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Heart Failure Worsening and Exacerbation After Venlafaxine and Duloxetine Therapy

Associate Professor of Pharmacy Practice, Skaggs School of Pharmacy, College of Health Professions and Biomedical Sciences, The University of Montana, Missoula, MT

Bradley D Berry, MD FACC

International Heart Institute, St. Patrick Hospital and Health Sciences

Reprints: Dr. Colucci, The University of Montana College of Health Professionals and Biomedical Sciences, Skaggs School of Pharmacy, Department of Pharmacy Practice, 32 Campus Dr., Skaggs Bldg., Missoula, MT 59812, fax 406/243-4353, Vincent.colucci{at}umontana.edu

	Abstract

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OBJECTIVE: To report 2 cases of worsened heart failure (HF) after the introduction of venlafaxine or duloxetine therapy in patients with previously stable disease.

CASE SUMMARIES: Two patients, a 39-year-old female and a 68-year-old male, both diagnosed with HF of left ventricular systolic dysfunction, had worsening symptoms in the presence of the serotonin and norepinephrine reuptake inhibitors (SNRIs) venlafaxine 75 mg twice daily and/or duloxetine 30–60 mg/day. Both patients developed tachycardia, which remitted after the discontinuation of these agents. The woman was rechallenged with duloxetine 60 mg daily after her HF worsened with venlafaxine, only to have the tachycardia and HF symptoms return. Other iatrogenic causes and metabolic disturbances (eg, anemia) were ruled out.

DISCUSSION: Increased levels of norepinephrine secondary to reuptake inhibition may be potentially deleterious in patients with chronic HF of left ventricular dysfunction owing to the "progressive HF model" and neurohormonal compensatory responses. Use of the Naranjo probability scale showed a probable relationship between venlafaxine/duloxetine use and these adverse outcomes. Venlafaxine and duloxetine were discontinued.

CONCLUSIONS: Use of drugs that increase serum norepinephrine levels, such as the SNRIs, may be potentially deleterious in individuals with unstable or advanced HF. These medications should be avoided or used with caution and monitored regularly in this patient population.

Key Words: duloxetine, heart failure, norepinephrine, tachycardia, venlafaxine

Published Online, April 29, 2008. www.theannals.com, DOI 10.1345/aph.1L031

Downregulation and uncoupling from the adenyl cyclase receptor site of β receptors are 2 proposed mechanisms thought to be responsible for the loss of β signal transduction.⁸ Upregulation of β-adenyl receptor kinase may also contribute to uncoupling. The use of β₁-adrenergic receptor antagonists has clearly shown that the attenuation of excess catecholamine and norepinephrine bombardment of the cardiac β₁-receptors results in receptor upregulation, recoupling of available receptors to catecholamines, reverse remodeling, dehybridization, and decreased morbidity and mortality.^8,10-14

In theory, stopping β₁-adrenergic antagonist therapy or increasing the norepinephrine concentration by other means (eg, norepinephrine reuptake inhibitors) may pharmacologically exacerbate or worsen HF of LVSD that was previously stable, secondary to mechanisms described.

For obvious ethical reasons, there are few data examining discontinuation of β-blocker therapy once the signs and symptoms of HF have been reversed or normalized and the cardiovascular hemodynamics stabilized. However, one may intuit that unintentional or episodic exposure to increased levels of norepinephrine, either via pharmacologic introduction or β₁-antagonist discontinuation, may worsen HF associated with LVSD.

We report 2 cases of worsened or exacerbated HF after the introduction of duloxetine and/or venlafaxine in 2 patients with HF that was previously hemodynamically stable. We posit that the mechanism of action of these agents, specifically an increase in the concentration of norepinephrine secondary to inhibited reuptake at the synapse, is associated with tachycardia and subsequent worsening of HF of LVSD.

