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Cardiol- heart failure

Primary Care Corner with Geoffrey Modest MD: Metformin in those with CKD, CHF, CLD

6 Feb, 17 | by EBM

By Dr. Geoffrey Modest

A systematic review from the VA synthesized data on use of metformin in patients with chronic kidney disease (CKD), congestive heart failure (CHF), or chronic liver disease (CLD) with hepatic impairment (see doi:10.7326/M16-1901). The goal was to assess all-cause mortality, major adverse cardiac events (MACEs), and other outcomes in patients with these underlying diseases (patients with these diseases having been the ones in whom the FDA initially had warned against using metformin).


  • 17 observational studies that included patients with CKD, CHF, or CLD with hepatic impairment were analyzed. These studies compared patients on diabetes regimens that included Metformin vs those that did not.


  • CKD
    • 6 studies were included, with sample sizes ranging from 1246 to 11,481 patients, median age ranging from 65 to 76. Only one study reported median daily metformin dose (1100 to 1900 mg in the different subgroups)
    • All-cause mortality
      • 22% lower for patients on metformin, HR 0.78 (0.63-0.96)
      • 2 studies reported CKD severity subcategories:
        • eGFR of 30 to <45 had neither benefit nor harm
        • eGFR of 30 to 60 had clear benefit of around 38%
        • eGFR <30 (one study) had neither benefit nor harm
      • MACEs:
        • 2 studies were evaluated, finding no difference in outcomes with metformin in the subgroups of patients with eGFR <45
        • And much, much more hypoglycemia in those on non-metformin-based regimens (specifically, glyburide or insulin)
      • CHF
        • 11 observational studies were included, with sample sizes from 346 to 13,930 patients, median age 55 to 77 years old. No studies included median metformin dose
        • All-cause mortality:
          • 22% lower for patients on metformin, HR 0.78 (0. 71-0.87)
          • 2 studies reported CHF severity subcategories:
            • One study looked at LVEF, finding that both an LVEF of 30-39% and LVEF<30% had a nonsignificant 13% decreased mortality; another study looked at patients with LVEF < 40%, finding a nonsignificant 21% decrease
          • MACEs:
            • The relative chance of readmission for CHF during follow-up was 13% lower for patients on metformin: HR 0.87 (0.78-0.97)
            • The relative risk for cardiovascular mortality was 23% lower in those on metformin (their figure shows that the three studies that looked at this found statistically significant improvement with metformin, but their overall summary said it was nonsignificant?????)
          • CLD
            • 3 observational studies included, with sample sizes ranging from 82 to 250 patients, median age 60-61. No studies reported median metformin dose.
            • All cause mortality:
              • The one study with low risk of bias (n=250) found significantly longer survival: HR 0.43 (0.24-0.78), regardless of cirrhosis severity. Post hoc analysis found a positive association between metformin and survival only in those with nonalcoholic steatohepatitis, though the number of patients in the other subgroups was small.
            • The other studies in those with moderate-to-high risk of bias showed a trend to lower all-cause mortality with metformin


  • Metformin is accepted as the first line drug for diabetes in the US and other countries that I know of. It is such a good and appropriate drug, given both its positive effects on diabetes (including its being weight-neutral or leading to weight loss) as well as data suggesting decreased cardiovascular disease and all-cause mortality. As a result, many clinicians have been using it despite FDA precautions/contraindications, with estimates that 20-30% of patients have been prescribed metformin who have had these precautions/contraindications. The FDA itself has been progressively relaxing these restrictions. In 2006 they removed CHF as a contraindication (though acute or unstable CHF remains a precaution). In addition in 2016, the FDA changed the warning for CKD to be based on eGFR instead of creatinine, making approximately 1 million additional patients with moderate CKD eligible to receive metformin. See blogs noted below for other studies promoting the use of metformin.
  • Most of the above conclusions were based on studies which had low strength-of-evidence, moderate risk-of-bias. However there was consistency in their finding that metformin therapy was associated with reduced all-cause mortality among patients with moderate CKD, CHF, or CLD; fewer CHF admissions among those with moderate CKD or CHF; and a much lower hypoglycemia rate among those with moderate CKD
  • There are other concerns about a meta-analysis such as above, including the fact that they don’t have data on doses of metformin for most studies, what other medications were being used in addition to metformin (the studies did not have rigorous details about which patients were on which other hypoglycemic medications), whether there was “confounding by indication” (where people might have been selected to be on or off metformin based on unknown individual clinical considerations), or even more than baseline data on metformin use in most studies (i.e. patients may have started on metformin but somewhere during the study had stopped it; or alternatively patients may have started off metformin but then put on it during the course of the study)

But, bottom line, these studies reinforce not just the safety of metformin in what had previously been considered concerning underlying comorbidities, but strongly suggest a significant benefit of metformin-based regimens. I.e., there really is an imperative to use metformin as the first-line therapy. We know through our clinical practice that metformin’s major adverse reactions are GI. This is clearly less the case in those on lower doses or if metformin is taken with meals. The somewhat skimpy data suggest that much of the benefit of metformin is conferred by much less than full doses (one oft-repeated quote is that about 80% of the benefit of metformin is by giving 1000mg vs 2000mg). My personal experience is that many people get much better glucose control on just 500mg once a day (which is my starting dose, though I leave it there if there is good control, as happens pretty frequently), and I even have a person on 250mg (1/2 tablet) because of GI intolerance, who seems to get benefit…

