October 2013 FAQs

Should perioperative beta blockers be used to prevent cardiac complications

in non-cardiac surgeries?

Introduction

The use of perioperative beta blockers to prevent cardiac complications in non-cardiac surgeries has been a controversial practice after 3 publications in 2008 – a large randomized, controlled trial known as the PerioOperative Ischemic Evaluation (POISE) trial, a retrospective cohort study, and a meta-analysis – all of which suggested the risk of beta blocker use in the perioperative setting outweighed the benefit.1-3 The details of these articles were summarized in a previous FAQ (http://dig.pharm.uic.edu/faq/non-cardiac.aspx). 4 Despite these data, the guidelines published by The European Society of Cardiology (ESC) and the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) for the management of cardiovascular status in the perioperative setting continue to recommend the use of perioperative beta blockade in certain situations.5-6 However, recent investigations into the validity and accuracy of some data included in these guidelines have led to a clinical controversy on whether or not perioperative beta blockers should still be recommended in non-cardiac surgical procedures.7

Background

Cardiovascular disease afflicts 80 million people in the US and its incidence and prevalence increases with age.8,9 Additionally, most surgical procedures are performed in patients of advanced age, as much as 4 times more often than the general population.10 Previous research has shown an association between surgical procedures and cardiovascular morbidity and mortality. 5 Morbidity is especially prevalent for patients at least 70 years of age undergoing major thoracic, abdominal, or vascular surgery. It has been postulated that the increased metabolic demand and vascular inflammatory processes which occur in surgical procedures causes a mismatch in the supply to demand ratio of blood flow.6 This mismatch clinically presents similar to ischemic heart disease and acute coronary syndromes, and prolonging this type of hemodynamic and cardiac stress increases the risk of cardiovascular complications.

The guidelines published by the ESC and ACCF/AHA help clinicians assess cardiovascular risk and guide therapy in non-cardiac surgeries.5,6 Pharmacological risk reduction strategies, perioperative monitoring, anesthesia, and specific comorbidities are covered in these guidelines. Both guidelines recommend initiation of beta blockers in the preoperative setting (between 7 and 30 days prior to the procedure) for individuals meeting certain criteria. Beta blockers are thought to help decrease myocardial oxygen consumption by decreasing contractility, thereby reducing the mismatch between supply and demand of blood flow. These recommendations are based on a large body of literature evaluating outcomes of various beta blockers such as bisoprolol, atenolol, and metoprolol which were initiated 30 days to 1 week prior to the procedure or on the day of the procedure, depending on the study. The ESC has 3 Class I recommendations for beta blocker use while the 2009 updated ACCF/AHA guideline lists only one Class I recommendation for beta blocker use (Table 1).

Table 1. Current guideline recommendations for perioperative beta blockade.5,6

ACCF/AHA=American College of Cardiology Foundation/American Heart Association; BP=blood pressure; CAD=coronary artery disease; CEA=carotid endarterectomy; CVD=cardiovascular disease; DM=diabetes mellitus; HR=heart rate; IHD=ischemic heart disease; MI=myocardial infarction; TIA=transient ischemic attack.

Controversy

The recommendations for beta blocker use in the perioperative setting were based on several clinical trials, including 3 from the Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography (DECREASE) group of studies (Table 2).5,6 After publication of the guidelines, an investigation into the academic and scientific integrity of the DECREASE studies led to the dismissal of one of the authors, Dr. Don Poldermans, from the Erasmus Medical Center in 2011 as well as his resignation from the ESC committee.7 The Journal of the American College of Cardiology issued an official notice regarding interpretation of the data from 3 trials in which Dr. Poldermans was involved as the first or last author.11 However, the manuscripts were not retracted since they were unable to determine that all the findings were erroneous. The uncertainty, according to this notice, was reason enough to caution readers while interpreting the data. In addition to stopping the trials early (which may have exaggerated the mortality benefit) the committee found fictitious methods, databases, adjudication committees, methods of outcome establishment, absence of written consent forms, and absence of some patient records.7,12-13

Table 2: Findings from relevant DECREASE studies14-17

ACCF/AHA=American College of Cardiology Foundation/American Heart Association; CAD=coronary artery disease; ESC=European Society of Cardiology; MI=myocardial infarction.

