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Sep 2015 FAQs


Can intermittent proton pump inhibitor dosing be used in acute upper gastrointestinal bleeding?

What data support the safety and efficacy of the intravenous P2Y12 inhibitor cangrelor?

Is the recently updated cholesterol guideline cost-effective and better at identifying at-risk patients than the previous ATP III guideline?


Can intermittent proton pump inhibitor dosing be used in acute upper gastrointestinal bleeding?


Acute upper gastrointestinal bleeding (UGIB) is stratified into variceal and nonvariceal bleeding.1  The annual rate of nonvariceal UGIB has been reported to occur at a rate of 48 to 160 cases per 100,000 people.  However, hospitalization incidence rates related to UGIB and peptic ulcer bleeding in the United States (US) have decreased from 2001 to 2009.2  During this same time period, the age- and sex-adjusted case fatality rate for UGIB decreased from 3.61% in 2001 to 2.87% in 2009. Nonvariceal UGIB is most commonly caused by peptic ulcer bleeding (31% to 67% of all cases), but erosive disease, esophagitis, malignancy and Mallory-Weiss tears are other identified etiologies.1  Nonvariceal UGIB is most prevalent in the elderly as the majority of patients are over 60 years of age.  Helicobacter pylori infection and use of nonsteroidal anti-inflammatory drugs, aspirin, and antithrombotic drugs are known risk factors for peptic ulcer bleeding.  The risk of rebleeding and mortality is variable based on patient characteristics and individual prognosis.  Patients with increasing age, severe comorbidities, hemodynamic instability on presentation, and rebleeding are at a higher risk for mortality after a nonvariceal UGIB.  Rebleeding after endoscopic hemostatic therapy (EHT) and acid-suppressive therapy occurs in about 10% of the population. The predictors for recurrent bleeding are mostly related to the characteristics of the ulcer and extent of bleeding.3  Active bleeding, hemodynamic instability, and ulcer size have been independently identified as risk factors for rebleeding in patients with high-risk ulcers undergoing EHT.4

Guideline recommendations

The International Consensus Upper Gastrointestinal Bleeding Conference Group and the American College of Gastroenterology have published recent guidelines for the management of nonvariceal UGIB.5,6  Both guidelines strongly recommend EHT for patients with high-risk stigmata, active bleeding or a visible vessel in ulcer bed, and make a conditional recommendation for those with an adherent clot.  Patients with a clean base ulcer or a flat, pigmented spot do not require EHT.  After successful EHT, high-dose intravenous (IV) proton pump inhibitor (PPI), 80 mg bolus followed by 8 mg/h continuous infusion, is strongly recommended to promote ulcer healing and reduce the risk for rebleeding, surgery, and mortality.  Both guidelines acknowledge that there is evidence that directly compares high-dose IV therapy with intermittent dosing after EHT.  However, they do not make a recommendation that alternative PPI doses are equivalent mostly due to issues related to the trial design and underpowered results of those comparative studies.  The international guidelines do provide a caveat that for patients in whom high-dose IV therapy is not feasible, lower IV doses or high-dose oral therapy can be considered, particularly in the Asian population which has more data to support intermittent therapy.5

Literature review

As eluded to in the guidelines, the published trials that compare various PPI dosing regimens are primarily smaller studies that are underpowered to detect a difference between groups.5,6 Additionally, there is a wide variety of dosing regimens used in trials that qualify as intermittent PPI therapy.  Therefore, the reliance on meta-analyses is especially important in examining if there is adequate evidence to support lower doses of PPIs than the guideline-recommended dosing (80 mg bolus followed by 8 mg/h continuous infusion for the first 72 hours).  Since the publication of these guidelines, there have been 3 meta-analyses published examining alternative PPI regimens.7-9