Relevant past blogs: is a systematic review of studies in patients with chronic kidney disease, finding for example no cases (as in, zero) of lactic acidosis in 70,490 patient-years on metformin​  which gives the updated FDA changes for metformin prescribing in those with CKD, with reference to a study of 813 patients with creatinine >6 who did NOT have increased mortality on low dose metformin (<= 500 mg/d), as well as the study finding that metfomrin induces changes in the microbiome, which leads to decreased insulin resistance.

Primary Care Corner with Geoffrey Modest MD: Generic Drug Price Variation for Heart Failure Drugs

18 Nov, 16 | by EBM

By Dr. Geoffrey Modest

Most of us, I believe, usually prescribe generic medications to patients, especially for patients who have limited or no insurance and have large out-of-pocket medication costs. A recent study looked at the variability of 3 generic drugs used for heart failure finding dramatic differences within similar geographical areas (see doi:10.1001/jamainternmed.2016.6955).


  • Data reflect 153 chain and 22 independent pharmacies in a 2-state region (Missouri and Illinois), across 55 zipcodes
  • They compared the cost for uninsured patients of low and high dose digoxin (0.125 and 0.25 mg/d), lisinopril (10 and 40 mg/d), and carvedilol (6.25 and 25 mg bid) for 30– and 90–day supplies.
  • They also correlated the costs with the annual income by zipcode


  • Median annual income within pharmacy zipcodes was $53,122, with a range of $10,491 – $112,017
  • The number of manufacturers was about 8 for each drug
  • Only one chain had consistent pricing across its stores
  • For a 90-day supply of the highest dose of the meds:
    • Digoxin 0.25mg varied from $10 to $910.99, with median $114.99
    • Lisinopril 40mg varied from $6.75 to $223.95, with median $34.25
    • Carvedilol 25mg varied from $6 to $208.44, with median $41.23
    • And, for all 3, $30 to $1,144.98, with median $180.46
  • Only 1.7% of pharmacies charged less than $25 for 30-day supply and 5.3% less than $100 for 90-day supply.
  • Overall, they found:
    • Pharmacy type (chain vs. independent) was not significantly associated with pricing
    • Pharmacy pricing did not vary by median annual income of the area, whether median income was $85,883, $59,347 or $31,032
    • Pricing did not vary significantly by state, or clustering by zipcode (review of their figure showed very close proximity of pharmacies with very high and very low price drugs)


  • So, pretty shocking differences in generic drug pricing, independent of the income of the neighborhood, the type of pharmacy, or drug dose/duration of therapy.
  • And, it is clear from several studies that the cost of medications does correlate with medication adherence.
  • We do seem to have a counterintuitive (and counterproductive) system in the US: patients without insurance, often those with the least income, have to pay much more for medications than insurance companies negotiate (ie, the above prices are likely much higher than an insurer would pay, even with the patient co-pay added).
  • This study only looked at 3 drugs, and though more data is needed on other meds, my own experience is that there is large variability in pricing for other drugs as well

So, bottom line: I think the study reinforces that patients without insurance really should call around to different pharmacies to check pricing. Patient should understand that there are potentially huge variations in drug costs from one pharmacy to another, even in the same neighborhood. And we really should move to a more transparent and consistent system of drug pricing in this country.

Primary Care Corner with Geoffrey Modest MD: NSAID Use and Risk of Heart Failure

16 Nov, 16 | by EBM

By Dr. Geoffrey Modest

There was a recent large case-control study confirming several other studies showing a significant risk of heart failure with the use of NSAIDs (see


  • Five large population health care databases from Europe, with 92,163 hospital admissions for heart failure, matched with 8,246,403 controls.
  • Mean age 77, 45% men, patients who developed heart failure were more likely to have history of cardiovascular disease (acute MI in 3.3 vs 1%, atrial fibrillation in 5.0 vs 1.3%, valvular heart disease in 2.6 vs 0.9%, hyperlipidemia in 20.4 vs 14.1%, diabetes in 19.4 vs 8.8%; and be on more meds (ACE/ARB in 42.1 vs 24.6%, b-blockers in 24.4 vs 15.2%, diuretics in 53.2 vs 18.6%)


