Prescribing Pitfalls in Heart Failure With Multiple Comorbidities

October 09, 2017

GRAPEVINE, TX — "Over-the-counter medications are too weak to cause any harm, so they're all safe. Right?"

That common misconception highlights a major challenge in patients with heart failure, Dr Sheryl Chow (Western University of Health Sciences, Pomona, CA) observed: they can have major comorbidities and perhaps see a multitude of specialists, each armed with a prescription pad and recommendations for nonprescription meds.

As a result, patients often "get competing or directly conflicting advice from multiple prescribers" and may find themselves on an assortment of over-the-counter (OTC) and prescription drugs that may or may not sit well together, Dr Zachary L Cox (Vanderbilt University Medical Center, Nashville, TN) said in an interview with | Medscape Cardiology.

Cox, Chow, and other experts here at a special session during the Heart Failure Society of America (HFSA) 2017 Scientific Meeting outlined drug-drug interactions, strategies for avoiding them, and related challenges clinicians face when managing their heart-failure patients with chronic conditions like arthritis, diabetes, or clinical depression or who are quietly self-medicating with OTC drugs, supplements, or alternative therapies.

The issues underscore the importance of a multidisciplinary care strategy for these patients, Dr William L Baker (University of Connecticut, Mansfield), who moderated the session, and other speakers concluded.

Treating their comorbidities can be just as important to outcomes as treating their heart failure, Baker said in an interview. "There are going to be drug-drug interactions; we need to acknowledge that," he noted. One of the ways to minimize their impact is to "embrace the team approach."

"It's difficult enough to get them to take what they should, let alone getting them to avoid taking what they shouldn't, and having that multidisciplinary approach can really help."

The help can come from the patient, too, he added. Education and advocacy efforts can encourage "patients to be their own advocate—or their families, or their surrogates—to understand what their disease is, to really feel ownership of it, and ownership of their medicines so that they know exactly what they should and shouldn't take."

Ibuprofen, Naproxen, Diclofenac, and That Lot

Dr Zachary Cox

Motivation to treat painful chronic conditions is high, and nonsteroidal anti-inflammatory agents (NSAIDs) are used by 83% of the population, Cox said. Fully one-third believe NSAIDs are safe to combine with prescription agents.

"We often do a good job of telling our patients not to take NSAIDs, but we don't leave them with any better choices," Cox said in an interview. The conversation with patients should be "not just about avoidance, but providing safe options to treat the pain." They will choose either to be in pain or not, he said, "and people usually choose not to be in pain."

Perhaps most important for HF patients with ischemic heart disease, it's well recognized that NSAIDs interfere with the antiplatelet effects of aspirin. Most NSAIDs bind reversibly to platelet cyclooxygenase 1, whereas aspirin binds to the enzyme for the 5- to 7-day life of the platelet, Cox observed.

The implications: ibuprofen, in particular, attenuates aspirin's antiplatelet potency when ingested before aspirin, but less so when it's given afterward[1].

Whether the same is true for other nonaspirin NSAIDs isn't known, but it's recommended that ibuprofen be taken either 30 minutes following or 8 hours before aspirin, Cox said. If ibuprofen is taken around the clock, however, it interferes with aspirin regardless of the order in which they are taken.

Moreover, Cox said, nonaspirin NSAIDs given chronically raise blood pressure and attenuate the effects of antihypertensive agents. And, "in patients at risk for heart failure, NSAIDs have been shown to increase new-onset heart failure. In patients with heart failure, there's better and more consistent evidence [they] are linked to worsening heart failure."

Also in HF patients, he said, NSAIDs appear to significantly raise all-cause mortality, dose-dependently, by a hazard ratio (HR) of 1.9 (95% CI 1.0–2.8) for ibuprofen and 9.0 (7.4–10.6) for diclofenac, and risk of hospitalization from any cause, by HRs of 1.5 (1.2–1.9) and 1.6 (1.2–2.3), respectively[2,3].