A 2014 meta-analysis by Sachar and colleagues sought to determine whether intermittent PPI therapy was non-inferior to guideline-recommended PPI therapy.7  Randomized controlled trials (RCT[s]) comparing the 2 PPI regimens were included if patients had UGIB with a high-risk stigmata (active bleeding, visible vessels, or adherent clot) and underwent successful EHT. There were no restrictions on regimens included in the intermittent PPI therapy intervention; studies used a variety of doses, frequencies, and routes of administration (both IV and oral).  The primary objective was to examine recurrent bleeding at 7 days.  Other outcomes that were analyzed included: recurrent bleeding at 3 days and 30 days, mortality, need for various types of interventions, red blood cell (RBC) transfusions, and length of hospitalization.  The primary analysis was analyzed with a non-inferiority design.  Intermittent PPI regimen would be considered non-inferior if the upper boundary of the 95% confidence interval (CI) for the absolute risk difference between groups did not exceed the non-inferiority margin of 3%. Thirteen RCTs comprising 1691 patients were included in the analysis comparing intermittent PPI versus guideline-recommended continuous IV infusion.  The risk ratio (RR) of recurrent bleeding within 7 days was 0.72 (upper boundary of 95% CI, 0.97) and the absolute risk difference was -2.64% (upper boundary of 95% CI, -0.28%).  This met the predefined definition of non-inferiority and suggests that intermittent PPI therapy has advantages over guideline-recommended therapy as the upper boundary of the absolute risk difference fell below 0%.  However, a standard superiority analysis was performed using 2-sided 95% CIs which showed no difference between therapies (RR, 0.74; 95% CI, 0.52 to 1.06).  Secondary outcomes of rebleeding at 30 days and 3 days also met non-inferiority criteria with an absolute risk difference of -0.97 (upper boundary of 95% CI, 1.49) and -2.36 (upper boundary of 95% CI, 0.17), respectively.  Non-inferiority was also demonstrated for mortality and surgery or radiologic intervention.  Overall, these results suggest that intermittent PPI therapy is non-inferior to the current guideline-recommended regimen.  The authors do note that because a wide variety of dosing regimens were included in the intermittent dosing group, it is difficult to recommend a specific regimen that is most appropriate.  However, they suggest that high-dose PPIs given at least twice daily, given either IV or orally, may be an effective approach for patients with high-risk stigmata.

A 2013 Cochrane review by Neumann and colleagues compared the effects of various PPI doses and routes of administration in patients with endoscopically-confirmed acute bleeding from a peptic ulcer.8  The main analysis aimed to evaluate if there were any differences between high-dose PPI to other PPI regimens on mortality, rebleeding, surgical intervention, further EHT, length of hospital stay, or transfusion requirements.  High-dose PPIs were defined as ≥600 mg over 72 h (for reference, the guideline-recommended regimen delivers 656 mg over 72 h).  Twenty-two RCTs comprising 2388 patients were included in the analysis; however, only 13 RCTs were eligible for the main analysis of high-dose PPI versus lower dose PPI (<600 mg over 72 h). The evidence in the main analysis was rated as low quality and it was determined that the RR for mortality (RR, 0.85; 95% CI, 0.47 to 1.54), rebleeding (RR, 1.27; 95% CI, 0.96 to 1.67), surgery (RR, 1.33; 95% CI, 0.63 to 2.77), and further EHT (RR, 1.39; 95% CI, 0.88 to 2.18) could not exclude either a potential reduction or increase for harm for use of lower dose PPI therapy.  Overall these results show that high-dose PPI therapy is not superior to other PPI regimens in patients with peptic ulcer bleeding.  However, the authors strongly caution against the interpretation that lower dose PPI regimens are equivalent to the guideline-recommended PPI therapy.

A 2013 meta-analysis by Tsoi and colleagues approached the question of whether there is a difference in outcomes between oral and IV PPI therapy in patients with peptic ulcer bleeding.9 The meta-analysis included RCTs that recruited patients with bleeding that required EHT and compared the 2 routes with no limits on the dose.  The primary outcome was recurrent bleeding, but transfusion requirements, length of hospital stay, surgical intervention, and mortality were also evaluated.  Six RCTs comprising 615 patients were included in the analysis.  The patients included in the analysis were not exclusively those with high-risk stigmata where EHT is recommended, 26% had a clean base ulcer and 8% had a flat/red spot.  For recurrent bleeding, there was no difference in rates between groups (8.6% oral vs 9.3% IV; RR, 0.92; 95% CI, 0.56 to 1.50).  Additionally, no statistical difference was found between oral and IV PPIs for volume of blood transfusion (mean difference, -0.02 units; 95% CI, -0.29 to 0.24 units), mortality (RR, 0.88; 95% CI, 0.29 to 2.71), and surgical intervention (RR, 0.82; 95% CI, 0.19 to 3.61). The length of hospital stay was modestly, but significantly different for those receiving oral PPI therapy (mean difference, -0.74 days; 95% CI, -1.10 to -0.39 days).  Overall, the meta-analysis concluded that there were no differences between IV and oral PPI therapy in recurrent bleeding and mortality in patients with peptic ulcer bleeding. The authors acknowledged that their analysis was likely underpowered based on the number of patients included and low bleeding rate (8.9%) observed.