Recent meta-analysis

In July 2013, the data for these recommendations were re-evaluated without inclusion of the data from the DECREASE trials.18 Bouri and colleagues conducted a meta-analysis of randomized, placebo-controlled trials evaluating beta blocker therapy for prevention of all-cause mortality in patients undergoing non-cardiac surgery. Secondary endpoints in this analysis were non-fatal myocardial infarction (MI), stroke, and hypotension. Eleven trials met criteria, 2 of which were from the DECREASE family of studies. Of the 9 remaining trials, there was a statistically significant increase in mortality in the group receiving beta blockers compared to placebo (relative risk [RR] 1.27, 95% confidence interval [CI] 1.01 to 1.60, p=0.04). Six trials met inclusion for the secondary endpoints. Treatment with beta-blockers significantly reduced non-fatal MI compared to placebo (RR 0.73, 95% CI 0.61 to 0.88, p=0.001), but increased the risk of stroke (RR 1.73, 95% CI 1.00 to 2.99, p=0.05) and had a significantly higher incidence of hypotension compared to placebo (15.2% vs. 10.0%, RR 1.51, 95% CI 1.37 to 1.67, p<0.00001). Conversely, the 2 DECREASE studies showed a nonsignificant decrease in mortality (RR 0.42, 95% CI 0.15 to 1.23, p=0.11) and MI (RR 0.21, 95% CI 0.03 to 1.61, p=0.13). The DECREASE I study showed a nonsignificant increase in risk of stroke (RR 1.33, 95% CI 0.33 to 5.93, p=0.71). The results from the DECREASE studies were significantly different from the remaining 9 trials in terms of mortality but not stroke or MI.

The authors concluded that the initiation of beta blockers preoperatively increases mortality by 27%, which is a new finding after removal of the DECREASE family of studies.18 The authors further suggest that the guidelines be retracted and that any recommendations on perioperative beta blocker use be based solely on the well-designed, secure randomized-controlled trials.

Clinical Application

The ESC and ACCF/AHA guidelines have slightly different recommendations regarding the perioperative use of beta blockers for non-cardiac surgery. 5,6 Three recommendations are similar – patients who are already taking beta blockers should remain on their therapy preoperatively, high-dose initiation of beta-blockers is not recommended without titration, and titration should be based on heart rate and arterial pressure. However, the other recommendations for beta blockers are different, and the recent controversy regarding the data from the DECREASE trials potentiate the confusion for clinicians deciding whether or not to initiate a beta blocker in their patients.

In the recent meta-analysis excluding the DECREASE trials, mortality, stroke, and hypotension were significantly increased in patients taking beta blockers compared to those taking placebo. Nonfatal MIs were decreased regardless of the DECREASE study data. These results reflect the data from the largest trial included in the meta-analysis, in which beta blockers initiated on the day of the procedure were associated with decreased nonfatal MI, at the expense of increased mortality, stroke, and hypotension.1 Given the variability in the methods for the relevant trials (for further discussion on this data, refer to the 2008 FAQ), initiation of beta blockers in the perioperative setting should be carefully considered given the individual patient’s risk factors and surgical risk.4 Maintaining beta blocker therapy in those already stabilized on beta blocker therapy seems to be the most appropriate recommendation at this time.

In a joint statement, both the ACCF/AHA and ESC have indicated their intention to update the 2009 guidelines for perioperative cardiac care, and recommend that beta blocker initiation prior to surgery not be routine practice, but should be decided on a case-by-case basis.19

References :

1. Devereaux PJ, Yang H, Yusuf S, et al; POISE Study Group. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. 2008;371(9627):1839-1847.

1. Kaafarani H, Atluri PV, Thornby J, Itani K. ß-blockade in noncardiac surgery: outcome at all levels of cardiac risk. Arch Surg. 2008;143(10):940-944.

3. Bangalore S, Wetterslev J, Pranesh S, Sawhney S, Gluud C, Messerli FH. Perioperative ß blockers in patients having non-cardiac surgery: a meta-analysis. Lancet. 2008;372(9654):1962-1976.

4. Are perioperative beta blockers effective in preventing cardiovascular complications in non-cardiac surgery? Frequently Asked Questions. http://dig.pharm.uic.edu/faq/non-cardiac.aspx. Published December 2008. Accessed September 4, 2013.

5. Fleisher LA, Beckman JA, Brown KA, et al. 2009 ACCF/AHA focused update on perioperative beta blockade incorporated into the ACC/AHA 2007 guidelines on perioperative cardiovascular evaluation and care for noncardiac surgery: a report of the American college of cardiology foundation/American heart association task force on practice guidelines. Circulation. 2009;120(21):e169-e276.

6. Poldermans D, Bax JJ, Boersma E, et al; Task Force for Preoperative Cardiac Risk Assessment and Perioperative Cardiac Management in Non-cardiac Surgery; European Society of Cardiology (ESC). Guidelines for pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery. Eur Heart J. 2009;30(22):2769-2812.