  • Current use of any NSAID in the preceding 14 days (vs past use greater than 183 days in the past) was associated with a 19% increase of hospital admission for heart failure with OR 1.19 (1.17 to 1.22)
  • In terms of specific NSAIDs, odds ratios of first admissions for heart failure:
    • ketorolac: OR 1.94 (1.71 – 2.19)
    • indomethacin: OR 1.52 (1.31 – 1.77)
    • diclofenac: OR 1.21 (1.16 – 1.26)
    • ibuprofen: OR 1.15 (1.08 – 1.21)
    • naproxen: OR 1.19 (1.08 – 1.31)
    • nabumetone: OR 1.07 (0.81 – 1.43), nonsignificant
    • celecoxib: OR 0.95 (0.89 – 1.02), nonsignificant
  • Almost all of these associations were more profound in those with prior history of heart failure admissions (most extreme was for ketorolac, which developed an OR of 5.09; though the association with naproxen and diclofenac became nonsignificant in those with prior history)
  • There were pretty evident dose-response curves, with the higher doses of NSAIDs associated with more heart failure for many of the NSAIDs. This was measured using Daily Dose Equivalents (DDD), which is the “average maintenance dose”, not specifically defined for each NSAID, but they found the following, with medium dose being 0.9-1.2 DDD, high 1.3-1.9, and very high (>=2): [note: there were only 2 databases which provided this info, and the numbers of people in some of the categories was small]
    • Diclofenac went from insignificant increase in heart failure at low to medium dose, then to OR 1.1 for high and 2.2 for very high
    • Indomethacin increased with increasing dose (p<0.001) for the trend, with OR 1.7 for medium and high dose, jumping to 2.5 for very high, but too wide a confidence interval to make it significant
    • Naproxen OR 1.3 for high and 1.4 for very high
    • Not a clear trend (the very high DDD had OR 1.9, but very wide confidence intervals)
    • Celecoxib: no trend


  • This study basically confirms that NSAIDs are associated with heart failure, and that some are better than others (though I should add that those who developed heart failure were sicker and had more co-morbidities that would make heart failure more likely, even though there were attempts to mathematically control for that). Of note, this study and some others have found that celecoxib (as opposed to pretty much any of the other COX-2 inhibitors) seems to be better [and other studies have found that it does not seem to provoke MIs as does rofecoxib/Vioxx]
  • Most of the above associations applied to men and women, though were stronger in men
  • The dose response curve found with several of the meds (higher dose with more heart failure) serves to reinforce the likely causality of the association
  • The likely mechanisms are related to inhibition of prostaglandin synthesis, which leads to increased peripheral resistance (and blood pressure, another important adverse effect), decreased renal perfusion/GFR (and renal dysfunction, yet another), and decreased sodium excretion/sodium retention
  • As many of you know, I am very concerned about long-term use of NSAIDs and PPIs, in part because they are used so frequently (and are available OTC, which also creates the impression that they must be safe) and because of their litany of significant adverse events (for some of my previous blogs on NSAIDs, see links below). And, of course, the reason they are used so much is because they are really effective. Which makes our tasks harder: how to convince patients to use less toxic meds
    • By downgrading NSAIDs, preferably to nonpharmacologic therapies such as PT or yoga; or through local injections, often given once or infrequently, which do spare systemic side effects in general
    • And downgrading PPIs to H2-blockers or calcium antacids along with sometimes helpful dietary changes

See for FDA warning about NSAIDs and increased risk of heart attack or stroke

See for blog on the role of H pylori in increasing the risk of GI bleeds in those on NSAIDs

See for increased risk of afib with NSAIDs

Primary Care Corner with Geoffrey Modest MD: Vigorous Exercise Helps Those with Heart Failure

9 Nov, 16 | by EBM

By Dr. Geoffrey Modest

There was a recent systematic review/meta-analysis finding that in patients who have heart failure with reduced ejection fraction, vigorous exercise training significantly improved their quality of life (see DOI: 10.1159/000448088).

  • 25 studies were included with 2385 participants (1223 exercising and 1162 controls) [of note, 8 of these studies had <30 patients, and 6 studies had >100]
  • They used the Minnesota living with heart failure total score (MLWHF), a 6-part inventory, all graded 0 to 5, assessing physical and emotional symptoms. A 5-point change is considered clinically meaningful.
  • They did not specifically define the different exercise groups, but an example of high-intensity is cycling 45 minutes at 90% peak work three days per week. An example of vigorous-intensity exercise was cycling for 30 minutes at 60-70% peak VOthree times a week. An example of moderate-intensity exercise was 15 minutes of cycling and 15 minutes of treadmill at 50% peak VO2 three times a week.


  • MLWHF total score was significantly reduced after high-intensity (mean difference -13.74, P=0.0004) and vigorous-intensity training (mean difference -8.56, P<0.0001). No difference with moderate-intensity training.
  • Significant differences were noted with aerobic training (mean difference -3.87, p=0.01) and combined aerobic and resistance training (difference -9.82, p=0.001), but no difference with resistance training alone.


  • There was concern many years ago that vigorous exercise might put too much stress on the heart in those with heart failure. This changed considerably over the past several years, as some of the above studies came out.
  • Review of the forest plot in the above article, which displays the individual studies, found that in all 3 studies where high-intensity exercise was done there was statistically significant benefit; those looking at vigorous-intensity training were pretty consistently favoring the exercise group, with only one study finding statistically significant benefit in the control group (and, that study included only 60 patients, out of a total of 924 overall)
  • This study, as well as some other recent ones, suggest that there is more general benefit with the combo of aerobic and resistance training (i.e., not just aerobic)
  • So, I think this analysis confirms that we should encourage exercise in patients with heart failure and reduced ejection fraction, and that patients should anticipate improved physical and emotional symptoms as they progress to higher intensity exercise. Of course, those with potentially ischemic symptoms should have an appropriate workup prior to beginning an intensive exercise program.