There are several limitations that should be considered in evaluating the data from the meta-analyses.  In all of the meta-analyses, many of the trials included have methodological issues that could have introduced bias.7-9  The majority of trials (8 of 13 in Sachar et al, 19 of 22 in

Neumann et al, and 6 of 6 in Tsoi et al) were not adequately blinded. Additionally there was an unclear risk of bias noted in the allocation consignment, as the majority of the trials did not report their allocation methods, potentially introducing selection bias.7,8  The patients included in each meta-analysis did vary as well. The analysis by Sachar and colleagues included trials that only evaluated patients who had a high-risk stigmata for which EHT is indicated per the current guidelines.7  Patients with ulcers that have a clean base or flat spots were not included in the analysis.  This is an important consideration as physiologically fewer complications are expected in patients at low-risk for bleeding. The other meta-analyses evaluated trials which included patients that had a flat pigmented spot or clean base ulcer.8,9  Additionally, there were a variety of different therapies used to achieve hemostasis in EHT.7-9  Use of epinephrine alone is significantly less effective in preventing rebleeding and is not recommended by the guidelines.5,6 The variety of different modalities used in the RCTs, including use of epinephrine only, can impact the expected rebleeding rate and may limit external validity.

The external validity of these results to the US population has also been questioned.7,8  The majority of trials that have compared continuous versus intermittent PPI dosing have been conducted in Asia.  As the majority of PPIs are metabolized through cytochrome P450 (CYP) 2C19, certain phenotypes result in differences in PPI elimination and plasma concentrations.10 The healing rates of peptic ulcers can be affected by a patient’s genotype.  It has been noted that intermediate and poor metabolizers are more likely to respond to PPIs than extensive metabolizers.  The Asian population has a greater prevalence of CYP2C19*2 and CYP2C19*3 alleles which are associated with reduced or absent enzyme activity.  CYP2C19*2, which results in a loss-of-function of CYP2C19 activity, is present in approximately 29% to 35% in Asians, 15% in African-Americans, and 12% in Caucasians.  CYP2C19*3 is present in 2% to 9% of Asians while the prevalence in <1% for most other populations.  Therefore, these trials may include more poor metabolizers than what would be reflective of the US population.  From a logical standpoint, the presence of more poor metabolizers would skew the results in favor of intermittent PPI therapy as these patients may be exposed to adequate serum concentrations longer than extensive metabolizers.


Despite these limitations, intermittent PPI therapy may be appropriate for select patients especially those in the Asian population.  While the trials included in the meta-analyses did not address using risk stratification to select patients who are most appropriate for intermittent therapy, this strategy may help in identifying patients who would benefit from intermittent PPI dosing.  Stigmata characteristics, Rockall score, or Glasgow-Blatchford score can be considered for an individual patient.  The Rockall and Glasgow-Blatchford bleeding scores are used to predict mortality risk by combining known risk factors into a prediction scoring system.3  Patients with a lower risk of rebleeding and mortality may be potential candidates for intermittent therapy.  Intermittent therapy can provide advantages to patients as they may be

discharged more quickly especially if they have no other concomitant medical issues that would prevent discharge.  However, only Tsoi and colleagues reported reduced length of stay with oral therapy compared to IV therapy.9  The trials included in the meta-analyses have diverse doses, frequencies, and routes of administration used for intermittent therapy.7-9   For example, in the Sachar meta-analysis, the intermittent doses ranged from 120 mg over 72 h (administered as 40 mg IV daily or 20 mg orally twice daily) to 560 mg over 72 h (80 mg IV bolus followed by 40 mg IV every 6 hours).7  The authors suggest using high-dose PPIs at least twice daily and using oral therapy once tolerable for a patient.  However, due to the varied dosage regimens, the available data precludes the ability to provide an exact recommendation for the best dosage to use for intermittent therapy.


1.            Rotondano G. Epidemiology and diagnosis of acute nonvariceal upper gastrointestinal bleeding. Gastroenterol Clin North Am. 2014;43(4):643-663.