7. Husten L. Prominent Dutch Cardiovascular Researcher Fired for Scientific Misconduct. http://www.forbes.com/sites/larryhusten/2011/11/17/prominent-dutch-cardiovascular-researcher-fired-for-scientific-misconduct/. Updated November 17. 2011. Accessed September 4, 2013.

8. Lange RA, Hillis LD. Cardiovascular Testing. In: Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=7969194. Accessed September 4, 2013.

9. Alcock RF, Kouzios D, Naoum C, Hillis GS, Brieger DB. Perioperative myocardial necrosis in patients at high cardiovascular risk undergoing elective non-cardiac surgery. Heart. 2012;98(10):792-798

10. Naughton C, Feneck RO. The impact of age on 6-month survival in patients with cardiovascular risk factors undergoing elective non-cardiac surgery . Int J Clin Pract. 2007;61(5):768-776.

11. Notice of Concern. J Am Coll Cardiol. 2012;60(25):2696-2697.

12. Montori VM, Devereaux PJ, Adhikari NK, et al. Randomized trials stopped early for benefit: a systematic review. JAMA. 2005;294(17):2203-2209.

13. Erasmus Medical Center Follow-Up Investigation Committee, 2012. Report on the 2012 follow-up investigation of possible breaches of academic integrity. http://cardiobrief.files.wordpress.com/

2012/10/integrity-report-2012-10-english-translation.pdf. Published September 30, 2012. Accessed September 4, 2013.

14. Poldermans D, Schouten O, Bax J, Winkel TA. Reducing cardiac risk in non-cardiac surgery: evidence from the DECREASE studies. Eur Heart J Suppl. 2009;11(Suppl A):A9-A14.

15. Poldermans D, Boersma E, Bax JJ, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med. 1999;341(24):1789-1794.

16. Dunkelgrun M, Boersma E, Schouten O, et al; Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. Bisoprolol and fluvastatin for the reduction of perioperative cardiac mortality and myocardial infarction in intermediate-risk patients undergoing noncardiovascular surgery: a randomized controlled trial (DECREASE-IV). Ann Surg. 2009;249(6):921-926.

17. Poldermans D, Bax JJ, Schouten O, et al; Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echo Study Group. Should major vascular surgery be delayed because of preoperative cardiac testing in intermediate-risk patients receiving beta-blocker therapy with tight heart rate control? J Am Coll Cardiol. 2006;48(5):964-969.

18. Bouri S, Shun-Shin MJ, Cole GD, Mayet J, Francis DP. Meta-analysis of secure randomised controlled trials of β-blockade to prevent perioperative death in non-cardiac surgery. Heart. 2013. doi: 10.1136/heartjnl-2013-304262.

19. Joint Statement: issued by the American College of Cardiology, American Heart Association and the European Society of Cardiology [press rele . http://www.escardio.org/about/press/press-releases/pr-13/Pages/joint-statement-perioperative-guidelines.aspx. Updated August 5, 2013. Accessed September 4, 2013.

October 2013

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What comparative data are available for biologics in the setting of rheumatoid arthritis?

Introduction

Rheumatoid arthritis (RA) is a relatively common autoimmune disorder that can cause significant complications, disability, and cost burden to those it affects.1 According to the Centers for Disease Control and Prevention the prevalence of RA is estimated to range from 0.5% to 1%.2 Data from the US ambulatory health care system, 2001 to2005, estimated that 1.5 million US adults have RA. Although the exact cause of RA is unknown, advances in the understanding of the disease have led to many novel treatments that are efficacious and thus, greatly decrease morbidity and improve quality of life.

In 2012, the American College of Rheumatology (ACR) released an update to the 2008 recommendations for the use of Disease-Modifying Antirheumatic Drugs (DMARDs) and biologic agents in the treatment of rheumatoid arthritis.3 This update evolved largely from the rapidly increasing knowledge in RA management and treatment. The recommendations for the use of DMARDs and biologic agents are largely framed in terms of clinical scenario. When determining indications for starting a biologic agent, the clinician needs to quantify disease duration, determine disease activity, and identify presence or absence of poor prognostic features (defined in the guidelines) to reach the appropriate recommendation.

The ACR guidelines largely group the biologic agents into 2 categories: anti-tumor necrosis factor (TNF) biologics and non-TNF biologics.3 The recommendations are based on these 2 categories, and seldom refer to individual agents. The guidelines recommend that patients with early RA and features of poor prognosis (e.g., functional limitation, extraarticular disease, positive rheumatoid factor, etc.) receive an anti-TNF biologic agent. An additional option is infliximab used in combination with methotrexate (MTX). In patients with established RA and moderate or high disease activity who failed to respond to 3 months of treatment with either MTX monotherapy or combination DMARDs, the guidelines recommend adding or switching to an anti-TNF biologic, abatacept, or rituximab.If moderate or high disease activity persists after reassessment at 3 months, due to a lack or loss of benefit, it is recommended that therapy be switched to another anti-TNF biologic or a non-TNF biologic. In patients who fail to respond to a non-TNF biologic, the guidelines recommend that therapy be switched to another non-TNF biologic or an anti-TNF biologic.