Alternatives to NSAIDs include acetaminophen, "which is safe and doesn't have these effects, we think, and there's some evidence that topical NSAIDs are equally efficacious and may not have the same risks," Cox said.

Still, the effects of topical NSAIDs are mostly unknown in heart failure, he said, "and we should not just automatically extrapolate [that their] lower systemic levels may not automatically cause lower cardiovascular events."

As for other agents, "I hesitate to ever say narcotics, but non-NSAID pain-control medication might be necessary in extreme circumstances, for short courses, in chronic heart failure."

Dietary Supplements and Herbal Medicines

There are about 55,000 "unique dietary supplements" in the US, Cox said. Up to half of US adults use them when they are also taking prescription meds, and the likelihood is 2.5 times greater in association with cardiovascular prescriptions than with scrips for other diseases.

"If this seems out of proportion to what you see in your practice, it could be because about half of dietary-supplement users don't report to their providers that they actually use them," he said.

"Most of the time it's innocent, in that they don't think it's important information to share," Cox commented. According to surveys, the top three reasons for not mentioning use of dietary supplements are, "I anticipated they weren't going to like it," "I thought it was irrelevant to my medical care," and "Nobody asked me about it."

Clinicians typically phrase the screening query in terms of prescriptions, he noted. For example, "What prescriptions do you take? Did you bring your prescription bottles with you?" So whether they are taking supplements, herbals, or other OTC meds "doesn't register with them," he said. "That we don't intentionally ask, and they don't think about it, is a big part of the problem."

Dr Sheryl Chow

Chow said one-third of patients with heart failure in the US report using herbals, or "complementary alternative medicines," but finding out whether a patient is one of them can be problematic.

"You have to be nonjudgmental," she told | Medscape Cardiology. "They can be very adamant about taking their herbals, so they'll continue without telling you. And you don't want that to happen." If the patient does disclose taking herbal medicines, "at that point you can only guide them."

Even without mixing dietary supplements and heart-failure meds, supplements account for account 23,000 emergency-department visits annually in the US, most commonly for cardiovascular symptoms, according to Cox. Excluding the one-fifth of those due to accidental ingestion in kids, he said, 25% are related to weight-loss products and 10% to "energy products."

Many have hidden ingredients, as well. From 2004 to 2002, he said, the Food and Drug Administration issued 237 class 1 recalls of dietary supplements due to undeclared ingredients, sometimes anabolic steroids or sildenafil.

Interest in the popular supplement coenzyme-Q10 (CoQ10) in heart failure stems in part from its biochemical role in mitochondria, antioxidant effects, and cell-membrane integrity, plus the observation that its levels are reduced in HF patients[4], Chow said.

Clinical trials of CoQ10 in heart failure include a 1993 study with 641 patients in NYHA class 3–4 on medical therapy that was standard for the time[5]. The supplement was associated with significantly reduced risk of HF hospitalization (P<0.001).

Much more recently, the Q-SYMBIO trial randomized 420 patients with NYHA class 3–4 heart failure to receive the supplement or placebo for 2 years on top of standard care, which included ACE inhibitors in 90% and beta-blockers in 72%[6].

Risk of the primary end point (worsening HF, CV death, implantation of a mechanical assist device, or urgent heart transplantation) declined by about half on the supplement (HR 0.50, 95% CI 0.32–0.80; P=0.003). The mortality risk alone went down 42%.

"But there were some major issues with the trial," other than its unconventional mixed primary end point, Chow said. Its enrollment fell short of the 550-patient target, and, in any case, enrollment would have to have been in the thousands for sufficient statistical power. Absolute numbers of clinical events were low, and no baseline CoQ10 levels were recorded.

Adverse events occurred at similar rates in the CoQ10 and control groups, but in practice, according to Chow, the supplement can reduce blood pressure and attenuate the effects of warfarin, "so you're going to have to check INRs more frequently."

Hawthorn, the ground-up leaves, berries, and flowers of various Crataegus species and one of the world's most widely used herbal medicines, has a number of effects relevant to patients with heart failure, Chow noted.

