By Dr. Geoffrey Modest
Again, I was dusting off old medical articles and saved another from the recycle bin, this one revealing that the profound effect of medication adherence (whether a med or placebo) leads to improved outcomes (see Lancet2005; 366: 2005). The CHARM trials (all published in the September 3, 2003 issue of Lancet) were a multinational set of trials from 618 sites in 26 countries, enrolling adult patients with symptomatic heart failure (NYHA class II-IV): the CHARM-Alternative trial had patients with low left ventricular ejection fraction (LVEF ≤40%) who did not tolerate an ACE-inhibitor; the CHARM-Added trial had patients with LVEF ≤40 and taking an ACE-I; and the CHARM-Preserved included patients with a preserved LVEF (i.e. >40%) with or without ACE-I. All were randomized to candasartan vs placebo. Overall, each of these studies found efficacy for candasartan (though in the CHARM-Preserved one it was limited to a decrease of 16% for heart failure hospital admissions; the others showed benefit in cardiovascular deaths of about 20% as well as heart failure admissions of 17-39%). But in the current study, done by the CHARM investigators, they looked at the effect of good medication adherence and clinical outcomes.
Details:
- 7599 patients with heart failure (69% men, 45% NYHA class II/52% class III, 71% had recent heart failure admission, mean LVEF in those with systolic dysfunction was 29% and in the study with preserved LVEF was 54%), median follow-up of 38 months
- Results, controlling for a variety of parameters, including age, sex, LVEF, NYHA class, number of meds, smoking, blood pressure:
- 89% of the patients were “good adherers” (patients taking >80% of their assigned meds, whether candasartan or placebo); 11% were <80% med adherent
- Good adherence was associated 35% decrease in all-cause mortality [HR 0.65 (0.57-0.75), p<0.001]
- There was NO DIFFERENCE if patients were in the candasartan vs placebo wing!!
- For candasartan, good adherers had a 34% decrease in all-cause mortality [HR 0.66 (0.55-0.81), p<0.001]
- For placebo, good adherers had a 36% decrease in all-cause mortality [HR 0.64 (0.53-0.78), p<0.001]
So, what does this mean???
- There may well be very important differences in those who take their meds regularly vs those who don’t. This study did control for the anticipated demographic and medical differences (blood pressure, etc.) which could explain this variance. But there certainly may be very important other variables not controlled for, including psychosocial variables (e.g. depression, social isolation, life stressors, etc.) that could affect clinical outcomes.
- But, given the limitations of this retrospective analysis, are there other possible explanations?
- Candasartan and perhaps all angiotensin receptor blockers really don’t do much and really are no better than placebo, and we have been hoodwinked yet again. Though, of note, other studies (e.g. the Coronary Drug Project and the Beta Blocker in Heart Attack Trial) also found lower mortality in those adherent to placebos, though this was not found in the Lipids Research Clinics Primary Prevention Trial.
- Poor medication adherence to candasartan could also mean poor adherence to other meds or therapies that are even more important clinically.
- The people who take their meds regularly are probably the subgroup more likely to have positive expectations about treatment and are more likely to have a placebo response. Since one of the recent emails has not yet been posted on the website, I will excerpt a relevant section: “one interesting study found, not surprisingly, that people who had positive expectation of treatment had a much higher placebo response than those with negative expectations (see Science Translational Medcine 2011; 70(3):70ra14). And, in this study, subjects exposed to experimental heat pain but had a negative expectancy did have some benefit from an infusion of a m-opioid agonist remifentanil; but, when they thought the infusion had stopped, they had a full restoration of pain intensity.”i.e., this study found that even with continued infusion of a potent opiate in those with negative expectation of benefit, they reported lack of effect when they thought the infusion stopped….)
- So, are there practical implications for this study?
- My (anecdotal) experience is that patients take their meds more consistently when I present the value of the med more enthusiastically. And I think there are important ways to involve patients more in their care and improve medication adherence (e.g., making sure that we incorporate the patient’s own approach to care to the extent we think appropriate or at least not harmful, making sure the patient understands and can verbalize him/herself what the goals of treatment are, asking the patient what their concerns are — which ironically may be increased when they see TV ads which highlight the potential adverse effects of meds, having a check-in visit or phone call to see if there are any problems with the meds, involving the patient more in self-care—e.g. checking their own blood pressure at the pharmacy, making sure there are no obstacles to care — insurance copays, etc. etc.)
- But, of course, I have no data to show that any of these interventions would equalize the effects of placebo vs active meds as in the study, though I do think they at least help reinforce the general therapeutic effect of a strong clinician-patient relationship.
Also regarding placebos, a recent blog (https://stg-blogs.bmj.com/bmjebmspotlight/2015/05/07/primary-care-corner-with-geoffrey-modest-md-placebo-genetics-and-the-placebome/ ) notes that there may well be a strong role for genetics in determining the placebo response.