June 2014 FAQs
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What are the recommendations regarding blood pressure management in patients with an acute ischemic stroke?
What are the recommendations regarding blood pressure management in patients with an acute ischemic stroke?
Role of hypertension in acute ischemic stroke
Hypertension is the single most important modifiable risk factor for ischemic stroke.1 The International Society of Hypertension (ISH) states that high blood pressure (>140/90 mmHg) is very common early after ischemic stroke (~75% occurrence) and that high blood pressure is independently associated with a poor functional outcome.2
The approach to blood pressure management in ischemic stroke specifically is different compared to other stroke subtypes due to the underlining pathophysiology. Under normal circumstances, the rate of cerebral blood flow is determined by changes in the diameter of the vessel and is maintained at a constant level despite variations in perfusion pressure. This concept is referred to as cerebral autoregulation, and it is impaired during the acute phase of an ischemic stroke.3 In an ischemic stroke, blood flow to the brain is reduced, resulting in decreased oxygenation and ultimate death to the involved tissues. The early hypertensive response following an ischemic stroke can occur due to under-treated or undiagnosed chronic hypertension or, in a large number of patients, as a result of the brain ischemia. It is theorized that this acute increase in blood pressure may be a neuroendocrine response to physiologic stress.4 The body responds to the ischemia by compensation; cerebral perfusion pressure to the brain is diminished leading to vessel dilation and increased flow. However, once the pressure drops beyond the brain’s ability to compensate, flow is again decreased leading to deprivation of glucose and oxygen to the brain.
Extremely elevated blood pressure during an ischemic stroke can lead to encephalopathy, cardiac complications, and renal insufficiency.4 However, moderately elevated blood pressure has been proposed to produce several advantages during the acute phase of an ischemic stroke: improved cerebral perfusion, reduced cerebral edema, prevention of concurrent myocardial injury, and hastening the transition to long-term antihypertensive therapy. 4,5 Conversely, early reductions in blood pressure have produced mixed results as well. Some studies show a reduction in infarct size and deficits with a reduction in blood pressure, while others suggest significant blood pressure changes may be associated with an increased risk of neurological deterioration and death at 90 days.4,6 Prior trials (ACCESS, BEST, INWEST, and NINDS rtPA) surrounding immediate blood pressure management following an ischemic stroke have reported conflicting results (possibly due to the different antihypertensive regimens used), with insufficient evidence to provide recommendations in favor or against treatment.
Although the guidelines for treatment of high blood pressure were recently updated in the eighth report of the Joint National Committee (JNC), they do not specifically address blood pressure goals for stroke patients or guidance on lowering elevated blood pressure post-stroke.7 However, the previous report, JNC 7, noted controversy in management of blood pressure associated with ischemic stroke and recommended “cautious reduction” and monitoring for neurological stability with individualized goals for special circumstances.8
The guidelines published by the American Heart Association (AHA) in accordance with the American Stroke Association (ASA) have recommendations for early management of patients with acute ischemic stroke and are summarized in Table 1.4 Guidance on blood pressure management extends to patients who may also be eligible for recombinant tissue plasminogen activator (rtPA) and patients who may be chronically hypertensive.
Table 1. American Heart Association/American Stroke Association guidelines for blood pressure management with acute ischemic stroke.4
Recommendations Class/Level of Evidence Patients who have elevated blood pressure and otherwise eligible for treatment with intravenous fibrinolytic therapy should have their blood pressure carefully lowered prior to initiation:
- SBP <185 mmHg/DBP <110 mmHg
- Blood pressure should be maintained:
- SBP <180 mmHg/DBP <105 mmHg for the first 24 hours after treatment
Class I/B Patients with markedly elevated blood pressure who DO NOT receive fibrinolysis:
- Lower blood pressure by 15% during first 24 hours after onset of stroke (based on clinical judgment and underlying conditions)
- Medications should be withheld unless SBP > 220mmHg or DBP >120mmHg
Class I/C Patients who have pre-existing hypertension and are neurologically stable:
- Re-starting antihypertensive therapy medications is reasonable after the first 24 hours unless a specific contraindication is known
Blood pressure is often higher in acute stroke patients with a history of hypertension than those without, and these patients who are chronically hypertensive typically experience cerebral autoregulation at higher arterial pressures compared to the average individual who is normotensive due to adaptation.6 The ISH reports that roughly 50% of patients admitted with stroke are receiving antihypertensive therapy.2 Due to the uncommon nature of acute processes like hematomas or ischemic penumbra occurring more than 24 hours following a stroke, it has routinely been safe practice for oral hypertensive agents to be initiated at 24 to 48 hours with favorable outcomes.2,4
Guidelines do not suggest a particular medication class for lowering blood pressure because of the lack of data to support a prevailing class. However, they do provide a list of reasonable choices based on a general consensus.4 Patients may also experience a spontaneous decline in blood pressure during the first 24 hours after the onset of stroke, and since there are currently no definitive data showing the benefit of treating arterial hypertension in the setting of ischemic stroke, recommendations regarding management are not well established.