It contains a number of cardioactive glycosides and as a result has effects similar to those of digoxin. Hawthorn also has vasoactive properties due to high concentrations of oligomeric procyanidins, as is true with tea, cocoa, and red wine. It therefore can potentiate the effects of digoxin but also reduce blood pressure, she said.

But the SPICE trial, in which researchers randomized more than 2600 patients with reduced-EF heart failure (HFrEF) to receive a commercial hawthorn extract (WS-1442, Schwabe Pharmaceuticals, Karlsruhe, Germany) on top of standard meds, failed to show a significant effect for a primary end point consisting of sudden death, fatal or nonfatal MI, or death or hospitalization due to progressive heart failure at 24 months[7].

There were hints of benefit for all-cause mortality and in sudden death at several intermediate intervals, "but this was a secondary analysis, and I wouldn't put very much weight on that," Chow said.

"Of course, you're going to have patients who may be taking it, whether they disclose it or not." The message to them, she said, should be that hawthorn isn't guidelines-recommended and won't benefit them.

Antidepressants: Mixed Results and Drug Interactions

Clinical depression is up to 70% more likely in patients with heart failure than the general population, and among patients with heart failure is associated with a threefold higher risk of hospitalization and two- to threefold increase in mortality, according to Dr Michael Moranville (Hospital of the University of Pennsylvania, Philadelphia).

Outcomes associated with depression may be worse for various reasons, direct and indirect, including increased fatigue and poorer self-care, both of which are associated with reduced treatment compliance; weight gain; associated upregulation of the hypothalamic-pituitary-adrenal axis, which can elevate aldosterone levels; and autonomic imbalance, associated with reduced heart-rate variability "and potentially more arrhythmias," he said.

As for treatment of depression in heart failure, "unfortunately there aren't a lot of great trials to point us in the right direction," Moranville said. But there are plenty of drugs approved for treating depression overall.

The guidelines in psychiatry "actually find most antidepressants to be equally effective, and they don't recommend any one over another. They recommend choosing the medication based on side effects, drug interactions, and trial and error."

If adverse drug-drug interactions develop, "it's not reason to stop the medication but certainly respond to it," Moranville said. "Consider what remission of depression symptoms means to your heart-failure patients," he suggested. "No matter how we achieve that, there are good data showing that reduction of those symptoms can improve heart-failure outcomes."

The data on medical interventions in depression and heart failure "are sparse, and results are mixed," Moranville added. Some trials associate antidepressant therapy with improved depression scores and LVEF; others suggest they may worsen outcomes in heart failure.

"These studies were probably confounded by the fact that the antidepressant groups were composed primarily of patients with very advanced heart failure, which explains their high mortality."

Two standout antidepressant trials in patients with clinical depression and NYHA class 2–4 reduced-EF heart failure, the 12-week SADHART-CHF trial with an enrollment of 469, and the 2-year MOOD-HF with 372 patients, didn't show harm from treatment with selective serotonin reuptake inhibitors (SSRIs). But also, Moranville said, "at the end of the day, there was no difference in anything in these studies. Depression scores were no different; hospitalization, mortality, again no difference."

The reason, he said, may be that patients in both groups had more clinician contacts than likely happens in practice, and "all patients in these studies benefited from close follow-up by nursing providers with specialized psychiatric training."

From MOOD-HF, said Moranville, "What I think you can take away is the subgroup analysis looking at patients who responded in a positive way and achieved remission of their depression, who did show improvement in cardiovascular outcomes."

Orthostatic hypotension is a side effect of a number of drugs for depression, including tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs), and serotonin antagonist and reuptake inhibitors. Tricyclics and SSRIs can also lead to QT-interval prolongation, he observed.

The risk of bleeding is also increased by SSRIs, apparently from serotonin-mediated suppression of platelet aggregation, and especially when taken with antiplatelet agents. But the data have been mixed "about how severe a side effect it may actually be," Moranville said.