Primary Care Corner with Geoffrey Modest MD: Orthostatic Hypotension and Increased Heart Failure and Mortality

19 Oct, 16 | by EBM

By Dr. Geoffrey Modest

There was an interesting subgroup analysis of the ACCORD blood pressure wing (Action to Control Cardiovascular Risk in Diabetes) which found that those with orthostatic hypotension (OH) had a significantly higher risk of mortality and heart failure events (see Fleg JL, Hypertension. 2016;68:888 ). Details:

  • The ACCORD trial had 10,251 high-risk patients with type 2 diabetes, hemoglobin A1c >7.5%, and were between 40 and 79 years old with cardiovascular disease or 55 to 79 years with anatomic evidence of subclinical atherosclerosis, albuminurea, LVH, or >= 2 additional cardiovascular risk factors. 4733 were randomly assigned to intensive vs standard blood pressure control in a non-blinded trial, with target systolic blood pressure (SBP) of <120 vs <140 mm Hg, and with no requirements as to what medications to give (clinicians’ decisions)
  • 4266 participants were involved in this analysis, with blood pressure measured at baseline, and at the 12 month, and 48 month follow-up visits. The blood pressure was measured using an automated oscillometric device after the patient had been seated at least five minutes, with the blood pressure determined three times at one minute intervals. The patients then stood up and had their blood pressure measured every minute for three minutes. The patients were asked if they experienced dizziness or felt light-headed.
  • Orthostatic hypotension (OH) was defined as a decline in SBP > 20 mmHg or decline in DBP > 10 mmHg
  • The average difference in blood pressure achieved between the intensive vs standard groups was 14.2/6.1 mmHg, with the mean number of medications being 3.4 for the intensive group and 2.1 for the standard group.
  • Serious adverse events related to the intervention, including hypotension and syncope, were found in 3.3% of the intensive group compared to 1.3% of the standard group, with p<0.001


  • OH occurred at least once in 852 people (20.0%). In the adjusted model, this occurred most commonly in women, current smokers, those with higher baseline SBP, higher A1c, and those on beta blockers, alpha blockers or insulin. Of note, neither age nor assignment to intensive vs. standard BP treatment goals was associated with OH
  • Approximate 5% of all patients, independent of group, felt dizzy on standing. The incidence was slightly more in the intensive group but only at the 48 month examination.
  • There was no significant difference in OH prevalence, incidence, or resolution between those in the intensive vs. control groups.
  • People with OH were about twice as likely to report symptoms of dizziness on standing than those without OH, but this was only in about 17-20% of the patients who were symptomatic.
  • Those with OH had an 85% higher risk for heart failure deaths or hospitalizations (p= 0.01) and 62% higher risk for total mortality (p= 0.02).


  • In my experience, beta blockers are the medication most commonly associated with OH and large decreases in blood pressure on standing, even in those with high sitting pressures.
  • It is not so surprising that those with higher A1c’s and on insulin have more OH, since they may well have more autonomic neuropathy, and there may also be some direct insulin-induced vasodilation, perhaps through endothelium-dependent mechanisms.
  • Or that smokers have more OH (probably more atherosclerotic disease of their large arteries, leading to higher SBP but lower DBP because of their nondistensibility)
  • Or in those who had initially higher SBP (again perhaps related to more atherosclerotic large vessel disease, leading to more isolated systolic hypertension)
  • It is, however, unexpected and striking that they found no correlation of OH with age. All of the studies I have seen have shown a significant increase with age. Perhaps part of the reason is that in this study they had an 80-year-old cut off.
  • And, there was no association with whether the patient was in the more aggressive blood pressure lowering group or not (which also supports checking orthostatics in patients with higher blood pressures)
  • So, in this study, it was unclear whether OH was simply a marker of people at higher risk of morbidity/mortality (e.g. more advanced diabetes, with more autonomic neuropathy, etc. as above), or whether it was the cause. but given the not-so-unlikely possibility of the latter being part of the issue, I think it makes sense to assess OH regularly in patients (and i do so in all elderly hypertensive patients, even if they do not have diabetes, and have found, i think, pretty impressive 30+ mmHg drops in blood pressure even in those with systolics in the 150-160 range, and not so uncommonly…) and customize therapy to avoid excessive falls in blood pressure, whether they are symptomatic or not (the reason being: even if asymptomatic, perhaps there are times when they eat/drink less at home or outside in the heat and they become symptomatic, fall, etc; and perhaps the low flow associated with OH really is not so good for the brain, heart, kidneys, etc in the longterm.)
  • For example, there are some studies showing cognitive decline with low blood pressure: see
  • Another important point from the study was that dizziness is not commonly reported with clear-cut OH by blood pressure measurement (i.e. we should not rely on reported dizziness as a reliable marker of OH), and that OH is not a consistent finding each time it is measured.
  • All of this supports my prior suggestions that we measure orthostatic blood pressures in older patients on a regular basis, even if the SBP is in the 150 range, and adjust meds accordingly (?ACCORDingly).