Despite guidelines from the ACR, the lack of recommendations for specific agents leaves much interpretation to the clinician. Presented below are summaries of recent trials that will add to the available literature and ultimately help clinicians more effectively manage therapy in patients with RA.

Comparative studies of biologics for RA

In the AMPLE trial (abatacept vs. adalimumab for RA), Weinblatt and colleagues compared the efficacy and safety of the anti-TNF, adalimumab, with a T-cell costimulation modulator.4 AMPLE is a 2-year, prospective, randomized, investigator-blinded, noninferiority study in biologic treatment-naïve patients with an inadequate response to MTX. Patients had a confirmed diagnosis of RA for ≤5 years with currently active disease, defined as a score of 3.2 or greater on the Disease Activity Score in 28 joints using C-reactive protein level (DAS28-CRP). Patients were then randomly assigned to receive 125 mg abatacept, administered subcutaneously (SC) once weekly, or 40 mg adalimumab SC biweekly. Patients in both groups concomitantly received MTX between 15 and 25 mg weekly (or at least ≥7.5 mg weekly in patients with documented intolerance to higher doses). Additionally, patients were allowed to receive hydroxychloroquine or sulfasalazine; other DMARDs were not allowed. The primary study endpoint was the ACR 20% improvement response (ACR20) at 1 year. Notable secondary end points included a 50% and 70% level of improvement according to the ACR response criteria (ACR50 and ACR70) and changes in the DAS28-CRP score. This trial is still ongoing and only the first year results, reported here, are available.

A total of 646 patients were randomized to the treatment groups.4 A similar proportion of patients completed 12 months of treatment in each group (86.2% receiving abatacept and 82% receiving adalimumab). Baseline demographics were similar between treatment groups. Mean age was 51.4 and 51 years in the abatacept and adalimumab groups, respectively. The mean DAS28-CRP score was 5.5 and the percentage of patients using concomitant corticosteroids, sulfasalazine, and hydroxychloroquine were similar in both groups. At 1 year, 64.8% of patients in the abatacept group and 63.4% in the adalimumab group demonstrated an ACR20 response. The estimated difference between groups was 1.8% (95% confidence interval (CI) -5.6% to 9.2%), which satisfied the noninferiority criteria. For the secondary end points of ACR50, ACR70, and changes in the DAS28-CRP score, there were no statistically significant differences found between the abatacept and adalimumab groups.

Adverse events were similar between the treatment groups.4 In the abatacept and adalimumab groups, the incidence of serious adverse events was10.1% and 9.1%, respectively, and the rate of serious infection was 2.2% and 2.7%, respectively. Injection site reactions occurred in 9.1% of patients in the adalimumab group compared to 3.8% patients in the abatacept group (p=0.006). Discontinuations due to adverse events occurred in 3.5% of patients treated with abatacept and 6.1% with adalimumab. One death occurred in the abatacept group and was considered to be unrelated to the study treatment.

The authors concluded that abatacept and adalimumab have comparable efficacy when used in patients with RA on background MTX therapy over 1 year of treatment. These results demonstrate that abatacept and adalimumab are comparable in terms of efficacy in patients with RA maintained on MTX. The safety profiles of these medications also appear similar, with exception of injection site reactions which occurred more frequently in adalimumab treated patients.

Another recent study by Gabay and colleagues compared monotherapy with either tocilizumab or adalimumab (ADACTA) in RA patients treated for ≥6 months and who were intolerant to MTX therapy or were deemed inappropriate for continued treatment by the study investigator.5

This was a randomized, double-blind, parallel-group, superiority study that took place in 76 centers in 15 countries.Patients were ineligible if they had a previous history of biologic DMARD use. All non-biologic DMARDs were stopped 2 weeks or more before baseline, except for leflunomide, which was stopped 12 weeks or more before baseline. Patients were randomly assigned to receive tocilizumab 8 mg/kg intravenously every 4 weeks or adalimumab 40 mg SC every 2 weeks plus matching placebos. The primary endpoint was change in disease activity score using 28 joints (DAS28) from baseline to week 24. This study also looked at the secondary endpoints of ACR20, 50, and 70 responses, as well as achieving a DAS28 of ≤3.2 and ≤2.6.

