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Cardiol- heart failure

Primary Care Corner: Decreasing sudden-death in heart failure

13 Jul, 17 | by

by Dr Geoffrey Modest

A recent meta-analysis found that the risk of sudden death in patients with symptomatic heart failure and reduced ejection fraction (HFrEF) has decreased significantly over the past 20 years (see Shen L. N Engl J Med 2017; 377: 41).
— 12 clinical trials from 1999 through 2014, in which patient-level data were available, included 40,195 patients, but excluded those with implantable cardioverter-defibrillators (ICD)
— Mean age 65, 77% men, 95% with NYHA class II or III heart failure, mean ejection fraction 28% (varied from 23% to 32%), 62% with ischemic heart failure, ACE-I/ARB use was >90%.
— sudden death was determined in 3583 patients
–Those with sudden death were more often older (low 60s vs mid 60s​), male (low 80% vs mid 70%), had an ischemic cause of heart failure (70% vs 60%), and had worse cardiac function(LVEF 26% vs 29%). There was also minimally lower systolic blood pressure, minimally higher heart rate, minimally worse heart failure symptoms, minimal difference in renal dysfunction, but there was a somewhat more prominent history of myocardial infarction and diabetes in those with sudden death.​ [These were my rough calculations from the supplementary material, no formal calculations done by them]. Also NT-proBNP was higher in those with sudden death, though this was not checked in many of the studies.
— over time, there was a 44% decline in the rate of sudden death across the trials over the 19 years
— the cumulative incidence of sudden death at 90 days after randomization was 2.4% in the earliest trial, and 1.0% in the most recent trial. At 180 days the cumulative incidence of sudden death was approximately double that at 90 days, with these same trend of decrease in the more recent trials.
–My review of the individual trials showed a relatively consistent pattern: those with the same heart failure medications in both the control and experimental groups (as in a trial looking at the role of statins or another medication added on) did not show much difference between these groups in terms of sudden death outcomes. However those in which an additional heart failure medicine, either a beta-blocker or a mineralocorticoid antagonist, was added, there generally was a more impressive benefit: ie, maximizing the standard heart failure regimens seems to be beneficial. Only one study used sacubitril/valsartan, finding some added benefit on top of otherwise maximal therapy
— sudden cardiac death was not higher among patients with a recent diagnosis of heart failure than those with longer standing heart failure
–This study basically reinforces that maximal therapy for HFrEF patients significantly decreases the risk of sudden death, and to levels where automatically implanting an ICD may not be indicated, particularly in the primary prevention of sudden death. It would be important to determine if there is a subset of those patients who might benefit. One leading contender has been ischemic vs nonischemic cardiomyopathy, where the myocardial scar in those with ischemic cardiomyopathy might be the nidus for ventricular arrhythmias (and, indeed, this study confirmed about a 10% increased risk vs non-ischemic cardiomyopathy).
— Another issue is how long to wait to see the degree of myocardial recovery after the presenting symptoms of heart failure or myocardial infarction. There are studies confirming that multiple drugs and maximal doses lead to more reversal of ventricular remodeling and that the LVEF may still improve over 6 to 12 months after starting treatment (which is significantly longer than the 40 days post myocardial infarction highlighted in the ICD guidelines, suggesting that this time interval may still be too short).
–Current recommendations for ICDs include patients with NYHA class II or III symptoms and LVEF< 35%, independent of cause. However, the recent DANISH trial of patients with nonischemic systolic heart failure showed that adding ICD to maximal medical therapy  led to no difference in total mortality, though there was a reduction in sudden death in those with ICDs (4.3% vs 8.2%). It was notable in the above meta-analysis that only 9% of the patients (3180 in total) had had an ICD implanted and were excluded from this study. Given the low LVEF (median 28%) in these symptomatic patients, so that the majority actually met guideline criteria for an ICD, this 9% number suggests that we clinicians have not been pursuing ICDs very vigorously, even though these patients in the meta-analysis were more likely to have been in cardiovascular centers in big academic medical sites, replete with academic cardiologists….
— This study reinforces that we clinicians are doing quite well in preventing sudden cardiac death by putting patients on maximal heart failure medications.  These meds really work
— As with all interventions, in this case ICD placement, there are real risks for the intervention (in this case: infections, ICD failure, documented decreases in quality of life, and in my experience significant PTSD from patients having been shocked either appropriately are not). Therefore, the more targeted we are at selecting patients for this intervention, the better. Further investigation is warranted to determine those subgroups of patients who really benefit from ICD placement (and those who really do not benefit much and ICDs should be a non-issue).
see blog   for a recent review of  the medications for heart failure (including HFpEF), and another which reviewed Medicare patients showing that only 8.1% who qualified for ICDs got them