The 2 most recent clinical studies evaluating blood pressure management following an acute ischemic stroke are summarized in Table 2. The SCAST trial, which looked at patients with both ischemic and hemorrhagic stroke, randomized patients to receive an angiotensin receptor blocker (candesartan) or placebo for 1 week.9 Patients were permitted to receive antihypertensive agents at the physicians’ discretion and were given to 28% of patients in the candesartan group versus 26% of patients in the placebo group. The trial showed a 5-point systolic blood pressure reduction in the candesartan group at the end of the 7 days, which was significant from placebo (p<0.001). There was no significant difference in the composite vascular endpoint (death, myocardial infarction, or recurrent stroke) between groups at 6 months. A subtle worsening of the main functional outcome in the candesartan group versus placebo (p=0.048) was seen in an adjusted analysis at 6 months.
The second trial, CATIS, was unique as it only included patients with ischemic stroke and analyzed blood pressure lowering in a more controlled manner, limiting additional antihypertensive therapy for extreme circumstances only.5,10 The CATIS trial focused on an aggressive target for blood pressure lowering in the intervention group (see Table 2). The absolute difference in systolic blood pressure at 24 hours between treatment and control groups was substantially greater in the CATIS trial as compared to the SCAST (8.2 mmHg vs. 3.3 mmHg).5 Despite lowering blood pressure faster and more substantially in the intervention group, both the primary and secondary end points were found to be not significant.
Table 2. Summary of most recent clinical trials in the management of blood pressure control following acute ischemic stroke.
Clinical Study Interventions Endpoints Results Conclusions SCAST 20119
RCT, DB, PC, MC
N=2029 patients with acute stroke (ischemic [~85%] or hemorrhagic)
Mean BP: ~171/90 mmHg
Mean age: ~71 years
Day 1: 4 mg
Day 2: 8 mg
Days 3 to 7: 16 mg
Composite of vascular death, MI, or stroke during the first 6 months; and functional outcome (mRS) at 6 months
Death from any cause, vascular death, ischemic stroke, hemorrhagic stroke, MI, stroke progression, neurological status (SSS) at 7 days, and activities of daily living (Barthel index)
12% vs. 11% (candesartan vs. placebo), p=0.52
Unadjusted OR 1.13 (0.97 to 1.32), p=0.12
Adjusted OR 1.17 (1 to 1.38), p=0.048
All outcomes were nonsignificant
No indication that an angiotensin-receptor blocker (candesartan) for blood pressure lowering is beneficial in patients with acute stroke and elevated blood pressure. CATIS 201410
N = 4071 patients with ischemic stroke
rtPA patients excluded
Mean BP: 166/96 mmHg
Mean age: 62 years
49.1% taking antihypertensive on admission
Antihypertensive treatment to lower SBP 10% to 25% within first 24 h and goal of <140/90 mmHg
All antihypertensive medications were discontinued during hospitalization
Composite of death and major disability at 14 days or hospital discharge
Composite of death and major disability (mRS) at 3 months post-treatment
33.6% antihypertensive group vs. 33.6% control, p=0.98
Death as 1.2% in each group (p=0.99)
Median mRS score=2 for both groups (p=0.70)
Blood pressure reduction with antihypertensive medications vs. absence of hypertensive medication did not reduce the likelihood of death and major disability at 14 days or hospital discharge Abbreviations: BP, blood pressure; DB, double-blind; MC, multicenter; MI, myocardial infarction; mRS, modified Rankin Score; OR, odds ratio; PC, placebo-controlled; RCT, randomized controlled trial; rtPA, recombinant tissue plasminogen activator; SB, single-blind; SBP, systolic blood pressure; SSS, Scandinavian Stroke Score.