Antidiabetic Agents and HF: Cautions and "Good News"

Until recently, cardiologists in general might have seen diabetes drugs as "potentially more harmful than good, causing side effects that actually mimic the symptoms of heart failure, or as a result of their adverse effects, increase the risk of heart failure, " according to Dr Jacob A Udell (Toronto General Hospital and University of Toronto, ON).


Dr Jacob Udell

A number of antidiabetic meds tend to increase BMI, which is associated with HF risk, said Udell. His own research points to a 6% increase in risk of new HF per kilogram increase in weight over 1 year (P=0.005) on antidiabetic meds across randomized controlled trials[8]. The meta-analysis findings were "hypothesis-generating, but pretty intriguing."

Such agents that tend to raise weight include insulin, sulfonureas, and thiazolidinediones (TZDs) like pioglitazone (Actos, Takeda Pharmaceuticals), which he recommends be avoided in patients with heart failure. Dipeptidyl peptidase-4 (DPP-4) inhibitors such as saxagliptin (Onglyza, Bristol-Myers Squibb/AstraZeneca) and alogliptin (Nesina, Takeda Pharmaceuticals), should probably be avoided or at least used cautiously.

As for metformin, one of the oldest of contemporary agents for type 2 diabetes, "turns out it's okay!" Udell says, and is considered a first-line antidiabetic agent in patients with heart failure.

And for some of the newest antidiabetic medications, "there's some good news," he said. Some "actually have the effect of lowering the risk of heart failure," sometimes indirectly allowing the clinician to pull back on some medications often used in heart failure.

Two classes of antidiabetic agents recently made a splash by showing cardiovascular protective effects. They are the sodium–glucose cotransporter 2 (SGLT2) inhibitors like canagliflozin (Invokana, Janssen), dapagliflozin (Farxiga/Forxiga, AstraZeneca) and empagliflozin (Jardiance, Boehringer Ingelheim); and glucagonlike peptide-1 (GLP-1) agonists including liraglutide (Victoza, Novo Nordisk), semaglutide (Novo Nordisk), and lixisenatide (Lyxumia, Sanofi).

Natriuresis is a likely mechanism behind some of the cardiovascular effects of SGLT2 inhibitors. They've been associated with plasma volume reductions of about 7%, reduced blood pressure, and a 30% to 40% decline in albuminuria, Udell notes.

Indeed, he said, the drugs seem to work somewhat in synergy with diuretics. "If you see good hemodynamic changes" once SGLT2 inhibitors are initiated in HF patients on diuretics, it may be possible to pull back on diuretic dosages.

Thiazide doses should be maintained unless blood-pressure changes suggest a reduction may be appropriate. For patients on loop diuretics, "consider reducing doses by 50%" while monitoring blood pressure and weight. If blood pressure declines, stop them; and in patients who become hypotensive, hold or reduce loop diuretics but resume them as needed, he said.

Whether the recently recognized cardiovascular benefits of some antidiabetic agents mean they might benefit nondiabetic patients with heart disease or work as secondary-prevention agents in patients with established heart failure remain open questions, Udell observed.

Two small studies, the FIGHT trial in 300 patients with HFrEF, 60% of whom had diabetes, and the 241-patient LIVE study in HFrEF, with only 31% of patients with diabetes, suggested no benefit and maybe some harm from treatment with liraglutide.

Several ongoing studies using SGLT2 inhibitors are looking at the issue, Udell pointed out.

Two randomized outcomes trials, one in HFrEF (EMPEROR-Reduced) and the other in preserved-EF heart failure (EMPEROR-Preserved), are comparing empagliflozin with placebo on top of standard care, with estimated enrollments of 2850 and 4124, respectively. And another in HFrEF (DAPA-HF) is comparing dapagliflozin with placebo on top of standard care in a projected 4500 patients.

Baker, Chow, Cox, and Moranville had no relevant financial relationships. Udell discloses receiving research grants from AstraZeneca and Novartis, honoraria for speaking from Janssen, and serving as a consultant for Amgen, Boehringer-Ingelheim, AstraZeneca, Janssen, Merck, Novartis, and Sanofi-Pasteur.

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