Primary |Care Corner with Geoffrey Modest MD: Spironolactone helps heart failure with preserved EF

5 Jun, 17 | by

by Dr Geoffrey Modest

One concern about patients having heart failure with preserved ejection fraction (HFpEF) is the dearth of effective treatments for long-term outcomes in this quite common problem. One of the most influential studies was the TOPCAT study, which found a nonsignificant benefit for spironolactone. A subsequent post hoc analysis (see below), however, found a significant outcome benefit ​ from spironolactone in those patients enrolled from the United States, Canada, Brazil, and Argentina (the Americas) but not in those from Russia and Georgia.

Details, in brief, of TOPCAT:

— 3445 participants with symptomatic HFpEF (EF>45%) were randomized to spironolactone vs placebo, mean dose 28mg/d, followed 3.3 years, around 80% also on a diuretic, ACE-I/ARB, and/or b-blocker, finding no difference in the primary outcome of the combination of cardiovascular death, aborted cardiac arrest, or hospitalization for heart failure. But the rate of hospitalization, as an isolated outcome, was improved a bit (12% vs 14%)


But in 2015 there was an article looking more directly at the regional variations in outcomes of the study, spurred on by the fact that the event rate in the placebo group in Russia/Georgia was so much lower than in the Americas (see Pfeffer MA. Circulation. 2015;131:34), finding:

— there was an unusually large, greater than fourfold, increase in primary outcomes in the patients in the Americas vs those in Russia/ Georgia, being 11.5 per 100 patient-years in the Americas vs 2.4 per 100 patient-years in Russia/Georgia.
— further breakdown showed that even in the placebo group, the respective numbers were 12.6 per 100 patient-years in the Americas and 2.5 per 100 patient-years in Russia/Georgia; and in the spironolactone group were 10.4 versus 2.3 per 100 patient-years– in the Americas, the primary composite event rate was actually a significant 18% lower in those on spironolactone, HR 0.82 (0.69-0.98); though in Russia/Georgia was nonsignificantly higher at HR 1.10 (0.79-1.51)

— review of all of the different cardiovascular outcomes assessed found a highly significant difference in the spironolactone groups in comparing the regional differences of these 2 areas, with almost all having p<0.001. Of note, there was also a much more significant increase in creatinine above 3.0 mg/dL, and lack of hypokalemia with potassium <3.5 mmol/L , in the Americas only (suggesting they were taking more spironolactone there)​

–My understanding is that these regional inconsistencies in the TOPCAT study, with the significant benefit in the Americas wing and suspicions about the accuracy of the Russia/Georgia group, led to the recent AHA guidelines endorsing the use of spironolactone in HRpEF (a Grade IIb recommendation, moderate level of evidence)​


And, a new analysis just came out assessing the serum canrenone levels (metabolite of spironolactone) in the stored serum specimens (see de Denus, S. N Engl J Med 2017; 376: 1690):

–206 patients from the US and Canada, and 160 patients from Russia had serum samples to assay; these people were representative of the overall TOPCAT populations from the different regions.

–of the patients assigned to spironolactone who reported taking the drug at the 12-month visit (76 of 101 patients from the US/Canada; 66 of 70 patients from Russia):

–canrenone concentrations were undetectable in 30% of the Russian group and 3% of the US/Canada (p<0.001)

–a significant correlation was found in the US/Canada between doses of spironolactone that people said they were taking and the canrenone concentration; no correlation for the Russian group

​–only those who had canrenone detected from both areas had significant increases in serum potassium and aldosterone levels (as anticipated)


So, all of this shows a few things:

–it is undoubtedly quite difficult to have equal quality control at different sites of care, and this is no doubt aggravated in different countries/cultures. Which means that we, as readers of these studies, should maintain a healthy skepticism regarding the results, especially when they are so discordant from the different sites, as in this study

–spironolactone seems to actually modify disease progression/associated cardiovascular effects, which is really important since not much else seems to help. The TOPCAT study tried to deal with the often difficult problem of making sure the patients’ symptoms were actually from the HFpEF (as opposed to being from the comorbidities, which it can be hard to differentiate from those related to those from HFpEF itself), by enrolling patients who had a recent hospitalization predominantly for heart failure or those with high natriuretic peptide levels (and those specifically who had high natriuretic peptide levels on subgroup analysis did show benefit from spironolactone). And diuretics overall help the heart failure symptoms, as well as treating underlying associated conditions (hypertension, atrial fib, myocardial ischemia, hyperlipidemia)