The CATIS trial did have several limitations, however, that could have impacted the ability to see a favorable result. Namely, the ability to generalize results to other populations as the patient population of the trial is entirely reflective of China and the clinical practices there.5,10 Overall, the CATIS trial does provide evidence that optimal blood pressure management involves avoidance in the acute period (first 12 hours) following an ischemic stroke and re-initiation in the 12 to 36 hour period to prevent secondary injury. This is based in part on the low frequency of composite recurrent events for untreated blood pressure versus little risk of infarct extension when blood pressure was actively treated in the first 2 weeks.5 In addition, a subgroup analysis in the CATIS trial suggested better outcomes among patients treated 24 or more hours after stroke. 10
Despite the lack of benefit shown by immediate blood pressure reduction in the CATIS and SCAST trials described above, management following an acute ischemic stroke should be made on an individual basis due to other patient specific circumstances, including stroke subtype or specific conditions such as myocardial infarction, aortic dissection, or eligibility for fibrinolytic reperfusion. For unique cases requiring antihypertensive therapy, blood pressure management goals should be made based on established goals for that particular disease state in combination with clinical judgment and the current guidelines set forth by AHA/ASA.4
Overall, based on current literature, the effects of immediate blood pressure reduction in patients with ischemic stroke remain unclear. Similarly, the available AHA/ASA guidelines do not provide strict recommendations for managing blood pressure after an acute stroke. They recommend managing blood pressure in a controlled fashion with intravenous therapies but stress that neither an optimal agent nor optimal time currently exist to control blood pressure or restart long-term antihypertensive medications.4 Although there are limited data regarding re-initiation of antihypertensive medications, based on the current literature and guidelines, it would be reasonable to temporarily discontinue antihypertensive medications at the onset of an acute ischemic stroke and consider re-starting these medications within 24 hours after the acute period has lapsed. However, this decision must be made on an individualized basis, considering relevant co-morbidities and baseline blood pressure readings.
Currently, 3 clinical trials are in progress regarding blood pressure management following an acute stroke. The results of the ENOS, ENCHANTED, and FAST-MAG studies will hopefully be able to provide more definitive recommendations on this topic when they are complete.5
1. Sacco RL, Benjamin EJ, Broderick JP, et al. American Heart Association Prevention Conference. IV. Prevention and rehabilitation of stroke. Risk factors. Stroke. 1997;28(7):1507-1517.
2. Bath P, Chalmers J, Powers W, et al. International Society of Hypertension Writing Group. International Society of Hypertension (ISH): statement on the management of blood pressure in acute stroke. J Hypertens. 2003;21(4):665–672.
3. Markus HS. Cerebral perfusion in stroke. J Neurol Neurosurg Psychiatry. 2004;75(3):353-361.
4. Jauch EC, Saver JL, Adams HP, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870-947.
5. Saver J. Blood pressure management in early ischemic stroke. JAMA. 2014;311(5):469-470.
6. Qureshi AI. Acute hypertensive response in patients with stroke: pathophysiology and management. Circulation. 2008;118(2):176-187.
7. James PA, Oparil S, Carter B, et al. 2014 Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520.
8. US Department of Health and Human Services. The Seventh Report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. https://www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.htm. Accessed May 13, 2014.
9. Sandset EC, Bath PMW, Boysen G, et al. The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomized, placebo-controlled, double-blind trial. Lancet 2011;377(9767):741-750.
10. He J, Zhang Y, Xu T, et al. Effects of immediate blood pressure reduction of death and major disability in patients with acute ischemic stroke: the CATIS randomized clinical trial. JAMA. 2014;311(5):479-489.
Margaret Oates, PharmD
University of Illinois at Chicago
What evidence supports the efficacy of the new oral factor Xa inhibitor, edoxaban?
What evidence supports the efficacy of the new oral factor Xa inhibitor, edoxaban?