After randomization, 325 patients were included in the intention-to-treat population.5 Baseline characteristics were similar between groups. In the adalimumab and tocilizumab groups, the mean age was 53.3 and 54.4 years, respectively, while women made up 82% and 79% of the study groups, respectively. The mean DAS28 score was 6.8 in the adalimumab group and 6.7 in the tocilizumab group. At week 24, the mean change from baseline in DAS28 was significantly greater in the tocilizumab group (-3.3) compared to the adalimumab group (-1.8) (difference ‑1.5, 95% CI -1.8 to -1.1; p<0.0001). Significantly more patients in the tocilizumab group (51.5%) compared to the adalimumab group (19.8%) had a DAS28 score of 3.2 or less (p< 0.001). Similarly, 39.9% of patients in the tocilizumab group and 10.5% of patients in the adalimumab group achieved a DAS28 score of <2.6 (p< 0.0001). Other secondary endpoints of ACR20, 50, and 70 responses were all statistically significantly in favor of tocilizumab compared to adalimumab.

Overall, 83% of patients in the adalimumab group and 82% of patients in the tocilizumab group reported at least 1 adverse event.5 Serious adverse event rates in patients who received adalimumab compared to those who received tocilizumab were 10% and 12%, respectively, with infection being the cause in 4% in each group. Two deaths occurred during the study, both in the tocilizumab group. One death was possibly related to tocilizumab, but the cause of death was unknown.

The authors of the ADACTA study concluded that tocilizumab monotherapy was superior to adalimumab monotherapy for RA patients who were not on background MTX therapy. Although this trial only looked at 24 weeks of therapy, the results of ADACTA seem to suggest that tocilizumab is superior to adalimumab when used as monotherapy for RA for the endpoints described above. Using these agents as monotherapy is an important consideration here, as many RA patients received dual therapy with MTX therapy and a biologic agent.

Placebo-controlled studies with indirect comparisons to biologics

Schiff et.al. conducted a phase III, double-blind, double-dummy, placebo-controlled trial comparing abatacept and infliximab, anti-TNF biologic, to placebo in patients with active RA and an inadequate response to MTX.6 Patients were excluded if they had any history of using abatacept or an anti-TNF agent. The primary endpoint was a reduction in disease activity as measured by DAS28 score with abatacept vs. placebo at 6 months. Secondary endpoints included mean reduction in DAS28 with infliximab vs. placebo at 6 months, mean reduction in DAS28 with abatacept vs. infliximab at 6 months and 1 year, and ACR20, 50 and 70 responses.

A total of 431 patients were randomized and treated with abatacept (n=156), infliximab (n=165), or placebo (n=110).6 At baseline, patients were receiving a mean MTX dose of 16.3 to 16.6 mg weekly for a mean duration of 18.3 to 23.7 months. There was a significantly greater reduction in DAS28 with abatacept vs. placebo at day 197 (-2.53 vs. -1.48, p<0.001). Infliximab also showed significant reductions in DAS28 when compared to placebo at day 197 (-2.25 vs. -1.48, p<0.001). Additionally, based on the DAS28 scores, the relative efficacy of abatacept compared to infliximab was similar. A greater reduction in DAS28 was seen with abatacept (-2.88 vs. ‑2.25), when compared to infliximab at day 365 with an estimated difference of -0.62 (95% CI -0.96 to -0.29). ACR20, 50, and 70 responses were statistically significantly greater in both abatacept and infliximab groups when compared to placebo at day 197. When compared to each other, abatacept and infliximab had similar responses. However, after 365 days of treatment, ACR20 responses were higher with abatacept than with infliximab (72.4% vs. 55.8%, difference of 16.7%, 95% CI 5.5 to 27.8) and numerically higher in the abatacept group in regards to ACR50 and 70 responses (45.5% vs. 36.4% and 26.3% vs. 20.6%, respectively).

Serious adverse events occurred in 9.6% of patients in the abatacept group and 18.2% of patients in the infliximab group during the entire 12-month study period.6 Discontinuations due to serious adverse events also occurred less with abatacept than infliximab (2.6% vs. 3.6%, respectively).

Although this study reports results between the 2 agents that seem to favor abatacept over infliximab, the study was not designed to make these head-to-head comparisons.6 Therefore, drawing conclusions about which agent performed better in this study cannot be done with certainty. However, this study provides clinicians with information on an anti-TNF biologic and a non-TNF biologic studied in the same patient population under the same study design.