(See for more studies on orthostatic hypotension, including the finding that initial hypotension on standing is in fact much more common than standard orthostatic hypotension after a couple minutes)

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

22 Jul, 16 | by EBM

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

  • 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


  • 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 , 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).

Primary Care Corner with Geoffrey Modest MD: Heart Failure Guidelines: The New Meds

10 Jun, 16 | by EBM

By Dr. Geoffrey Modest

The Am Heart Assn/Am College of Cardiol just published their updated 2016 guidelines on the pharmacological therapy of heart failure (HF), focusing on the newer therapies (see doi:10.1161/CIR.0000000000000435/-/DC1)


  • Meds for Stage C (symptomatic) HF with reduced ejection fraction (HFrEF). Clinical strategy is to use one of these meds in combo with evidence-based b-blocker and aldosterone antagonist in appropriate patients.
  • ACE-I (Level A evidence): reduces morbidity and mortality in patients with any stage of symptomatic HF (also in asymptomatic, as an aside), with or without coronary artery disease (CAD). Associated with hypotension; renal insufficiency; elevated K; angioedema in <1%, though higher in women and black patients.
  • ARBs (Level A evidence): thought to help also with decreasing angiotensin II production (which continues despite ACE-I through alternative enzymatic pathways). ARBs reduce mortality, esp in ACE-I intolerant patients (they have the same adverse effects, though less cough, presumably because of the ACE-I associated bradykinin increases). [They do point out that an ARB should be used in those intolerant of ACE-I for cough or angioedema, but commenting that they be used in caution in those who develop angioedema with ACE-I; and I have personally sent a patient to the ICU twice with severe angioedema, first from an ACE-I, then from an ARB. So I am really cautious to the point of avoiding ARBs if at all possible in ACE-I associated angioedema]. ACE-I may have some advantage over ARBs in their beneficial vasodilatory effects through the kininase inhibition.
  • ARNI(Level B evidence — moderate quality from 1 or more RCTs): a combo of an ARB and neprilysin, an enzyme that degrades natriuetic peptides, bradykinin, adrenomedullin, and other vasoactive peptides. Valsartan/sacubitril vs enalapril was associated with 20% decrease in composite of cardiovascular death or HF hospitalization (see McMurray JJ. N Engl J Med. 2014;371:993). ARNIs are also associated with renal insufficiency, hypotension. And they should not be given within 36 hours of last dose of ACE-I, since they can lead to angioedema (because both ACE and neprilysin affect bradykinin). Also, should not use ARNI in setting of patient with any history of angioedema. No head-to-head comparison of ARB and ARNI
  • Ivabradine (Level B evidence — moderate quality from 1 or more RCTs): lowers heart rate by a direct effect on the sinoatrial node, with heart rate lowering being the posited mechanism of action for improving HF. one RCT (the SHIFT trial, Swedberg K. Lancet 2010; 376: 875)showed reduction in HF hospitalizations. The target of treatment was lowering the heart rate, BUT only 23% of the patients were on the optimal dose of b-blockers
  • One confusing thing in this guideline is that, though they promote ACE-I and ARB with strong ratings (both Level A evidence), they pretty clearly highlight the one positive study of valsartan/sacubitril and do seem to push the ARNI, albeit with caveats about the angioedema (e.g., stating: “In patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, replacement by an ARNI is recommended to further reduce morbidity and mortality”). One general concern of mine is that ARNIs do have a pretty wide effect on major enzyme systems (i.e., shotgun vs targeted bullet), which does raise the concern about other adverse effects, those not detected in the short-term 27-month N Engl J Med study above. This study did find twice as many patients developed angioedema (19 vs 10 patients, in a study of 8442 patients, though statistically nonsignficant). Would that number increase with more prolonged use? What about the long-term effects of all the other vasoactive/other enzymes which are inhibited by neprilysin? [i.e., those general enzyme systems are likely there for a reason….]
  • Ivabradine has a somewhat lower recommendation: it “can be beneficial to reduce HF hospitalizations for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF<35%)… on a beta blocker at maximum tolerated dose” and who are in sinus rhythm with a resting heart rate of >=70.
  • The committee chairs had no conflicts of interest reported, though 6 of the 15 committee members did.

So, how should this change practice?