	Case Reports

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CASE 1
A 39-year-old female presented to the emergency department with increasing dyspnea and fluid retention following an episode of diagnosed viral bronchitis. Other potential causes for her acute shortness of breath and dyspnea were ruled out (eg, negative computed tomography scan for pulmonary embolus, no history of respiratory disease or toxin exposure). Echocardiography revealed severe LVSD with an ejection fraction estimated to be 15%. Ischemic cardiomyopathy was ruled out and she was admitted with a diagnosis of nonischemic dilated cardiomyopathy with dramatically reduced systolic function. During hospitalization, the patient was initiated and stabilized on a loop diuretic, a β₁-antagonist, and an angiotensin-converting enzyme inhibitor. On discharge, she was prescribed furosemide 40 mg daily, carvedilol 12.5 mg twice daily, spironolactone 25 mg daily, and lisinopril 10 mg twice daily. She also resumed her previous medications including alprazolam 0.25 mg at bedtime as needed, venlafaxine 75 mg twice daily, rizatriptan 5 mg as needed, triamcinolone nasal spray, fexofenadine 180 mg daily, and dicyclomine 10 mg before meals.

Despite remaining reasonably stable, the woman continued to be fatigued and exercise intolerant for the next 2 months. She was without orthopnea and paroxysmal nocturnal dyspnea and did not require rehospitalization. Follow-up in an ambulatory HF clinic revealed a lack of complete resolution of symptoms or progression to baseline cardiology health, which was unexpected given her age and prior lack of disease. On follow-up examinations, her weight averaged 98 kg (range 96–100) and mean blood pressure averaged 104/78 mm Hg (ranges, systolic 98–111, diastolic 73–84), but she continued to be tachycardic, with a mean heart rate of 101 beats/min (range 96–107). There was no evidence of significant fluid retention, cyanosis, or clubbing. Heart sounds demonstrated S1 and S2, without murmurs. A 2-month (posthospitalization) echocardiogram revealed improvement, but the ejection fraction was below normal at 25–30% and was still assessed as globally hypokinetic. Her LV diastolic dimension was mildly dilated at 58 mm. There was slight mitral regurgitation, but less so than at her emergency department presentation and initial echocardiogram.

Adenosine stress imaging and perfusion scintigraphy were assessed as normal without any evidence of ischemic burden. Cardiology impression continued to be that of nonischemic cardiomyopathy with small improvement over a couple of months, perhaps longstanding or of viral etiology. The patient remained tachycardic throughout this period, with heart rates greater than 100 beats/min. Consideration was given to carvedilol-induced fatigue, as the dosage was being titrated at the time from 12.5 mg twice daily to 25 mg twice daily, but this did not explain the tachycardia. Final impression was nonischemic cardiomyopathy of uncertain etiology and LVSD with euvolemia, as shown on echocardiogram and examination. Importantly, the patient's renal function, brain natriuretic peptide levels, thyroid study results, liver function test results, and complete blood cell count were all normal throughout this period, ruling out any electrolyte or anemic causes of her symptoms. She was believed to be adherent to her drug therapy regimen.

Subsequent follow-up in one month revealed a similar presentation without resolution of fatigue. Afternoon episodes of uncontrollable diaphoresis were also noted. At this visit, the patient's weight was 98 kg, blood pressure 136/74 mm Hg, and heart rate 109 beats/min. A screen for pheochromocytoma was negative. At this point, consideration was given to venlafaxine as the cause of the fatigue, diaphoresis, and tachycardia because of its pharmacology of norepinephrine and serotonin reuptake inhibition, and it was discontinued.

Two weeks later, the patient had no symptoms of HF; blood pressure was 102/64 mm Hg and heart rate was 70 beats/min. Her afternoon sweating had abated. However, her mood disorder and anxiety symptoms were considerably worse. At this point, members of the HF team (cardiologist, pharmacist) believed that venlafaxine was associated with the patient's HF symptoms and thus continued to withhold it. The cardiologist deferred to the primary care physician for treatment of the anxiety/mood disorder. The primary care physician then prescribed duloxetine 60 mg daily to replace venlafaxine. This effectively treated the patient's mood disorder but resulted in tachycardia (heart rate 105 beats/min), sleep disturbance, and a return of mild HF symptoms (fatigue, afternoon sweating, exercise intolerance), but no fluid retention or orthopnea.