2.         Laine L, Yang H, Chang SC, Datto C. Trends for incidence of hospitalization and death due to GI complications in the United States from 2001 to 2009. Am J Gastroenterol. 2012;107(8):1190-1195.

3.         Chiu PW, Ng EK. Predicting poor outcome from acute upper gastrointestinal hemorrhage. Gastroenterol Clin North Am. 2009;38 (2):215-230.

4.         Garcia-Iglesias P, Villoria A, Suarez D, et al. Meta-analysis: predictors of rebleeding after endoscopic treatment for bleeding peptic ulcer. Aliment Pharmacol Ther. 2011;34(8):888-900.

5.         Barkun AN, Bardou M, Kuipers EJ, et al. International consensus recommendations on the management of patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med. 2010;152(2):101-113.

6.         Laine L, Jensen DM. Management of patients with ulcer bleeding. Am J Gastroenterol. 2012;107(3):345-360..

7.         Sachar H, Vaidya K, Laine L. Intermittent vs continuous proton pump inhibitor therapy for high-risk bleeding ulcers: a systematic review and meta-analysis. JAMA Intern Med. 2014;174(11):1755-1762.

8.         Neumann I, Letelier LM, Rada G, et al. Comparison of different regimens of proton pump inhibitors for acute peptic ulcer bleeding. Cochrane Database Syst Rev. 2013;6:CD007999.

9.         Tsoi KK, Hirai HW, Sung JJ. Meta-analysis: comparison of oral vs. intravenous proton pump inhibitors in patients with peptic ulcer bleeding. Aliment Pharmacol Ther. 2013;38(7):721-728.

10.       Scott SA, Sangkuhl K, Shuldiner AR, et al. PharmGKB summary: very important pharmacogene information for cytochrome P450, family 2, subfamily C, polypeptide 19. Pharmacogenet Genomics. 2012;22(2):159-165.

September 2015

The information presented is current as of August 7, 2015. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What data support the safety and efficacy of the intravenous P2Y12 inhibitor cangrelor?


Antithrombotic therapy is an important adjunct in percutaneous coronary intervention (PCI). Guidelines for PCI, management of ST-elevation myocardial infarction (STEMI), and management of non-STEMI (NSTEMI) recommend use of an injectable anticoagulant, aspirin, and an oral P2Y12 inhibitor.1-3 Among P2Y12 inhibitors, newer guidelines have implemented stronger recommendations for the newer agents ticagrelor and prasugrel over clopidogrel because of trials demonstrating their ability to reduce adverse cardiovascular (CV) events compared to clopidogrel, albeit at the risk of increased bleeding.4-6

Despite their efficacy, oral P2Y12 inhibitors have drawbacks. First, their onset of platelet inhibition is delayed by their required hepatic metabolism to active metabolites.7-9 Additionally, their absorption may be unreliable in patients with nausea, shock, or compromised perfusion.10,11 Clopidogrel may have variable efficacy based on pharmacogenomic-related variability in the cytochrome P450 (CYP) 2C19 enzyme, which metabolizes clopidogrel to its active form.12 The irreversible platelet inhibition with clopidogrel and prasugrel may be problematic in patients receiving these drugs who require urgent coronary artery bypass graft (CABG) surgery, before which P2Y12 inhibitors are recommended to be discontinued for 5 days.13 This is rooted in the risk of bleeding, which is why some physicians forego P2Y12 inhibitor administration prior to defining the coronary anatomy in patients with acute coronary syndromes (ACS) because the irreversible antiplatelet effect has been associated with increased perioperative bleeding in patients who require CABG.14

Cangrelor, a new intravenous (IV) P2Y12 inhibitor approved in June 2015, may address drawbacks of oral P2Y12 inhibitors via its rapid onset and offset of effect and metabolism independent of renal or hepatic clearance.11,15 Cangrelor is Food and Drug Administration (FDA)-approved as an adjunct during PCI for reducing the risk of periprocedural myocardial infarction (MI), repeat coronary revascularization, and stent thrombosis in patients who have not been treated with a P2Y12 inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor (GPI).15 The FDA initially denied approval of cangrelor in February 2014, which has raised questions about its efficacy and safety.

