approve that.