Upon cardiology and pharmacy recommendations, duloxetine was discontinued and substituted with sertraline, which resulted in reasonable mood and anxiety control, decreased heart rate (averaging 75 beats/min), and improved fatigue symptoms.

CASE 2
A 68-year-old male with a complex history of coronary artery disease, 2 instances of coronary artery bypass grafting, ischemic cardiomyopathy, and chronic HF of LVSD with ejection fraction approximately 25% had been stabilized over the past 6 months. His New York Heart Association (NYHA) HF classification vacillated from Class II to IV, but was Stage D. He received outpatient milrinone infusions approximately every 2 weeks. His medical history also included diabetes, atrial fibrillation, Staphylococcus aureus infection requiring below-knee amputation (right), several episodes of urosepsis, hyperlipidemia, chronic renal insufficiency, chronic anemia, and benign prostatic hypertrophy; the patient was also status-postimplantable cardioverter defibrillator/biventricular pacing device placement. Despite the patient's many medical issues, he was stabilized on a medical regimen of milrinone outpatient infusions, prednisone 10 mg daily, carvedilol 9.75 mg twice daily, bumetanide 2 mg twice daily, aspirin 81 mg daily, iron 325 mg daily, benazepril 20 mg in the afternoon and 10 mg in the evening, warfarin 4 mg for 4 days and 3 mg for 3 days, tamsulosin 0.4 mg daily, atorvastatin 20 mg daily, colchicine 0.6 mg daily, Humulin NPH insulin 40 units daily plus sliding scale, metolazone 1.25 mg as needed up to 3 times weekly, and acetaminophen/hydrocodone as needed for pain.

At the time of the purported adverse event sequence, the patient's laboratory chemistry data were reported as blood glucose 189 mg/dL, blood urea nitrogen 81 mg/dL, serum creatinine 2.4 mg/dL, sodium 130 mEq/L, potassium 5.0 mEq/L, chloride 90 mEq/L, bicarbonate 22 mEq/L, aspartate aminotransferase 44 IU/L, alanine aminotransferase 69 IU/L, hemoglobin 10.3 g/dL, hematocrit 31.4%, and platelets 298 x 10³/µL. These levels had been reasonably stable over the previous 6 months. He was followed regularly by internal medicine, cardiology, various other specialties (ie, infectious diseases, orthopedics, urology), and clinical pharmacy.

Because of ongoing diabetes-associated peripheral neuropathy, the patient was prescribed a trial course of duloxetine, initiated at 30 mg daily for 1 week, then increased to 60 mg daily. After approximately 2 weeks, the patient evaluated the neuropathic pain as significantly improved; however, his heart rate had increased to greater than 100 beats/min from a baseline of 70 beats/min. Additionally, he had gained 3.6 kg and was becoming more dyspneic and orthopneic. The cardiologist instructed him by telephone to increase the bumetanide dose to 4 mg twice daily and add 1.25 mg of metolazone daily for the next day, but to have a more complete assessment performed. On follow-up assessment and medication review, the cardiologist decided to discontinue duloxetine and continue the more aggressive diuresis. Within 2 days, the patient lost 3.2 kg of fluid and his heart rate returned to approximately 75 beats/min. Orthopnea disappeared and the fatigue resolved. Tachycardia-induced exacerbation of HF was thought to be associated with duloxetine; the drug was not continued.

	Discussion

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Congestive heart failure is a complex clinical syndrome that results from cardiac dysfunction predominantly caused by ischemic heart disease, chronic uncontrolled hypertension, and valvular heart disease.^1-3 However, in some individuals, the occurrence or precipitation of HF can be associated with the pharmacologic, and in some cases, cardiotoxic effects of drugs.¹⁵ Further, some drug classes can compromise existing hemodynamics and may act as a precipitating factor for exacerbation of HF symptoms in patients whose condition has been previously stable and compensated.