  • It is important to remember and acknowledge the baseline: the use of ACE-I, ARB, b-blockers and aldosterone antagonists has so dramatically improved the prognosis and function of patients with HFrEF over the past couple of decades, such that many of my patients, even with symptomatic HF and severely reduced EF are living long and active lives.
  • The data on valsartan/sacubitril is indeed impressive (including the 20% decrease in mortality on subgroup analysis), though given how well patients are doing with optimized older medical therapy, and given the somewhat shotgun effects that this new drug combo has on several important enzyme systems, I personally am not ready to use it until more and longer-term data is available (though I would really consider it in patients with suboptimal functional improvement with ACE-I/ARBs).
  • In terms of ivabradine, I am less enthusiastic because of the study limitations. This was also short term trial (23 months), and a significant majority were not on full-dose b-blockers. Given the strong data supporting the use of b-blockers, I would primarily promote them. I would consider ivabradine in those not tolerant of b-blockers, though keeping in mind that in the SHIFT trial there was a 15% higher rate of atrial fibrillation, and more symptomatic bradycardia and visual side-effects

Primary Care Corner with Geoffrey Modest MD: Diabetes DPP-4 Inhibitors and the Risk of Heart Failure

20 Apr, 16 | by EBM

By Dr. Geoffrey Modest

The FDA recently came out with a safety alert about 2 DPP-4 inhibitors and the increased risk of heart failure (released 04/05/2016) (see​ ).


  • Saxagliptin and alogliptin were singled out because of 2 clinical trials in diabetic patients with heart disease. In each trial more patients taking these meds were hospitalized for heart failure vs those on placebo
    • In the saxagliptin trial: 3.5% were hospitalized for heart failure (vs 2.8% on placebo). Risk factors included prior heart failure or kidney disease
    • In the alogliptin trial: 3.9% were hospitalized for heart failure (vs 3.3% on placebo)
  • Recommendation by the FDA:
    • We should consider stopping these drugs if the patient develops heart failure
  • I believe these trials (not cited specifically by the FDA) were the ones in the blog​ . The saxagliptin one was clearly the one in the blog, the alogliptin one probably was (reviewing the article, they did not have any breakdown for developing heart failure in the article or the supplementary materials. my guess is that the FDA got their hands on more specific data….)

Ironically, this FDA safety alert was published 2 weeks after the New England Journal of Medicine published a multicenter observational study of these meds and heart failure (N Engl J Med 2016;374:1145), looking at health care data from Canada, UK, and the US, using a nested case-control design (matching each heart failure case to 20 controls from the same cohort), finding:

  • 1,499,650 patients involved, 29,741 hospitalized for heart failure
    • For those without history of heart failure: HR 0.86 (0.62-1.19)
    • For those with history of heart failure: HR 0.82 (0.67-1.00)
    • ​No difference between those on DPP-4 inhibitors or GLP-1 agonists

So, how does this affect us?

  • As I have mentioned many times in the past, I do not see any big benefit from using these drugs: the A1C benefit is not very large (about 0.3% in several studies, including the above 2 studies as well as the sitigliptin one in the additional blog below), DPP-4 is a pretty ubiquitous enzyme which deactivates lots of different bioactive peptides (i.e., DPP-4 inhibitors are hardly magic bullets), and it is really not so surprising that there may be significant collateral damage.
  • The pretty small absolute increases in hospitalizations for heart failure (0.6-0.7%) is likely the tip of the iceberg. Diabetics get lots of heart disease (the vast majority of diabetics, in the 70-80% range, die from heart disease), most heart failure (I think) is treated as an outpatient and therefore not showing up in statistics for hospitalizations, and the mortality from heart failure may well be higher in patients not enrolled in a study, where study personnel tend to follow patients closely and patients have easy access to them (this may be especially true in areas of the country where there is not ready access to any high quality outpatient care or hospitals.)
  • Since so many diabetic patients develop heart failure just because of their diabetes and other risk factors, I think it is important that the FDA brings this drug association to our attention (i.e., one would not think necessarily that the drug caused the heart failure). Not exactly sure what to do with the recent NEJM article, though it was a retrospective matching of patients from many trials (albeit a pretty big one)
  • So, the DPP-4 inhibitors are not on my list of meds to use, even in patients without known underlying heart or kidney disease….. [Though, I should add, that I do use GLP-1 agonists, which have a much more dramatic effect on A1C levels, are more physiologic than exogenous insulin or sulfonylureas, and are very specifically targeted to meal-related endogenous insulin release (the “incretin” effect). So, though it might surprise you, I am really not against all new drugs…] , which looks at sitigliptin (not one of the ones singled out by the FDA), showing very small effects on A1C levels, showing no increase in cardiovascular outcomes, but does bring up the point that for the minimal-effect on A1c, DPP-4 inhibitors block a ubiquitous enzyme on the surface of most cells and deactivates a variety of bioactive peptides.

