By Dr. Geoffrey Modest MD: AHA List of Meds to Avoid in Patients with Heart Failure

By Dr. Geoffrey Modest

The American Heart Association has published a long article on medications which could cause or exacerbate heart failure (HF). For the complete text, see http://circ.ahajournals.org/content/circulationaha/early/2016/07/11/CIR.0000000000000426.full.pdf)

• HF is the leading hospital discharge diagnosis in patients >65yo. This group has a very high medication burden (given their age and the likelihood that they have multiple risk factors and medical comorbidities), and on average are on 6.8 medications/d with 10.1 doses/d, not including OTCs (over-the-counter meds) and CAMs (complementary and alternative meds). In one study, 88% of HF patients used OTCs and 35% herbal supplements/63% vitamins. These multiple meds expose patients to more adverse drug effects, exacerbated by the increased likelihood for drug-drug interactions
• These are the commonly used primary care drugs listed in the article:
  • NSAIDs – pretty well-documented increases in HF precipitation and exacerbation, including both the nonselective and COX-2 inhibitors
  • Anesthetics and oncology drugs – will not comment much, since not such a primary care issue, but many can affect cardiac function or exacerbate heart failure (an array of direct cardiotoxins, as well as those that cause peripheral vasodilation, hypotension, increased sympathetic nervous system activity)
  • Metformin – initial concerns about lactic acidosis (a carry-over from phenformin, its no-longer-available relative associated with severe lactic acidosis and frequent deaths). BUT the FDA in 2006 removed HF as a contraindication for metformin, noting that in patients with HF, “the risk of metformin-associated lactic acidosis was minimal and similar to that of other diabetes mellitus medications in patients with HF and that metformin was associated with an overall reduction in mortality” (my emphasis). There is still some concern about using metformin in unstable HF patients or those hospitalized for HF, and they cite the 2016 Am Diabetes Assn guidelines as the source (for further analysis of this, see my commentary below).
  • TZDs and DPP-4 inhibitors for diabetes – reasonable data against using these meds in patients with HF
  • The array of antiarrhythmics with negative inotropy (flecainide, esp inthose with existing LV dysfunction; disopyramine; sotalol; dronedarone)
  • Antihypertensives:
    • Calcium channel blockers (diltiazem, verapamil, nifedipine). [The nifedipine issue is a little unclear to me: a small study (n=21) found worsening of HF. For its cousin amlodipine, an initial study actually found benefit for amlodipine in those with HF, however not replicated in a follow-up study, but there was no overall harm. There is more peripheral edema and pulmonary edema with both of these drugs, so I would be hesitant to use them acutely in patients with unstable HF, but for unclear reasons nifedipine but not amlodipine are on the AHA list. Not sure why the difference
    • a-blockers (prazosin, doxazosin): cause vascular smooth muscle relaxation and increased HF (e.g. ALLHAT trial)
    • Centrally-acting a-agonists: (clonidine). Small studies actually show some improvement in patients with HF, by decreasing sympathetic tone and improving hemodynamics, but the potential for bradycardia and AV dissociation are of concern
  • Selective a1-blockers (tamsulosin, etc.): seem to be associated with increased HF hospitalizations, esp if not getting concomitant b-blockers (suggesting unopposed a₁ stimulation could lead to b₁-receptor stimulation, with increases in renin/aldo, and edema). No clear data that there are HF exacerbations, but still a concern and should be used cautiously
  • Itraconazole, though terbenifine also has liver toxicity but is not associated with HF and is not on the list
  • Albuterol (from decreased b-receptor responsiveness with continued use)
  • Cilostazol: associated with increased heart rate, PVCs/nonsustained ventric tach, though no data showing increased risk of arrhythmias in those with HF. But best to avoid
  • Stimulants (amphetamines, etc.): increase blood pressure, reports of sudden death, acute coronary syndromes, MI, etc. But large epidemiological studies do not confirm excess of serious cardiovasc events
  • Anti-epileptics: carbamazepine is associated severe LV dysfunction seen clinically only with overdoses, though there is potential for hypotension, bradycardia, AV block; pregabalin is associated with peripheral edema, perhaps from direct vascular effects and not from HF (as with dihydropyridine calcium channel blockers) though some HF case reports
  • Antipsychotics: both typical and atypical are associated with sudden cardiac death, arrhythmias, prolonged QTc intervals, tachycardia and hypotension
  • Antidepressants:
    • Tricylcic antiderpressants are associated with tachycardia, postural hypotension, AV conduction, increased QTc, and can be associated with cardiomyopathies.
    • Citalopram is associated with increased QTc, though very rare case reports of torsades, and hard to disentangle the many other meds being taken by patients in these case reports that could also cause torsades. Also, the limited case report data suggest no citalopram dose-relationship
  • Anti-parkinsons meds: valvular regurgitation with pergolide or cabergoline. Limited similar data on bromocriptine. But large epidemiological studies did not find much harm
  • Bipolar meds: lithium is associated with bradyarrhythmias, PVCs, AV block, T-wave depression, cardiomyopathy.
  • Hydroxychloroquine: 70 cases of cardiotoxicity
  • OTC meds: a few of the bad actors above (e.g. NSAIDs) are available OTC, along with vasoconstrictors (phenylephrine/pseudephedrine) which can cause cardiotoxicity, sympathomimetics (asthma meds), and many OTCs are formulated with lots of sodium (cough/cold meds, gaviscon)
  • CAMs: some of clear concern (ma-haung, an ephedra-like product which can cause increased blood pressure and heart rate), even vitamin E >= 400IU has been associated with HF. Some CAMs have significant interactions with cardiovasc meds used for HF (especially grapefruit juice, St. John’s wort, black cohosh). The major concern is the lack of studies showing the safety of the vast majority of CAMS