–my experience is also that spironolactone is a good augmenter of loop diuretics (I am treating a 93 yo patient with pretty severe symptomatic HFpEF, on torsemide 50mg but still symptomatic and with BNP of 639; I switched his diuretic therapy to torsemide 30mg and spironolactone 25 mg with quite dramatic clinical improvement and rapid decrease in BNP to 461, with further therapy limited by low blood pressure).

these studies therefore pretty much confirm that low-dose spironolactone is an important med in patients with symptomatic HFpEF, both in terms of symptomatic improvement (decreasing hospitalizations) and decreasing cardiovascular mortality, confirming guideline recommendations. And, it raises even further my respect for spironolactone — also seems to be a really potent agent in those with refractory hypertension


Primary Care Corner with Geoffrey Modest MD: New heart failure guidelines

3 May, 17 | by

These guidelines update the 2013 guideline for the management of heart failure, focusing on biomarkers, new therapies for both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved injection fraction (HFpEF), as well as new information on managing comorbidities including anemia, hypertension, and sleep apnea; and some new insights into the prevention of heart failure (see DOI: 10.1161/CIR.0000000000000509). This guideline is a 2nd part to the 2016 guideline on new therapies, which included recommendations for the angiotensin receptor-neprilysin inhibitor valsartan/sacubitril (an ARNI) and the sinoatrial node modulator ivabradine. Seven of 17 on the AHA committee members had ties to drug companies, though neither the chair nor vice chair did. My comments are embedded in the text


— B-type natriuretic peptide (BNP) and N-terminal pro-B type natriuretic peptide (NT-proBNP) track similarly for both the presence and severity of heart failure, and either can be used, though not interchangeably

— it is important to note that BNP, but not NT-proBNP, is a substrate for neprilysin, and therefore the ARNI  increases BNP levels. So, in studies using the ARNI, the NT-proBNP levels were reduced, associated with improved clinical outcomes [ie, it makes sense to use the NT-proBNP if starting the ARNI]

— several studies have found that these biomarkers assist in the diagnosis or exclusion of heart failure as a cause of symptoms such as dyspnea or weight gain in the setting of chronic ambulatory heart failure, or in the setting of acute heart failure decompensation.

— This still are no clear, consistent data showing that these biomarkers improve mortality or cardiovascular outcomes, so there is no specific recommendation regarding biomarker-guided therapy or the utility of serial measurements of these biomarkers in reducing hospitalization or deaths

— other biomarkers include troponins I and T, which may be elevated in chronic or acute decompensated heart failure, and do have prognostic significance in the setting acute heart failure

— and there are a slew of newer biomarkers (e.g., some reflecting inflammation, oxidative stress, vascular dysfunction, myocardial and matrix remodeling, myocardial fibrosis), which have in some studies predictive value for hospitalizations and deaths, and may have incremental prognostic value over the currently accepted biomarkers, but there need to be more studies on them

— the STOP-HF study, an unblinded single center study evaluating patients who are at risk for heart failure because of hypertension, diabetes, or nonvascular disease but without systolic dysfunction or symptomatic heart failure at baseline, patients were randomized to screening BNP testing versus usual care, finding that those with BNP levels > 50, who then had echocardiograms and team-based therapy including a cardiovascular specialist, had reduced composite endpoint of asymptomatic left ventricular dysfunction with or without newly diagnosed heart failure.


— for patients at risk for developing heart failure, natriuretic peptide screening followed by team-based care can be useful in preventing heart failure. strength of recommendation IIa, moderate quality evidence

— for patients hospitalized with heart failure, a predischarge natriuretic peptide can be useful to establish a postdischarge prognosis, based on observational studies showing that those who did not have a significant decrease in these levels during hospitalization had worse outcomes. [This could key clinicians to more aggressive post-discharge management, though no specific biomarker thresholds for changes have been tested prospectively ,and they do not mention studies documenting the effectiveness of this approach]. Grade IIa recommendation, moderate quality evidence

— measurement of other biomarkers (e.g. soluble ST2 receptor, galectin-3, high-sensitivity troponin) may be considered for additional risk stratification. Grade IIb, moderate strength of evidence

HFrEF (for Stage C, symptomatic failure):

— overall clinical strategy is to use an ACE inhibitor or ARB or ARNI, along with beta blocker and aldosterone antagonist in selected patients, to reduce morbidity and mortality. Grade I recommendation, high quality evidence