We observed 2 cases of worsened HF in previously stable patients after the addition of SNRIs to their drug regimens. We posit that this is likely the result of an increase in norepinephrine levels, with subsequent tachycardia. Conceivably, an increase in circulating and tissue norepinephrine levels brought about by serotonin and norepinephrine reuptake inhibitors (SNRIs) may negate the effects of sympatholytics (eg, β₁-adrenergic antagonists) and worsen existing or stable HF. Norepinephrine binds peripherally to and β receptors in the vasculature and myocardium, resulting in cardiovascular effects, including increases in baseline blood pressure and heart rate, augmentation of conduction velocity, and enhanced contractility. However, in a patient with cardiac disease or impaired LVSD, evidence of increased norepinephrine plasma spillover from cardiac and renal tissues suggests increased sympathetic activity in these beds.⁶ This may lead to myocardial ischemia, cardiac instability, and worsening systolic dysfunction and HF.

Tricyclic antidepressants (TCAs) have been the most studied antidepressants in individuals with cardiac disease; however, there remains a paucity of data owing to the small numbers of patients, short-term length, and limited evaluation of these trials. The actions of TCAs on cardiac tissue are multiple and include sodium channel blockade and inhibition of the fast-inactivating rapid component of potassium channels, thus slowing intraventricular conduction and prolonging the QT interval.¹⁶ Most patients who receive TCAs will experience tachycardia due to a basal increase in serum norepinephrine concentrations,^15,16 although 2 small trials with the TCAs imipramine and nortriptyline did not find tachycardias or further LV impairment, but both were associated with serious conduction abnormalities and orthostatic hypotension, with the latter presumably from blockade.¹⁶ These small studies concluded that the major concern with the use of TCAs in patients with heart disease, including LV impairment, was orthostatic hypotension and conduction abnormalities, and that with short-term use, TCAs do not seem to compromise LV function. There have been case reports of HF associated with the use of TCAs and experiments in animals have suggested a negative inotropic effect, yet these studies are difficult to extrapolate to humans.¹⁵ The influence of TCAs on cardiac conduction also makes the net effect on overall LF function difficult to ascertain, and there remains no convincing evidence indicating that TCAs are likely to have compromising effects on LV systolic function. Currently, they have a secondary and augmenting role in depression and their lower dosing in treatment of other indications (eg, sleep disorders, peripheral neuropathies) may offer further explanation for their lack of cardiac-associated problems.

The newer selective serotonin-reuptake inhibitors (SSRIs [eg, fluoxetine, sertraline]) are generally considered safe for use in patients with cardiovascular disease. Cardiovascular adverse effects of SSRIs have been estimated to be 0.0003% based on reports to pharmaceutical manufacturers.^15,16

Duloxetine and venlafaxine are SNRIs, although both reportedly have a potency greater for the serotonin than for the norepinephrine reuptake process.^17,18 Neither has appreciable activity at dopaminergic, cholinergic, adrenergic, histaminergic, glutamate, or opiate receptors, and neither inhibits monoamine oxidase. Duloxetine's inhibition of the norepinephrine reuptake process occurs at a considerably lower dose (>60 mg daily)¹⁷ compared with venlafaxine (>300 mg daily).¹⁸ Our patient (68-year-old male) had worsening heart failure with dosage titration of duloxetine from 30 to 60 mg/day, adding to the suggestion that patients with advanced HF, and perhaps renal compromise, may be much more sensitive to the norepinephrine reuptake effect and to any increase in norepinephrine levels.^6,9

Venlafaxine product information lists tachycardia as a potential adverse reaction and states that mild increases in heart rate have been reported (4–8 beats/min); these have occurred at mean doses greater than 300 mg daily.¹⁸ Modest blood pressure increases have been seen (10–15 mm Hg, both systolic and diastolic) and may present concern in at-risk patients. Fangio et al.¹⁹ reported an episode of acute heart failure after venlafaxine poisoning (5.5 g ingested). Several mechanisms were proposed, including multivessel epicardial spasm or catecholamine-induced myocardial damage. The woman in our report did not ingest toxic amounts and, further, this does not explain her response when duloxetine was substituted for venlafaxine.