Tofacitinib, a novel oral biologic agent for RA, was studied in similar fashion to ATTEST. This trial, know as ORAL, was a 12-month, phase III trial comparing tofacitinib or adalimumab to placebo in RA patients who were receiving stable doses of MTX.7 Eligible patients had active RA and were receiving 7.5 to 25 mg of MTX weekly with an incomplete response. Key exclusion criteria were current treatment with other antirheumatic agents (including biologic agents), prior treatment with adalimumab, or lack of response to prior anti-TNF biologics. Notable primary endpoints included ACR20 responses at month 6 and the percentage of patients at month 6 who had a DAS28 of less than 2.6.

Patients were randomized to 1 of 5 regimens: 5 mg of tofacitinib twice daily, 10 mg tofacitinib twice daily, 40 mg of adalimumab SC once every 2 weeks, placebo for 3 or 6 months followed by 5 mg tofacitinib twice daily, and placebo for 3 or 6 months followed by 10 mg of tofacitinib twice daily.7 A total of 717 patients were included in the analysis, with 556 patients completing the 12-month study. Demographic data were similar between groups at baseline, with the mean age ranging from 51.9 to 55.5 years. The percentage of patients receiving concomitant glucocorticoids ranged from 59.6% to 73.2%; doses of MTX at baseline in each group were not reported. At 6 months, a significantly greater percentage of patients receiving an active treatment had ACR20 responses than placebo: 51.5% in the 5 mg tofacitinib group, 52.6% in the 10 mg group, 47.2% in the adalimumab group, and 28.3% in the placebo group (p<0.001 for all comparisons). The percentage of patients achieving a DAS28 score of less than 2.6 was also significantly greater in the active treatment groups vs. placebo at month 6.

The rates of serious adverse events were numerically higher with tofacitinib 5 mg, 10 mg, and adalimumab than with placebo during months 0 to 3 (5.9%, 5.0%, 2.5%, 1.9%, respectively).7 Additionally, during months 6 to 12, the rates of serious adverse events for tofacitinib 5 mg, 10 mg, and adalimumab were 4.9%, 3.0%, and 3.4%, respectively.

This study included adalimumab, an anti-TNF biologic with established efficacy for RA. Although there were no direct comparisons between active drugs, the study allowed for an estimation of the relative efficacy and safety of tofacitinib; however, any conclusions drawn should be done with caution.

Conclusion

Although the updated ACR guidelines do not recommend specific agents, the comparisons made in AMPLE and ADACTA shed some much needed light on which agent may be preferred. AMPLE seems to show that adalimumab and abatacept have comparable efficacy results, and the decision to select one over the other could therefore be made on other important considerations such as success or failure with prior treatments. The ADACTA study provides similar evidence with tocilizumab and adalimumab. The ATTEST and ORAL standard trials are not designed to compare biologics head-to-head; they do provide an estimation of comparable efficacy and safety. Overall these studies add tremendous value to the available evidence for RA treatment, especially since the ACR guidelines lack recommendations of specific agents. Biologic agents represent a fast-growing segment of the pharmaceutical market. Clinicians must be aware of the published data to make decisions based on the populations studied, concurrent medications used in the trials, as well as safety and cost.

References

1. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365(23): 2205-2219.

2. Centers for Disease Control and Prevention. http://www.cdc.gov/arthritis/basics/rheumatoid.htm#5. Updated November 19, 2012. Accessed August 13, 2013.

3. Singh J, Furst D, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64(5): 625-639.

4. Weinblatt ME, Schiff M, Valente R, et al. Head-to-head comparison of subcutaneous abatacept vs. adalimumab for rheumatoid arthritis: findings of a phase IIIb, multinational, prospective, randomized study. Arthritis Rheum. 2013;65(1):28-38.

5. Gabay C, Emery P, van Vollenhoven R, et al. Tocilizumab monotherapy vs. adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet. 2013;381(9877):1541-1550.

6. Schiff M, Keiserman M, Codding C, et al. Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis. 2008;67(8):1096-1103.

7. van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus. placebo in rheumatoid arthritis. N Engl J Med. 2012;367(6):508-519.

Written by: Alex Luli, PharmD

PGY-1

NorthShore University HealthSystem

October 2013

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Is it necessary to bridge with heparin in high-risk patients before pacemaker or defibrillator surgery?

Introduction

Throughout the world approximately 1.25 million pacemakers and 410,000 implantable cardioverter defibrillators (ICDs) are placed each year.1,2 Between 14% and 35% of patients undergoing one of these procedures is receiving anticoagulation therapy.1,3-6 Clinicians must assess each patient receiving anticoagulation therapy, weighing the bleeding risk associated with continued therapy versus thrombotic risk of discontinuing therapy, prior to the procedure. There is no consensus on whether it is better for patients to continue warfarin therapy perioperatively or discontinue warfarin and bridge patients with heparin.