Unlike warfarin, the new oral anticoagulants rivaroxaban, apixaban, (factor Xa inhibitors) and dabigatran (direct thrombin inhibitor) are characterized by a faster onset of action, lack of frequent monitoring, predictable dosing, and fewer drug-drug and drug-food interactions.1 While the place in therapy for the new oral anticoagulants has not been fully determined, their inclusion in many clinical practice guidelines reflects the available efficacy and safety data. Recent guidelines from the American College of Chest Physicians (ACCP) recommend preferential use of dabigatran over warfarin for stroke risk reduction in patients with atrial fibrillation (AF).2 Current guidelines from the American College of Cardiology/American Heart Association/Heart Rhythm Society and the American Academy of Neurology suggest using warfarin or any of the new oral anticoagulants to reduce the risk of stroke in nonvalvular AF.3,4 The new oral anticoagulants are also mentioned in ACCP guidelines for treatment of venous thromboembolism (VTE), although these agents are not preferred.5
Edoxaban is the newest oral factor Xa inhibitor that has undergone Phase III clinical trials.6 Currently approved only in Japan for the prevention of VTE after major orthopedic surgery, the manufacturer of edoxaban (Daiichi Sankyo) has submitted a New Drug Application to the US Food and Drug Administration (FDA) for the reduction in risk of stroke and systemic embolic events in patients with nonvalvular AF, the treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), and to prevent recurrent symptomatic VTE.
Edoxaban has demonstrated linear pharmacokinetics in several studies conducted in healthy volunteers.7 Absorption after oral administration is rapid, with a time to peak concentration of 1 to 2 hours. There is little effect on absorption when administered with a high-fat meal, indicating that edoxaban can be administered without regard to food.8 Edoxaban has a large volume of distribution (>300 L) with low protein binding. 7 The half-life of edoxaban ranges from 5.8 to 10.7 hours. A pharmacokinetic study in healthy volunteers found that edoxaban was eliminated via both feces (62.2%) and urine (35.4%).9
Edoxaban is a P-glycoprotein (P-gp) substrate.7 When administered with strong P-gp inhibitors, the absorption of edoxaban may increase and elimination can decrease, which may result in increased plasma levels of edoxaban and a higher risk of bleeding.10 Several studies have tested the interaction of edoxaban with known P-gp substrates or inhibitors. The strong P-gp inhibitors verapamil, quinidine, and dronedarone had clinically significant effects on edoxaban exposure. When administered with these agents, it is recommended to reduce the edoxaban dose by 50% to decrease the risk of bleeding. Amiodarone is also considered a strong P-gp inhibitor, but in studies with edoxaban it showed minimal effect on bleeding risk; therefore, dose adjustments are not needed. Digoxin and atorvastatin had no clinically relevant interactions with edoxaban. Non-steroidal anti-inflammatory drugs (NSAIDs) and clopidogrel may increase bleeding time when coadministered with edoxaban.7 Additional studies are needed to determine the full extent of the drug interactions associated with edoxaban.
Efficacy of edoxaban for atrial fibrillation
A randomized, multicenter, noninferiority, double-blind, double-dummy, trial compared edoxaban to warfarin in 21,105 patients with AF with a median follow up of 2.8 years.11 Study participants included adults with documented AF, a CHADS2 risk score of 2 or greater, and anticoagulation planned throughout the trial. Pertinent exclusion criteria were reversible AF, other indications for anticoagulation, stroke or major cardiovascular event within 30 days, use of dual antiplatelet therapy, high risk of bleeding, and creatinine clearance (CrCl) <30 mL/min. Participants were randomized into 1 of 3 arms: dose-adjusted warfarin (international normalized ratio [INR] goal 2 to 3, n=7036), high-dose edoxaban (60 mg once daily, n=7035), or low-dose edoxaban (30 mg once daily, n=7034). Patients in both edoxaban groups received half of the dose if they had a CrCl 30 to 50 mL/min, body weight ≤60 kg, or were taking the concomitant P-gp inhibitors verapamil, quinidine, or dronedarone. The primary efficacy outcome was the time to first stroke (ischemic or hemorrhagic) or systemic embolism. There were a variety of composite secondary efficacy outcomes which included stroke, systemic embolic event, death, myocardial infarction, and death from cardiovascular events. The primary safety outcome was major bleeding during treatment.