— both ACE inhibitors and ARBs are recommended in patients with prior or current symptoms of chronic heart failure to reduce morbidity and mortality, with ARBs being recommended in patients who are ACE inhibitor intolerant because of cough or angioedema. Grade I recommendation, high quality evidence [I remain concerned about using ARBs in patients with angioedema, since I have seen 2 patients admitted to the ICU with angioedema in this situation, and there are many more in the literature, though I realize that small studies have found this not to be a problem, and there is no clear mechanistic reason why it should happen, other than those with ACE inhibitor-induced angioedema may be more generally allergic to other medications]

— ARNI is recommended in patients with chronic symptomatic HFrEF who tolerate ACE inhibitors or ARB, to further reduce morbidity and mortality, based on a study comparing ARNI versus enalapril showing improved clinical outcomes with the ARNI. Grade I recommendation, high quality evidence

— but, ARNI should not be used in conjunction with either ACE inhibitors or ARBs, and is associated with higher incidence of angioedema (and studies have shown that the combination of it with an ACE inhibitor is associated with unacceptable levels of angioedema and significant morbidity). As a result of this high incidence of angioedema with this combination, subsequent studies have excluded patients with a history of angioedema, so the recommendation is not to use the ARNI in patients with any history of angioedema, just to be safe. Black patients and smokers seem to be particularly at risk. The recommendation is that initiating ANRI should be at least 36 hours after terminating ACE inhibitors. [ARNI  seems to be a good drug clinically, but I am concerned about the fact that inhibition of the neprilysin enzyme, which has multiple biological targets, creates the potential for more downstream adverse effects detected over time]

— although not in a formal recommendation, in the flowchart they do promote the hydralazine-nitrate combination in black patients, and they do support ICD usage in patients with NYHA class II to IV heart failure and LVEF <35%; and cardiac resynchronization therapy in these same patients as with ICD but have a QRS interval greater than 150 ms and left bundle branch pattern

–Ivabradine, a selective inhibitor of the If current in the sinoatrial node, is useful for heart rate reduction, and has been found to be beneficial in reducing heart failure hospitalizations for patients with symptomatic stable chronic HFrEF on otherwise maximal management including a beta blocker at maximum tolerated dose, are in sinus rhythm, and have a heart rate>70 at rest. This is based on an RCT of patients with NYHA class II to IV HFrEF (though class IV HFrEF was not well represented), LVEF <35% and in sinus rhythm (though some had paroxysmal atrial fibrillation). However, as they note, only 25% of patients in the study were on optimal doses of beta blocker therapy, so they recommend starting ivabradine only in patients on maximal doses of beta blockers). grade IIa recommendation, with only moderate quality evidence

— there is a useful table of the maximal doses of drugs as well as the mean doses achieved in the clinical trials, with the following sampling:

— enalapril, maximum dose 10 to 20 mg BID, mean dose in trials 16.6 mg a day

— lisinopril, maximum dose 20 to 40 mg daily, mean dose and trials 35 mg per day

— losartan, maximum dose 50 to 150 mg a day, mean dose and trials 129 mg a day

— valsartan maximum dose 160 BID, mean dose and trials 254 mg a day

— carvedilol, maximum dose 50 mg b.i.d., mean dose in trials 37 mg a day

— metoprolol extended release, maximum dose 200 mg a day, mean dose in trials 159 mg day

— isosorbide/hydralazine, maximum dose 40 mg isosorbide dinitrate with 100 mg hydralazine TID, mean dose achieved not available

— spironolactone, maximum dose 25 mg daily or BID, mean dose in trials 26 mg a day

— eplerenone, maximum dose 50 mg a day, mean dose in trials 42.6 mg a day


— systolic and diastolic blood pressures should be controlled in accordance with current clinical guidelines, to prevent morbidity. Grade I recommendation, strength of evidence moderate

— diuretics should be used to relieve symptoms due to volume overload in patients with symptomatic HFpEF. Grade I, a low level of evidence

— coronary revascularization is reasonable in patients with symptomatic CAD that is felt likely to have an adverse effect on their HFpEF. Grade IIa, low level of evidence

— management of atrial fibrillation according to guidelines is reasonable to improve symptomatic heart failure. Grade IIa, low level of evidence

— use of beta blockers, ACE inhibitors, and and ARBs in patients with hypertension is reasonable to control blood pressure. Grade IIa, low level of evidence [a study found that ARBs might decrease hospitalizations for HFpEF patients], Grade IIb, moderate level of evidence