Clinical trials of cangrelor

Cangrelor was evaluated in patients undergoing PCI in the CHAMPION series of double-blind, double-dummy randomized controlled trials (RCTs).14,16,17  While the CHAMPION PHOENIX trial helped secure FDA approval, 2 initial RCTs (CHAMPION PCI and CHAMPION PLATFORM) showed no benefit with their predefined analyses.17

The CHAMPION PCI trial enrolled patients with stable angina (SA), unstable angina (UA), NSTEMI, and STEMI, whereas CHAMPION PLATFORM included patients with SA, UA, and NSTEMI. 14,16 Previous clopidogrel treatment was permitted in CHAMPION PCI, but not in PLATFORM. Patients who received GPIs were excluded in both trials. In CHAMPION PCI, patients were randomized to receive, at the beginning of PCI, either clopidogrel 600 mg or cangrelor bolus and infusion throughout PCI. 16 In contrast, CHAMPION PLATFORM randomized patients to cangrelor or placebo bolus and infusion throughout PCI, after which all patients received clopidogrel 600 mg at the conclusion of PCI. 14 The primary composite endpoint in both trials was death, MI, or ischemia-driven revascularization (IDR) at 48 hours, which was not found to be significantly different in either CHAMPION PCI (OR, 1.05; 95% CI, 0.88 to 1.24) or CHAMPION PLATFORM (OR, 0.87; 95% CI, 0.71 to 1.07).14,16  Enrollment in both trials was halted early after interim analyses determined futility. Significant improvements with cangrelor occurred only in CHAMPION PLATFORM for the secondary endpoints of stent thrombosis (OR, 0.31; 95% CI, 0.11 to 0.85) and death from any cause (OR, 0.33; 95% CI, 0.13 to 0.83).14 At 48 hours, minor bleeding was significantly higher with cangrelor in both trials according to criteria of Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) and Global Utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries (GUSTO).14,16 Major bleeding was significantly higher with cangrelor in CHAMPION PLATFORM by ACUITY criteria.14

A notable finding of both trials was that most primary outcome events comprised MI.14,16 Investigators theorized this was because MI was defined in these trials as Q-wave MI or specific post-PCI elevations of creatinine kinase-myocardial band (CKMB). However, CKMB levels that were elevated prior to PCI could have been mistaken for levels that elevated during PCI; therefore, this could have confounded adjudication of new MI events.10

Shortcomings of these trials were addressed by the subsequent CHAMPION PHOENIX trial, which also sought to evaluate stent thrombosis as part of a primary composite endpoint.18 This trial included patients with SA, NSTEMI, or STEMI undergoing urgent or elective PCI and compared cangrelor bolus and infusion followed by 600 mg of clopidogrel at the end of procedure to clopidogrel 300 or 600 mg at the beginning of PCI. The primary composite endpoint was death from any cause, MI, IDR, or stent thrombosis (defined as definite stent thrombosis or intraprocedural stent thrombosis [IPST]) at 48 hours. Importantly, the definition of MI was modified from the biomarker-based definition to be more clinically relevant (CKMB ≥3x upper limit of normal [ULN] in patients with normal baseline CKMB, or CKMB re-elevation and evidence of ischemia or electrocardiogram [ECG] changes in patients with abnormal baseline CKMB). Cangrelor significantly reduced the primary outcome (OR, 0.78; 95% CI, 0.66 to 0.93) as well as the component endpoint stent thrombosis (OR, 0.62: 95% CI, 0.43 to 0.9). The primary safety endpoint, severe bleeding not related to CABG, was not significantly different (OR, 1.5; 95% CI, 0.53 to 4.22).

In addition to trials in PCI, cangrelor was studied in one phase II trial that evaluated its use as bridge therapy in 210 patients with ACS or stents who were at increased risk of thrombotic events during oral P2Y12 inhibitor discontinuation prior to CABG.19 Compared to placebo infusion, more patients treated with cangrelor experienced the primary efficacy endpoint of a platelet reactivity index similar to that expected if oral P2Y12 inhibitors were continued (98.8% vs 19%, p<0.001). There were no differences in CABG-related bleeding. However, given the small and preliminary design, FDA unanimously denied approval of cangrelor for this use.

Criticisms of CHAMPION PHOENIX and initial FDA review

Given the nonsignificant findings of 2 trials in PCI, the CHAMPION PHOENIX trial is the primary evidence supporting cangrelor. However, numerous aspects of its design have been questioned, and the FDA’s review of the initial cangrelor  new drug application (NDA) submission resulted in a 7-2 vote against approval.18 Given the aforementioned limitations of clopidogrel, comparisons to prasugrel or ticagrelor may have shown a smaller incremental benefit with cangrelor.18 Furthermore, some have criticized the administration of clopidogrel as being inappropriately delayed until the start of PCI rather than prior to angiography. The onset of action of clopidogrel is several hours, and delayed administration may have resulted in inadequate antiplatelet effect during PCI. This may have biased results in favor of cangrelor.