Commentary:

• My concerns:
  • They lump together clear cardiotoxins, with documented meds which lead indirectly to HF exacerbations (NSAIDs), with really beneficial meds with little data suggesting adverse HF effects (e.g. metformin). Though they do defend their list by citing important studies, and they duly note that there are differing levels of HF concern, I fear that when the lists are published and widely spread, these major differences may be blurred over and may lead to fear of using important and helpful meds. And many of the above AHA concerns are based more on theoretical issues and not hard data (e.g. carbamazepine).
  • In terms of their listing metformin:
    • There are pretty impressive small studies showing benefit for metformin in those with HF. But the AHA listed that it was potentially a cause of problems (lactic acidosis) especially in those with unstable or hospitalized with HF. They cite the ADA recommendations, which cite a 2013 comparative safety and effectiveness study (see Eurich D. Circ Heart Fail. 2013; 6: 395), which not only did not cite any data on metformin use in such patients (and did not recommend against metformin use in these patients), but notes no increased risk of lactic acidosis overall and that metformin was associated with a small reduction in all-cause hospitalizations in those with HF (including those with LVEF <30%) and chronic kidney disease!!!
    • There are animal data suggesting that metformin improves cardiac function (decreases oxidative stress, improves insulin resistance, prevents progression of HF, improves cardiac structure/function/survival, attenuates LV remodeling and improves cardiac mechanical efficiency….)
    • And, in their assessment of the “Magnitude of HF induction or precipitation” they classify of metformin as being a “major” risk with the possible mechanism being “lactic acidosis”, which seems to me to be pretty unwarranted. especially since the studies overall and the FDA do not support an increase in lactic acidosis
  • But, this brings up an issue in medicine: carrying over information which may be distorted in one paper (the ADA recommendations), though on looking at the actual source, there was no such data or conclusion. I definitely see articles where the abstract distorts the conclusions from the actual study and, as above, where the supporting references for a statement in fact do not support the statement. I think this is less frequent now than several decades ago, but is still an issue (as in this metformin case)
• So, bottom line: I am concerned that this list could be used indiscriminately to avoid using important drugs, even though the different drugs are noted to have markedly differing levels of potential problems. Clearly there is a difference between drugs directly related to clinical HF and those with potential mechanisms but little clinical data. And I would add that there is a real difference between some very important drugs clinically (e.g. nifedipine/amlodipine, where the importance of lowering blood pressure and the attendant clinical benefits may far outweigh the potential adverse effects), and those drugs which either have not a huge clinical impact or there are safer alternatives (e.g., for onychomycosis, I do not use itraconazole anymore, mostly terbenafine; or citalopram, where there are no good clinical data that these really are bad, but there are so many alternatives that can be used, such as sertraline). And, even in terms of metformin (my biggest concern in this AHA list), I personally would still be careful using it in patients with unstable HF, since there is not much of an upside (no real harm in waiting a short time when the patient is unstable, though I would use it at low dose in those who are chronically unstable and with okay renal function, see blog below) and there is the potential (though not well-documented) downside of lactic acidosis. However, if the drug is on the above list, it certainly does make sense to watch these patients a bit more closely.

For more blogs on metformin, see https://stg-blogs.bmj.com/bmjebmspotlight/2016/04/26/primary-care-corner-with-geoffrey-modest-md-fda-changes-metformin-guidelines/ , which includes the revised and much more lenient FDA recommendations on metformin use in those with kidney disease, as well as other blogs (showing, for example, that metformin induces changes in the microbiome leading to decreased insulin resistance).