The current American College of Chest Physicians (ACCP) 2012 guidelines suggest that patients with a mechanical heart valve, atrial fibrillation, or recent venous thromboembolism (VTE) at high risk for thromboembolism receive bridging with anticoagulation instead of no bridging during interruption of vitamin K antagonist (VKA) therapy (Grade 2C).7 The Table below shows the ACCP guidelines definition for high-risk patients. For patients that discontinue warfarin therapy prior to surgery, the guidelines suggest stopping VKAs approximately 5 days before surgery and initiating a bridging agent.7

Table. Suggested risk stratification for perioperative thromboembolism.7

Adapted from: Chest. 2012;141(2 Suppl):e326S-e350S.

CHADS2, Congestive heart failure, Hypertension, Age >75 years, Diabetes mellitus, and Stroke or transient ischemic attack; VTE, venous thromboembolism.

Although the ACCP guidelines recommend bridging with heparin in high-risk patients over no bridging, there have been a number of published studies that show there is a decreased risk of device-pocket hematomas in high-risk patients if they do not receive bridging and simply continue uninterrupted warfarin therapy. A recent meta-analysis by Feng et al analyzed 6 different studies, 4 of which were retrospective, that compared oral anticoagulation continuation with heparin bridging among high-risk patients undergoing implantation of cardiac rhythm devices.8 The endpoints of the meta-analysis were pocket hematoma, severe hematoma requiring drainage/revision, thromboembolic events, and length of hospital stay. There was a statistically significant reduction in pocket hematoma (odds ratio [OR] 0.29; 95% confidence interval [CI], 0.17 to 0.49; P <0.00001) and hematoma drainage/revision (OR 0.15; 95% CI, 0.04 to 0.54; P=0.004) in the oral anticoagulation continuation group compared to the heparin bridging group. No statistically significant differences in thromboembolic events were seen between the 2 groups (P= 0.48).8 Another study, not included in the meta-analysis, analyzed 101 patients that were randomized to receive heparin bridging or continue oral anticoagulation prior to pacemaker or implantable cardiac defibrillator surgery.9 The authors reviewed hemorrhagic and thromboembolic complications at discharge, day 15, and day 45. In the heparin bridging group 4 of 51 patients (7.8%) had a pocket hematoma compared with 4 of 50 (8%) in the oral anticoagulation group (P=1.00). No patient in either group experienced a thromboembolic event. 9 Given the limited available data, a large, randomized trial was recently conducted to assess the need for heparin bridging in high-risk patients on VKAs.

Literature Review

The BRUISE CONTROL Trial—uninterrupted warfarin versus heparin bridging

In a study published by Birnie et al in the New England Journal of Medicine, patients who had uninterrupted warfarin therapy prior to pacemaker or defibrillator surgery were compared to those who received bridging with heparin after warfarin discontinuation.1 The study was a multicenter, single-blind, randomized, controlled trial. High-risk patients (defined as an annual risk of VTEs ≥ 5%) were randomly assigned to continue warfarin therapy or to bridge with heparin. Patients were excluded if they had a history of noncompliance with medications, heparin-induced thrombocytopenia, or a device infection. Patients that continued warfarin had a goal international normalized ratio (INR) of less than 3.0 on the day of surgery (actual median INR of 2.3). The only exception was in patients who had one or more mechanical heart valves; they had a goal INR of less than 3.5. In patients who did not continue warfarin, the drug was stopped 5 days prior to surgery and heparin, either low molecular weight or unfractionated heparin, was started 3 days prior to surgery.

The primary outcome of the study was device-pocket hematoma that required surgery, with either prolonged hospitalization or interruption of anticoagulation therapy. Power was estimated at 80%, based on a sample size of 984 patients and an expected 30% relative risk reduction in the primary outcome. Two interim analyses were planned. The study was terminated after the second interim analysis. A total of 681 patients underwent randomization, 659 underwent surgery and completed follow-up, but all 681 were included in the final analysis. The results of the study showed that patients who continued warfarin therapy were at a lower risk for developing device pocket hematoma compared with those who received bridging with heparin. Clinically significant device-pocket hematoma occurred in 12 of 343 patients (3.5%) in the uninterrupted warfarin group, as compared with 54 of 338 patients (16.0%) in the heparin-bridging group (relative risk, 0.19; 95% CI, 0.10 to 0.36; P <0.001). Both components of the primary outcomes (prolonged hospitalization and interruption of anticoagulation) were significant in favor of continued warfarin therapy. Among the secondary outcomes, a significant difference was seen between the 2 groups for one category; patients continuing warfarin therapy had higher self-reported patient satisfaction scores than the heparin bridging group (P<0.001). Some of the other secondary outcomes were death from any cause, pneumothorax, transient ischemic attack, thromboembolic events, and surgical complications, none of which were statistically different. During the study there were 4 deaths, all of which were in the continued warfarin group. Three of the deaths occurred before the surgery was performed, and the fourth occurred 10 days after surgery due to end-stage heart failure.