The median age of study participants was 72 years.11 Approximately 62% of patients in each group were male. The mean CHADS2 score at baseline was 2.8±1 in all groups. Nearly 25% of patients in each group received half doses of the study drug, and about one-third were taking concomitant aspirin therapy. Study drug discontinuation rates were similar between the groups (~ 34%). The most common reason for discontinuation was an adverse event or suspected endpoint event. In the warfarin group, the mean time within the therapeutic INR range was 64.9±18.7%. In the modified intention-to-treat population (patients who received at least 1 dose of any therapy), the primary endpoint occurred at a rate of 1.5% of patients/year in the warfarin group compared to 1.18% of patients/year in the high-dose edoxaban group (hazard ratio [HR] 0.79, 97.5% confidence interval [CI] 0.63 to 0.99, p<0.001 for noninferiority, p=0.02 for superiority) and 1.61% of patients/year in the low-dose edoxaban group (HR 1.07, 97.5% CI 0.87 to 1.31, p=0.005 for noninferiority, p=0.44 for superiority). In the prespecified superiority analysis using the intent-to-treat population, the primary endpoint occurred at a rate of 1.8% of patients/year in the warfarin group compared to 1.57% of patients/year in the high-dose edoxaban group (HR 0.87, 97.5% CI 0.73 to 1.04, p=0.08) and 2.04% of patients/year in the low-dose edoxaban group (HR 1.13, 97.5% CI 0.96 to 1.34, p=0.10). The rate of all secondary endpoints was significantly reduced with high-dose edoxaban compared to warfarin, but no differences were observed between warfarin and low-dose edoxaban. Death from any cause was similar between warfarin (4.35% of patients/year) and high-dose edoxaban (3.99% of patients/year, p=0.08) but was reduced with low-dose edoxaban compared to warfarin (3.8% of patients/year, p=0.006). Death from cardiovascular causes was significantly reduced with both edoxaban doses compared to warfarin. Major bleeding events occurred in 3.43% of patients/year taking warfarin compared to 2.75% of patients per year in the high-dose edoxaban group (HR 0.80, 95% CI 0.71 to 0.91, p<0.001) and 1.61% of patients/year in the low-dose edoxaban group (HR 0.47, 95% CI 0.41 to 0.55, p<0.001). Most of the other bleeding outcomes were significantly reduced with both edoxaban doses vs. warfarin, with the exception of gastrointestinal bleeding, which was significantly increased with high-dose edoxaban (1.51% of patients/year vs. 1.23% of patients/year with warfarin, HR 1.23, 95% CI 1.02 to 1.5, p=0.03).
When the 2 edoxaban doses were compared, high-dose edoxaban achieved lower rates of the primary outcome than low-dose edoxaban (p<0.001).11 Although high-dose edoxaban reduced the incidence of ischemic stroke, it also increased the incidence of hemorrhagic stroke and significantly increased other bleeding events compared to low-dose edoxaban (actual results not provided).
Efficacy of edoxaban for venous thromboembolism
A randomized, multicenter, double-blind, double-dummy, noninferiority study was performed in 8240 participants in 36 countries to compare the efficacy of edoxaban to warfarin in patients with VTE and at least 5 days of open-label enoxaparin or heparin.12 Participants were at least 18 years old with an objectively diagnosed symptomatic DVT and/or PE. Pertinent exclusion criteria included another indication for warfarin therapy, receipt of more than 1 dose of a vitamin K antagonist, aspirin doses >100 mg daily, dual antiplatelet therapy, or CrCl <30 mL/min. Participants were randomized to either edoxaban 60 mg daily (30 mg daily if CrCl 30 to 50 mL/min, body weight ≤60 kg, or use of potent P-gp inhibitors) or dose-adjusted warfarin (INR goal 2 to 3) for 3 to 12 months. The primary efficacy outcome was symptomatic recurrent VTE, which was defined as a composite of DVT or nonfatal or fatal PE. The primary safety outcome was the incidence of clinically relevant major or nonmajor bleeding.
The mean age was approximately 56 years in both groups and males comprised the majority of patients (~57%).12 Edoxaban 30 mg (or matching placebo) was given to about 17% of patients in both groups. Causes of VTE were similar between groups, including unprovoked DVT or PE (65.9% with edoxaban and 65.4% with warfarin), temporary risk factor (27.5% and 27.7%), previous VTE (19% and 17.9%), and cancer (9.2% and 9.5%). In the warfarin group, the mean time within the INR therapeutic range was 63.5%. By the end of the 12-month study period, the primary outcome occurred in 130 of 4118 (3.2%) patients in the edoxaban group and 146 of 4122 (3.5%) patients in the warfarin group (HR 0.89, 95% CI 0.7 to 1.13, p<0.001 for noninferiority). During the on-treatment study period the primary outcome occurred in 1.6% of the edoxaban group and 1.9% of the warfarin group (HR 0.82, 95% CI 0.60 to 1.14, p<0.001 for noninferiority). Major or clinically relevant nonmajor bleeding events occurred in 8.5% of the edoxaban group and 10.3% of the warfarin group (HR 0.81, 95% CI 0.71 to 0.94, p=0.004). Fifty-six patients (1.4%) in the edoxaban group and 66 patients (1.6%) in the warfarin group experienced major bleeding (p=0.35). Serious adverse events and adverse events leading to study drug discontinuation occurred at similar rates in both groups.
