Guideline recommended heart failure care is generally followed by most primary care doctors. They prescribe ACE inhibitors, beta-blockers, and occasionally mineralocorticoid receptor antagonists. Despite prescribing these proven medications many patients remain symptomatic, are frequently admitted to the hospital and maybe even die prematurely. One of the main problems is that doctors often don’t titrate medications to the doses used in the landmark studies of these agents. There are several reasons for this but one is just plain lack of knowledge of what the target doses are. I know I am guilty of not teaching my house staff what the target doses are. We often start a medication in the hospital or titrate it slightly but leave the final dose adjustments to the outpatient physicians (we of course assume they will do what’s right). A missed teaching opportunity on my part which I will be correcting this month on my inpatient service. I am going to use a nifty app on my iPad called MyStudies (no affiliation). The app is free but the full complement of journal articles costs $10/year. I plan to use it to review landmark trials with my house staff and I am focusing on making sure they know the target doses of drugs. Most of us adjust med doses based on symptoms or physical findings. Could using a lab test (that seems to always get checked by my ER no matter what the complaint) help us primary care physicians do a better job taking care of CHF patients? This month in the European Heart Journal Troughton and colleagues published an individual patient data meta-analysis on using B-type natriuretic peptide to guide therapy in patients with chronic, largely systolic CHF. Previous meta-analyses on this topic used study level data and had limitations in what they could adjust for- something that a patient-level meta-analysis is much better suited for. The methodology was fair but not Cochrane level (somewhat limited search strategy, not very explicit about how they did things, no information on publication bias, etc). They wanted to compare BNP guided therapy with clinically guided therapy and they found 9 studies with 2151 total patients that met their inclusion criteria (RCTs reporting all cause mortality). Despite the lack of statistical heterogeneity there is definitely clinical heterogeneity in their included studies ( different target levels of BNP, different study periods, different durations of follow up, different treatment algorithms). Most studies were fairly small with 69-499 patients enrolled.
What did they find? BNP guided therapy reduced all-cause mortality by 3.4% (19.3% mortality in clinically guided therapy vs 15.9% in BNP guided therapy). This difference was only seen in those under 75 yrs of age as can be seen in this figure. Heart failure hospitalizations were also reduced by 4.7% (27.5% in clinically guided therapy vs 22.8% in BNP guided therapy). Interestingly, there were similar levels of decline in proBNP levels in both groups. I had anticipated BNP guided therapy would result in greater reductions in proBNP levels.
What explains their findings? There are several possible explanations:
- The most obvious is that patients in the BNP guided arm received more dose titrations of medications. They found that only ACE or ARBs doses increased in the included studies and only by 8.4%. No dose increases were seen with beta-blockers or mineralocorticoid receptor antagonists. Loop diuretic doses also stayed the same. The authors found that increasing doses of each of these medications was significantly associated with reduced all-cause mortality.
- I wonder if cointerventions (like diet counseling, medication compliance counseling) were intensified in the BNP guided arms more so than in the clinically guided arms. This would not likely be captured in these studies and could explain lower event rates despite minimal increases in ACE inhibitor doses.
- Could other agents not measured (like digoxin) been added in the BNP guided arms. Digoxin does lower hospitalization rates. No information is given in the meta-analysis about this and I didn’t go back to the individual studies to see how they handled cointerventions.
- Referral to specialty care- this is possible I guess but one of the main effects would be greater titration of meds by cardiologists. ICDs or pacing could have also been done but again this would be related to cointerventions and I would hope this would not have been done differentially.
- BNP guided patients could have been seen more frequently by their providers- possible but this should mostly lead to dose titrations or lifestyle modification counseling.
- Hawthorne effect
I am not planning to order and follow BNPs on all my CHF patients. Why? Isn’t that what the evidence would say to do? I think the key is not necessarily the lab test but making sure you titrate doses to those used in the studies. Dose increasing is all that these studies seem to suggest improves mortality. I think BNP is just a reminder to do that. We need a study of BNP guided therapy vs a clinical pathway that titrates patients to goal doses independent of monitoring BNP. I suspect that study would show no differences in outcomes. You should also remember that BNP is not specific and is affected by renal function. None of the included studies enrolled patients with AKI or CKD (a problem I deal with often).