Primary Care Corner with Geoffrey Modest MD: Implantable Cardioverter Defibrillators in the Hospitalized Elderly

27 Aug, 15 | by EBM

By Dr. Geoffrey Modest

There was a pretty striking analysis of large numbers of elderly patients inappropriately receiving implantable cardioverter defibrillators (ICDs) during acute hospitalizations (see doi: 10.1136/bmj.h3529​)


  • The US implants more ICDs than any other country: 133,262 implants in 2009: 434 new implants/1M people, 1.5x higher than the second largest implanter
  • The age of implantation is slowly increasing, with average now of 74 yo
  • The major trials finding ICD efficacy were in outpatients with stable heart failure, with a mean age of 60 in the SCD-HeFT and 64 in MADIT II trials (in this latter study, there was no difference if symptomatic NYHA class 2-3 symptomatic or asymptomatic). The 23-31% survival benefit in these studies became apparent after 1-1.5 years.
  • But 1/3 of older Medicare beneficiaries have ICDs implanted during hospital admissions for heart failure or other acute co-morbidities
  • The current indications for AICD use for primary prevention include those at high risk of life-threatening ventricular tach or fib despite optimal med therapy (b-blocker, ACE-I), such as those with symptomatic cardiomyopathy (NYHA class 2-3) and LVEF (left ventricular ejection fraction) <35%, or those 40 days post-MI who are asymptomatic with LVEF <30%
  • Not much data in elderly: a substudy of MADIT-II found that those 121 people randomized to an ICD who were >75yo had only a non-significant mortality benefit.


  • This was a retrospective cohort study of 23,111 Medicare recipients who had a history of heart failure, were hospitalized with an acute condition, and were considered eligible for ICD therapy for primary prevention, e.g. with EF <35%. 5258 received ICD and 17,853 did not. Over 90% had the index admissions for heart failure. Follow-up 2.8 years. 53% died.
  • Mean age 80 in those not getting ICD and 75.5 in those getting one. Other differences: higher likelihood of ICD if male, lower LVEF (25% vs 29%), less psych comorbidites, more diabetes, ischemic heart failure, stroke.


  • Crude survival curves showed improvement in survival in the first few months only, no difference thereafter (see figure at the bottom). Matching patients with an ICD vs not by high dimension propensity scoring revealed no statistically significant benefit from ICDs.
  • Subgroup analysis: no statistical difference in cardiac mortality by history of non-recent MI (though there was a 37% lower total mortality). No diff in group with LBBB or by BNP levels. Those >81 yo did do better (RR 0.78, 0.65-0.93), though only 12% received an ICD

So, a few points:

  • A large number of ICDs are put in during acute hospitalizations, which had not been studied. Hospitalized patients are pretty different from stable outpatients: they may be more likely to die from heart failure itself (and ICDs don’t do much for that) instead of arrhythmia. This finding may be similar to the studies of patients admitted with MIs and getting early ICD placement: there was no benefit as compared to waiting 30-40 days and there were more non-sudden cardiac deaths in those getting early ICDs, those least likely to benefit from an ICD. Hence the recommendation to wait 40 days.
  • The benefit for this Medicare population was entirely within the first few months after ICD implantation (as per graph below). This result differs strikingly from the VA and MADIT-2 studies showing benefit only after 1-1.5 years, suggesting that in the Medicare study above there was a significant selection bias to ICDs in healthier patients (i.e., They did better in the next 4 months because they were healthier and therefore more likely to get an ICD). This also could explain the improved response in those >80 yo, where only 12% got the ICDs.
  • As an aside, other data show that women get ICDs less frequently than men, but there are other studies finding that they have lower risk of sudden cardiac death and are more likely to have complications for ICD implantation.
  • This study brings up a few issues: the most striking to me is the use of ICDs in acutely hospitalized patients, mostly hospitalized for heart failure, with no data to support that approach, and the observational data from this quite large Medicare study now going against it. ICDs clearly subject patients to adverse events and the system to very high costs (as another aside, I did have an 80+ year old patient who had a very large MI and the got an ICD, who for many years thereafter lived in fear of the ICD shocking him and therefore limited his activities significantly). The second big issue is the migration of indications from well-documented (those in their mid-60s) to much older individuals, based only on observational data, and not a lot of that.

implantable cardioverter defbrillators

Primary Care Corner with Geoffrey Modest MD: Implantable defibrillators post-MI

28 Jul, 15 | by EBM

By: Dr. Geoffrey Modest


A lead article in JAMA was a study of Medicare patients who had an MI with a low ejection fraction (EF) to see what % actually had a cardioverter-defibrillator (ICD) implanted and how the patients did (see JAMA. 2015;313(24):2433-2440). This was a retrospective observational study.


–10,381 patients had an MI with EF<35% from 441 US hospitals, between the years of 2007-2010

–mean age 76, 40% female, 10% nonwhite. 65% had NSTEMIs and 75% had in-hospital revascularization


–cumulative ICD implantation rate by 1 year was 8.1%

–ICDs more often done in patients with prior CABG (31% had ICD vs 20% without); those who had cardiogenic shock (13% had one vs 8% not), and in male patients (38% less likely for females to get ICD).

–the 2-year mortality rate was much lower in those who had ICD placement: 15.3 events per 100 patient-years with ICD (128 deaths in 838 patient-years) vs 26.4 events per 100 patient-years without (3033 deaths in 11479 patient-years), with adjusted HR of 0.64 (0.53-0.78)

There are some important results of the study:

–one likely useful lesson is that those patients with profound LV dysfunction post-MI, should usually receive another echocardiogram 40 days later, and if EF is depressed, should be considered for an ICD. The MADIT-2 trial (N Engl J Med 1996;335:1933-40) did find an impressive 35% decrease in all-cause mortality after only 20 months, at the expense of an increased hospitalization for heart failure, in patients with LVEF<30 and at least 30 days post-MI. It is undoubtedly true that waiting the 40 days, when the patient is an outpatient, will lead to fewer ICDs being implanted (as with statins post-MI: if not started in the hospital, they may never be given later). The recommendations for an ICD are those with an EF<35% from an MI and NYHA class 2-3 after 40 days (and optimal medical therapy), or those with EF<30% and NYHA class 1. The basis for the recommendation to wait 40 days after an MI is a few studies.