In a subgroup analysis of patients who met the criteria for edoxaban 30 mg, recurrent VTE occurred in 3% of patients in the edoxaban group and 4.2% of patients in the warfarin group (HR 0.73, 95% CI 0.42 to 1.26, p=0.42). Major or clinically relevant nonmajor bleeding were similar between groups in this cohort (p=0.0695).
Reversal of edoxaban
Currently, specific antidotes for the reversal of the new oral anticoagulants are not available.13 Positive results with prothrombin complex concentrate (PCC) as a reversal agent for rivaroxaban have led to the investigation of other prohemostatic therapies as possible reversal agents for the new oral anticoagulants.14 In the case of edoxaban, PCC, recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (aPCC) are potential reversal agents. In vitro, these agents all reversed the prothrombin time (PT) prolongation caused by edoxaban, with rFVIIa providing the most potent reversal effect. In rat models, rFVIIa and aPCC significantly shortened bleeding times that were prolonged with edoxaban. In this same model, PT was completely reversed by rFVIIa (0.3, 1, and 3 mg/kg) and aPCC (50 and 100 U/kg). The use of specific prohemostatic therapies as reversal agents for the new oral anticoagulants is supported by limited data (studies in healthy volunteers, animal models, and in vitro studies).13 PRT4445 is a novel recombinant protein that is currently being investigated as a universal reversal agent for factor Xa inhibitors.15 Another synthetic small molecule under investigation, PER977, binds to dabigatran, rivaroxaban, apixaban, and edoxaban and may prove to be a useful reversal agent. Until further data are available, reversal options for edoxaban remain limited.
Edoxaban was noninferior to warfarin for the prevention of stroke and systemic embolism in patients with AF, with significantly lower bleeding rates and lower rates of death. There were lower rates of ischemic stroke with edoxaban 60 mg and lower rates of hemorrhagic stroke with edoxaban 30 mg when the 2 doses were compared. The 30 mg regimen also had better overall safety compared to the 60 mg regimen. For the treatment of symptomatic VTE when given with 5 days of initial therapy with heparin or enoxaparin, edoxaban was noninferior to warfarin. Edoxaban also caused fewer bleeding events than warfarin. In this trial in patients with VTE, edoxaban 30 mg had similar efficacy and safety compared to warfarin. Once approved for marketing by the FDA, edoxaban will join the other oral factor Xa inhibitors as a therapeutic option for many patients with AF and VTE.
1. Schulman S. Advantages and limitations of the new anticoagulants. J Intern Med. 2014;275(1):1-11.
2. You J, Singer D, Howard P, et al. Antithrombotic therapy for atrial fibrillation. Chest. 2012;141(2 Suppl):e531S-e575S.
3. January C, Wann S, Alpert J, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014 [Epub ahead of print]. doi: 10.1016/j.jacc.2014.03.022
4. Culebras A, Messe S, Chaturvedi S, et al. Summary of evidence-based guideline update: Prevention of stroke in nonvalvular atrial fibrillation: Report of the guideline development subcommittee on the American Academy of Neurology. Neurology. 2014;82(8):716-724.
5. Kearon C, Akl E, Comerota A, et al. Antithrombotic therapy for VTE disease. Chest. 2012;141(2 Suppl):e419S-e494S.
6. Daiichi Sankyo submits SAVAYSATM (edoxaban) tablets new drug application to the U.S. FDA for once-daily use for stroke risk reduction in atrial fibrillation and for the treatment and prevention of recurrence of venous thromboembolism. January 8, 2014. http://www.daiichisankyo.com/media_investors/media_relations/press_releases/detail/006065.html. Accessed April 24, 2014.
7. Camm AJ, Bounameaux, H. Edoxaban: a new oral direct factor Xa inhibitor. Drugs. 2011;71(12):1503-1526.
8. Mendell J, Tachibana M, Shi M, Kunitada S. Effects of food on the pharmacokinetics of edoxaban, an oral direct factor Xa inhibitor, in healthy volunteers. J Clin Pharmacol. 2011;51(5):687-694.
9. Bathala M, Masumoto H, Oguma T, He L, Lowrie C, Mendell J. Pharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct factor Xa inhibitor, in humans. Drug Metab Dispos. 2012;40(12):2250-2255.