Drent et al.²⁰ reported on 2 patients with drug-induced pneumonitis and HF simultaneously associated with venlafaxine use. The authors suggested that alterations in metabolic drug clearance as the result of genetic factors or drug–drug interactions might be, in part, responsible for the drug-induced insult. We could not rule out intrinsic cytochrome P450 isoenzyme (eg, CYP2D6, CYP1A2) deficiency with either patient; however, we found no evidence of drug hypersensitivity, and chest X-rays showed no interstitial lung disease. The possibility of a carvedilol–SNRI interaction exists, as both are substrates of the CYP2D6 isoenzyme, but which drug would predominate has not been fully evaluated. Product information for duloxetine also recommends precaution with use of the drug in patients with cardiac disease and reports small increases in heart rate (2 beats/min) and mean systolic and diastolic pressures (2.1 and 2.3 mm Hg, respectively).¹⁷ Hypertensive crisis and supraventricular arrhythmias have been documented in postmarketing reports.¹⁷ Neither agent has been systematically studied in patients with cardiac disease, including HF. The manufacturers of both drugs indicate that no clinically important electrocardiographic abnormalities have been observed with either agent,^17,18 although one published report suggested an elevated defibrillator threshold with venlafaxine therapy in a patient with an implantable cardioverter defibrillator.²¹

Some researchers report that more complex indices of excess sympathetic (norepinephrine) activity are required for prognosis or risk stratification in patients with HF. These indices may include heart rate variability and baroflex sensitivity,^16,22 although the latter has been recently challenged.²³ Demonstrating reduced heart rate variability has been shown to be an indirect measure of the effects of sympathetic overstimulation and an independent predictor of mortality following acute myocardial infarction.¹⁶

Both of our patients presented with tachycardia, which might suggest an exaggerated or hypersensitive response to venlafaxine and duloxetine in patients with compromised cardiac function, particularly with duloxetine, which reportedly inhibits norepinephrine reuptake at doses of 60 mg or more daily. The hypothesized venlafaxine/duloxetine-associated tachycardia-induced cardiomyopathy and worsened HF symptoms that ensued may have been due to a reduced heart rate variability, decreased ventricular filling, a shortened time spent in diastole (diastolic dysfunction), or some other undetermined effect. Our male patient was 68 years old and had NYHA Class III–IV stage D HF and chronic renal insufficiency. This may have predisposed him to the pharmacologic effects, including adverse reactions, of duloxetine at doses lower than those used in younger, more healthy individuals. Duloxetine is oxidized by CYP2D6 and CYP1A2 enzymes; whether he was a poor metabolizer and lacked these isoenzymes is unclear. Hyponatremia and the syndrome of inappropriate antidiuretic hormone secretion have been reported with duloxetine.¹⁷ While this cannot be fully ruled out with our male patient, the acute onset and resolution in association with drug exposure and discontinuation and the lack of significant hyponatremia (serum sodium 130 mEq/L) lessen the probability.

Our female patient was, in effect, rechallenged, as discontinuation of venlafaxine was followed by a trial with duloxetine, presumably because her primary care physician did not know the pharmacologic relationship between the 2 drugs. Duloxetine also produced tachycardia and HF symptoms in the woman. Interestingly, she was taking the venlafaxine prior to her hospitalization for HF and apparently tolerating it well. The etiology of her HF was not clear and the cardiologist believed that perhaps a viral etiology caused the initial cardiac dysfunction. However, viral cardiomyopathies are often a diagnosis of exclusion after other possible etiologies have been ruled out and are usually retrospective. Applying the Naranjo scale to our reports reveals the associated adverse events as probable.²⁴

	Conclusions

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Introduction of venlafaxine and duloxetine in 2 patients with recovering or stable HF resulted in tachycardia and worsening symptoms. Discontinuation of these agents resulted in HF symptoms resolving, suggesting that the norepinephrine reuptake inhibition mechanism of this class of drugs and ensuing tachycardia may be responsible for HF worsening or decompensation. Clinicians should avoid these drugs or use them with caution in patients with advanced or unstable heart failure.

	References

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