–one older article (see Ann Intern Med. 2001;134(6):451) tracked echocardiograms after MIs, finding that 22% of patients with low EF totally normalized their EF, and 36% more had partial functional recovery, with 53% having > 5% improvement of EF over their post-MI baseline. And in the JAMA study above, 75% of those with MIs had revascularization – mostly PCI, which is more likely to lead to high levels of myocardial sparing and recovery over the short-term (after the stunned myocardial wakes up to its new reality). One concern in this Annals study is that there was not optimal medical therapy. Not clear that patients received aspirin, statin or b-blocker (this study was actually one testing the efficacy of ramipril post-MI, beginning on day 14 and with varying doses. So, the myocardial recovery rate they found might have been much higher with our current optimal medical therapy. And the rate of arrhythmias lower.)

–a few trials actually looked at immediate placement of ICDs in patients with MIs and reduced EFs (<35% or <40%): neither the DINAMIT trial (NEJM 2004; 351: 2481) nor the IRIS trial (NEJM 2009; 361: 1427)  found any difference in all-cause mortality by implanting ICDs right away

–subgroup analysis in the JAMA study showed that the mortality benefit was the same in patients < and >80 years old, and this suggests pretty strongly that we should still consider ICDs in older patients who were underrepresented in the clinical trials.​

But, I do not really trust this study (which basically promotes more patients receiving very expensive devices, for which there are clinically-important adverse effects), and for a variety of reasons:

–this was a quick-and-dirty study, data-mining a large database, but missing important elements: it was not randomized, so those who received ICDs may be very different from those who did not (eg, were some very sick patients excluded from getting ICDs because they were too sick, then only to die without an ICD?). Also, perhaps most importantly, they did not have any data on the EF 40 days after the patients had their MIs

–although the current JAMA study was sponsored by the Agency for Healthcare Research and Quality (AHRQ), the authors had a litany of drug and medical device company affiliations, including to a maker of ICDs (Boston Scientific). And needless to say, if there were a dramatic increase in ICD use, the magnitude of profit increase to these medical device companies would be mind-boggling to us mere mortals and add significantly to our health care costs.

–one last point. Especially in those areas with very rapid diagnostic and therapeutic advances (eg cardiology, or HIV treatments a few years ago), we often confront the problem that by the time a study is published, common practice has already moved beyond the starting point of the study, and the baseline medical management used in the study is no longer relevant.  In the current case, the ICD guidelines were based on older studies that did not really answer the questions that we want to know, and typically with suboptimal medical management compared to what we do now. The MADIT-2 study was done in 1996 and 75% of medical controls were on amiodarone, only 2/3 on ACE-I, and a minority on b-blockers. No comment on aspirin or statins. This was not even designed as a post-MI low EF study comparing patients with currently-conceived optimal medical therapy vs the same with ICD. Another big study, the SCD-HeFT trial (N Engl J Med 2005;352:225-37) included patients with both ischemic and nonischemic cardiomyopathy, and there was no clear breakdown of the meds the ischemic group was taking (so hard to know if they had optimal med therapy, though I doubt it given the study was published in 2005), and did not include patients who were NYHA 1 class. So, for example, are ICDs superior to medical management if all of the control patients were on b-blockers (which might prevent arrhythmias — though, the SCD-HeFT study showed no efficacy of amiodarone over placebo), plus aspirin (potentially preventing thrombosis and associated arrhythmias), plus ACE-I (potentially decreasing the vascular remodeling and the direct vasotoxic effects of aldosterone), plus a statin (perhaps preventing thromboses as well as improving endothelial function and being antioxidant, and thereby perhaps decreasing arrhythmias)?  So, it is actually hard to know with certainty if, with current aggressive medical management, an ICD would provide significant protection to all  patients with persistent low EF post MI, even after 40 days….

So, this article brings up several important issues. One is the role of drug and medical supply companies as drivers for expensive meds/devices, with major input into articles published in our best medical journals, guideline writing, etc. Another issue is that medical management if forever changing, leading to the pretty frequent problem of a moving target: soon after an article is published, medical management may have changed substantially enough that an intervention might not be useful. With all of this lack of certainty, it seems to me appropriate to repeat the echo after 40 days, and if persistently <35%, still to suggest an ICD to the patient. Also, a real concern in the sometimes hectic practice of primary care is to figure out a mechanism to make sure that important issues, including repeating the echo a month or so post-MI, are not lost in the shuffle, amidst the multitude of other issues we deal with pretty much on a daily basis for all patients we see…

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