10. Mendell J, Zahir H, Matsushima N, et al. Drug-drug interaction studies of cardiovascular drugs involving p-glycoprotein, an efflux transporter, on the pharmacokinetics of edoxaban, an oral factor Xa inhibitor. Am J Cardiovasc Drugs. 2013;13(5):331-342.
11. Giugliano R, Ruff C, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-2104.
12. Buller H, Decousus H, Grosso M, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369(15):1406-1415.
13. Siegal D, Cuker A. Reversal of novel oral anticoagulants in patients with major bleeding. J Thromb Thrombolysis. 2013;35(3):391-398.
14. Fukada T, Honda Y, Kamisato C, Morishima Y, Shibano T. Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents. Thromb Haemost. 2012;107(2):253-259.
15. Majeed A, Schulman S. Bleeding and antidotes in new oral anticoagulants. Best Pract Res Clin Haematol. 2013;26(2):191-202.
Mike Schmidt, PharmD Candidate 2015
University of Illinois at Chicago
Heather Ipema, PharmD, BCPS
Does testosterone increase the risk of a cardiovascular event?
Does testosterone increase the risk of a cardiovascular event?
Testosterone is a hormone that is essential for male growth and masculine characteristic development.1 Currently, testosterone products (patch, gel, buccal system, injection) are Food and Drug Administration (FDA)-approved for adult males with conditions associated with a deficiency or absence of endogenous testosterone such as primary hypogonadism or hypogonadotropic hypogonadism. The FDA has not approved the use of testosterone products in men with low testosterone levels in the absence of an associated medical condition; however, the off-label prescribing of these products has grown substantially.2
Cardiovascular safety concerns
With the increased use of testosterone replacement therapy, concerns have arisen regarding the potential for adverse cardiovascular events.2,3 The FDA has been monitoring this potential risk and published a safety alert in January 2014 urging healthcare providers to report testosterone-related adverse effects to the MedWatch program as part of its continuing evaluation.2 The alert was partially prompted by the recent publication of 2 separate studies that each suggested an increased risk of cardiovascular events among men receiving testosterone therapy.4,5 These study results were in contrast to historical data supporting the idea that a low testosterone level is associated with increased cardiovascular risk and that testosterone replacement therapy may be beneficial in such situations.6 A summary of published clinical studies supporting both negative and positive cardiovascular outcomes is presented in the Table.
Table. Summary of cardiovascular outcomes and testosterone treatment.4,5,7-9
Reference Study design Number of patients Outcomes Results Negative outcomes with testosterone therapy Finkle et al 20144 Cohort study involving a large health-care database; compared the incidence rate of MI in the 90 days following an initial testosterone prescription with the rate of MI in the year prior to the prescription N = 55,593 Diagnosis of acute MI
- Rate ratio for MI was 1.36 (95% CI 1.03 to 1.81) for all subjects
- Rate ratio for MI was 2.19 (95% CI 1.27 to 3.77) for men ≥ 65 years of age
- Rate ratio for MI was 1.17 (95% CI 0.84 to 1.63) for men < 65 years of age
- Rate ratio for MI was 2.90 (95% CI 1.49 to 5.62) for men < 65 years of age with a history of heart disease
- The risk of MI was substantially increased in older men and younger men with a history of heart disease
Vigen et al 20135 Retrospective cohort study of all male veterans who underwent coronary angiography between 2005-2011 and had a testosterone level checked; compared those who received testosterone therapy after angiography to those who did not N = 8,709 Combined endpoint of time to all-cause mortality or to hospitalization for MI or ischemic stroke
- There were 1,710 total outcome events (748 deaths, 443 MIs, and 519 strokes)
- Of patients not receiving testosterone (n = 7,486), there were 681 deaths, 420 MIs, and 486 strokes
- Of patients receiving testosterone (n = 1,223), there were 67 deaths, 23 MIs, and 33 strokes
- Three years after angiography, the Kaplan-Meier estimated cumulative percentages with events were 19.9% no testosterone vs. 25.7% testosterone; absolute risk difference: 5.8% (95% CI -1.4% to 13.1%)
- Testosterone use as a time-varying covariate was associated with an increased risk of negative outcomes: HR 1.29 (95% CI 1.04 to 1.58)
- Testosterone therapy was significantly associated with negative outcomes despite a reduced prevalence of baseline comorbidities in the testosterone group
Basaria et al 20107 Randomized, double-blind, parallel group, placebo-controlled trial involving older (≥ 65 years of age) community dwelling men with limited mobility and low testosterone levels N = 209 Incidence of adverse events
- Study was terminated early by the DSMB due to a higher rate of adverse events in the testosterone group
- Cardiovascular-related adverse events were reported in 23 of the testosterone-treated patients vs. 5 patients in the placebo group
Positive outcomes with testosterone therapy Muraleedharan et al 20138 Six-year prospective follow-up study of men with type 2 diabetes who had testosterone levels performed between 2002-2005; subjects were allocated to 2 groups based on testosterone level N = 581 All-cause mortality
- There was an increase in mortality in the low testosterone group as compared to the normal testosterone group (17.2% vs. 9%; p = 0.003)
- Testosterone replacement was associated with reduced mortality as compared to the untreated group (8.4% vs. 19.2%; p = 0.002).