Uninterrupted dabigatran versus uninterrupted warfarin

Because of the recent availability of new oral anticoagulants, such as dabigatran, the question may come up more frequently about how to manage patients perioperatively if they are on one of these newer agents. A retrospective study published by Jennings et al in May 2013 compared uninterrupted dabigatran with uninterrupted warfarin in patients undergoing cardiovascular implantable electronic device (CIED) surgery.10 Patients were excluded from the review if they received unfractionated or low molecular weight heparin. One of 48 patients (2.1%) with uninterrupted dabigatran experienced a bleeding complication (pericardial effusion) compared with 9 of 195 patients (4.6%, pocket hematoma) with uninterrupted warfarin (P=0.69). In addition, 5 of the 10 patients who experienced a bleeding complication were also taking concomitant antiplatelet therapy. Like the studies cited above on continued warfarin or heparin bridging, this study also did not observe any VTE complications in either group. The study concluded that there is a similar risk of bleeding complications during CIED implantation with uninterrupted dabigatran or warfarin. However, it is important to note that the study was retrospective, comparing 2 separate cohorts.

Discussion

Although there is building evidence for not interrupting warfarin therapy prior to cardiac surgery in high-risk patients, it is still important to consider the individual patient before deciding on the treatment plan. One thing that is important to note is the definition of “high-risk”. There is not a universal way that risk was defined in the above studies, and there is also some room for subjective interpretation when placing a patient in a specific category. According to the ACCP guidelines, high-risk patients have an annual risk of stroke of >10%, while the study by Birnie et al defined high-risk as having an annual stroke risk of at least 5%.1,7 Another aspect to consider is the type of surgery the patient will undergo. The studies discussed in this article specifically looked at patients undergoing pacemaker or cardiac defibrillator surgeries, while there are still a number of other procedures patients may undergo that may have different associated bleeding or thrombotic risks. Perioperative management of anticoagulation during these procedures requires a separate analysis.

Summary

Based on the available data, a safe alternative for certain high-risk patients is to undergo pacemaker or defibrillator surgery without interruption of warfarin therapy. High-risk patients who continued warfarin therapy experienced less device-pocket hematomas than patients who received bridging with heparin. The risk versus benefits of continuing warfarin therapy should be considered for each patient.

References

1. Birnie DH, Healey JS, Wells GA, et al. Pacemaker or defibrillator surgery without interruption of anticoagulation. N Engl J Med. 2013;368(22):2084-2093.

2. Mond HG, Proclemer A. The 11th world survey of cardiac pacing and implantable cardioverter-defibrillators: calendar year 2009 — a World Society of Arrhythmia’s project. Pacing Clin Electrophysiol. 2011;34(8):1013-1027.

3. Bardy GH, Lee KL, Mark DB, et al. Amiodarone or an implantable cardioverter–defibrillator for congestive heart failure. N Engl J Med. 2005;352(3):225-237.

4. Greenspon AJ, Hart RG, Dawson D, et al. Predictors of stroke in patients paced for sick sinus syndrome. J Am Coll Cardiol. 2004;43(9):1617-1622.

5. Nielsen JC, Thomsen PE, Højberg S, et al. A comparison of single-lead atrial pacing with dual-chamber pacing in sick sinus syndrome. Eur Heart J. 2011;32(6):686-696.

6. Tang ASL, Wells GA, Talajic M, et al. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med. 2010;363(25):2385-2395.

7. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy. Chest. 2012;141(2 Suppl):e326S-e350S.

8. Feng L, Li Y, Li J, Yu B. Oral anticoagulation continuation compared with heparin bridging therapy among high risk patients undergoing implantation of cardiac rhythm devices: meta-analysis. Thromb Haemost. 2012;108(6):1124-1131.

9. Tolosana J, Berne P, Mont L, et al. Preparation for pacemaker or implantable cardiac defibrillator implants in patients with high risk of thromboembolic events: oral anticoagulation or bridging with intravenous heparin? A prospective randomized trial. Eur Heart J. 2009;30(15):1880-1884.

10. Jennings JM, Robichaux R, McElderry HT, et al. Cardiovascular implantable electronic device implantation with uninterrupted dabigatran: comparison to uninterrupted warfarin. J Cardiovasc Electrophysiol. 2013 Jun 17. doi: 10.1111/jce.12214.

Written by: Whitney Dickson, PharmD

PGY-I

College of Pharmacy

University of Illinois at Chicago

October 2013

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