— it is reasonable in patients with symptomatic HFpEF to use aldosterone receptor antagonists to decrease hospitalizations in patients who have ejection fraction >45%, elevated elevated BNP levels or heart failure admission within one year, estimated GFR >30, creatinine 2.5 mg/dL, and potassium <5 mEq/l (see here ). Grade IIb, moderate level of evidence

— use of nitrates, phosphodiesterase-5 inhibitors, and nutritional supplements are not recommended, felt to have no benefit


–in those with NYHA class II or III heart failure and iron deficiency (ferritin <100ng/ml, or 100-200 if transferrin saturation <20%), intravenous iron therapy may improve functional status, based on 3 studies. In general patients did not have severe anemia (eg FAIR-HF trial, NEJM 2009; 361: 2436) had mean hemoglobin of 11.9 g/dL, MVC 92, ferritin 52, transferrin sat 18%), finding improved symptoms, functional capacity and quality of life (and, on further analysis, this was independent of having anemia).  Grade IIb, moderate level of evidence. No data on oral iron supplementation. And no benefit from erythropoietin-stimulating agents. so only intravenous iron recommended at this point.



–optimal blood pressure in those at increased risk of heart failure is <130/70, from the SPRINT trial of patients >75yo, established vascular disease or CKD, or Framingham Risk Score >15%, showing decrease in new onset heart failure, though they note that this goal is an approximation because office BP is typically about 5-10 mmHg higher than in this trial (see here, for issues about the unusual methodology of the SPRINT trial which limit its direct generalizability, and here for review/critique of the SPRINT trial subset in elderly). Grade I, moderate level of evidence.

— goal of systolic <130 in those with HFrEF, Grade I, expert opinion. Not tested in RCTs

— goal of systolic <130 in those with HFpEF. Avoid nitrates. Preferred choice ACE inhibitors, ARBs, and possibly ARNI, Grade I, expert opinion. Limited data to support


Sleep-disordered breathing

–perform sleep assessment in those with NYHA class II-IV heart failure and suspicion of sleep-disordered breathing or excessive daytime sleepiness, Grade IIa, not much data, but a study of patients with chronic heart failure found 61% had either central or obstructive sleep apnea, but treatments are different and one needs to know which one the patient has.

–in patients with cardiovascular disease and OSA, CPAP may be reasonable to improve sleep quality and daytime sleepiness, Grade IIb, moderate quality evidence.

— in patients with central sleep apnea and class II-IV HFrEF, using servo-ventilation treatment causes harm!! (higher mortality)

–[this recommendation befuddles me a bit: it is true that people with symptomatic OSA who use CPAP have better sleep quality and function better. But that is true if they have heart disease or not. And the study they quote (ORBIT-AF) just showed that those with atrial fib plus OSA and put on CPAP had less progression to more permanent atrial fib. Not sure that means much clinically, and this was not a study in heart failure patients. I assume that this section was added to highlight that sleep studies are indicated when people are not sleeping well (though this happens with heart failure a lot), and that we NOT go the servo-ventilation route if it is central sleep apnea, but that CPAP is okay for OSA. Which I guess is a reasonable point, but bringing in the atrial fib study in those not in heart failure seems a bit off-track.]


— although HFpEF seems to have pretty much the same prevalence as well as morbidity/mortality as HFrEF, it is quite striking how poorly equipped we are to provide great therapy. Personally I have had pretty good success with adding on spironolactone in patients with severe, resistant disease to help with symptoms and decrease multiple admissions.

— As noted in prior blogs, treating patients effectively with HPrEF has been one of the major advances in therapeutics over the last several decades. In my experience these patients do exceptionally well overall, can be treated effectively in the primary care setting, and do very well over the long-term and into very old age. I recently had a patient to had a severe MI at age 72, was resuscitated, maintained a left ventricular ejection fraction which never exceeded 10%, was basically asymptomatic with optimal heart failure therapy, and ultimately died over 20 years later..

— these guidelines do add some important new recommendations, especially: further promoting the use of natriuretic peptide​ biomarkers and integrating them more into care, considering using them to identify and manage patients at high risk of heart failure, and there seems to be value in checking iron levels in those with HFrEF​ even without anemia [I will integrate that into my approach to care, though will deviate to using oral supplementation if iron deficient]. And, as mentioned, I think these guidelines help us manage heart failure patients in a primary care setting, which I have found to be incredibly successful and satisfying for me (and I think for my patients)….

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

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