- Multivariate-adjusted HR for decreased survival in the untreated group was 2.3 (95% CI 1.3 to 3.9; p = 0.004)
- Low-testosterone levels were associated with an increase in mortality
- Testosterone replacement therapy may improve survival in this patient
Shores et al 20129 Observational, retrospective cohort study of men > 40 years of age who were treated on an inpatient or outpatient basis at a Veterans Affairs medical center and had a low testosterone level N = 1,031 Total mortality
- Total mortality was higher in untreated men vs. testosterone-treated men (20.7% vs. 10.3%; p < 0.0001)
- The mortality rate was 3.4 deaths/100 person-years for treated men vs. 5.7 deaths/100 person-years among untreated men
- After multivariate adjustment, testosterone therapy was associated with a reduced risk of death; HR 0.61 (95% CI 0.42 to 0.88; p = 0.008)
- Testosterone treatment was associated with decreased mortality as compared to no treatment
CI = confidence interval; DSMB = data safety monitoring board; HR = hazard ratio; MI = myocardial infarction.
Given the conflicting results, and inherent limitations of each study, healthcare providers and organizations are urging caution when prescribing testosterone replacement.3,10 In February 2014, the Endocrine Society released a statement on the risk of cardiovascular events in men receiving testosterone therapy.3 In this statement, the Society urged providers to discuss the risks and benefits of testosterone replacement with their patients, particularly those with existing heart disease. In addition, the Endocrine Society recommended that providers prescribe testosterone replacement products in accordance with the Society’s clinical guidelines. These guidelines are available at: https://www.endocrine.org/~/media/endosociety/Files/Publications/Clinical%20Practice%20Guidelines/FINAL-Androgens-in-Men-Standalone.pdf .11 Patients initiated on testosterone replacement should also have a standardized monitoring plan to optimize the dose and reduce the risk of adverse effects.3 Although there is clamor for a randomized controlled trial powered for safety to definitively answer the cardiovascular risk issue, such a study would take at least a decade to complete if it was even undertaken.10 Until such a time, the FDA and European regulators will continue to review the safety profile of testosterone products and issue alerts as warranted.
1. Androgel [package insert]. Abbvie, North Chicago, IL; 2013.
2. Food and Drug Administration. FDA evaluating risk of stroke, heart attack and death with FDA-approved testosterone products. http://www.fda.gov/Drugs/DrugSafety/ucm383904.htm?utm_source=rss&utm_medium=rss&utm_campaign=fda-evaluating-risk-of-stroke-heart-attack-and-death-with-fda-approved-testosterone-products . Accessed May 21, 2014.
3. Finkle WD, Greenland S, Ridgeway G, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One. 2014;9(1):e85805. doi: 10.1371/journal.pone.0085805.
4. Vigen R, O’Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829-1836.
5. Seftel AD, Morgentaler A. Does testosterone increase the risk of a cardiovascular event? Yes and No. J Urol. 2014;192:1-3. http://dx.doi.org/10.1016/j.juro.2014.04.021.
6. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010;363(2):109-122.
7. Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones TH. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol. 2013;169(6):725-733.
8. Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab. 2012;97(6):2050-2058.
9. Medscape. Testosterone and CV risk? No quick answers. http://www.medscape.com/viewarticle/824229. Accessed May 21, 2014.
10. The Endocrine Society. Testosterone therapy in adult men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. https://www.endocrine.org/~/media/endosociety/Files/Publications/Clinical%20Practice%20Guidelines/FINAL-Androgens-in-Men-Standalone.pdf . Accessed May 21, 2014.