The clinical relevance of the definition of MI in CHAMPION PHOENIX was also questioned, as this MI definition has not been definitively associated with increased risk for subsequent cardiovascular events.18,20 This definition was inconsistent with the established definition from the Society for Cardiovascular Angiography and Interventions (SCAI) for clinically relevant MI after coronary revascularization (post-PCI elevation of CKMB ≥10x ULN).20 Additionally, the inclusion of IPST in the composite endpoint was questioned because it is an angiographic finding that, without consequent MI, does not usually result in permanent morbidity.18

Given these concerns, FDA requested sensitivity analyses of CHAMPION PHOENIX with a modified primary endpoint that excluded outcomes of questionable clinical relevance – IPST and MI not categorized consistent with the SCAI definition.18 In these analyses, significant benefit was maintained with cangrelor when the composite endpoint excluded IPST alone (OR, 0.8; 95% CI, 0.67 to 0.95) and both IPST and MI not defined consistent with the SCAI definition (OR, 0.69; 95% CI, 0.51 to 0.92).18 Based on this, FDA determined cangrelor was effective in improving endpoints whose clinical meaningfulness is undisputed, granting it approval for use in PCI among the populations studied.

Pharmacist’s role

The use of cangrelor presents unique challenges for pharmacists. First, pharmacists who review data supporting the use of cangrelor should be aware that efficacy outcome data presented in the published CHAMPION PHOENIX trial did not primarily inform FDA’s approval; for this information, pharmacists should refer to FDA briefing documents containing results of the requested sensitivity analyses.17,18 Additionally, pharmacists should ensure appropriate transition from cangrelor infusion to an oral P2Y12 inhibitor (Table).15 This is because pharmacodynamic interactions would result in no antiplatelet effect of clopidogrel or prasugrel if they are administered during cangrelor infusion. These drugs therefore should be administered only when cangrelor infusion is discontinued. Considering this, there may be a transient window of inadequate platelet inhibition between the discontinuation of cangrelor and onset of effect of clopidogrel.18 As the consequence of this is undefined, it is prudent to monitor patients vigilantly for adverse outcomes during the several hours after cessation of cangrelor infusion until the onset of platelet inhibition is realized.

Table. Transition from cangrelor infusion to oral P2Y12 inhibitor therapy.15


180 mg at any time during cangrelor infusion or immediately after discontinuation.


60 mg immediately after discontinuation of cangrelor. Do not administer prasugrel prior to discontinuation of cangrelor.


600 mg immediately after discontinuation of cangrelor. Do not administer clopidogrel prior to discontinuation of cangrelor.


Cangrelor is an IV P2Y12 inhibitor that may address some shortcomings of oral drugs in its class. A single clinical trial supported its approval based on an unpublished sensitivity analysis; therefore, clinicians wishing to review this information should consult FDA briefing documents in addition to the CHAMPION PHOENIX trial. Its use as a bridging therapy during discontinuation of oral P2Y12 inhibitors prior to CABG cannot currently be recommended because of limited data. Appropriate transition from cangrelor to an oral P2Y12 inhibitor should be ensured and patients should be monitored for adverse thrombotic outcomes shortly after discontinuation of cangrelor. Although cangrelor may be a necessary alternative in patients who are not candidates for oral P2Y12 antagonists, its true role in PCI may not be fully elucidated until it is compared to prasugrel or ticagrelor.


1.         O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127:e362-425.

2.         Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130(25):e344-426.

3.         Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124(23):e574-651.

4.         Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130(25):2354-2394.

5.         Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057.

6.         Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001-2015.

7.         Effient [package insert]. Indianapolis, IN; 2015.

8.         Brilinta [package insert]. Wilmington, DE; 2015.

9.         Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2015. Accessed June 12, 2015.

10.       Keating GM. Cangrelor: a review in percutaneous coronary intervention.  Drugs. 2015;75(12):1425-1434.

11.       Waite LH, Phan YL, Spinler SA. Cangrelor: a novel intravenous antiplatelet agent with a questionable future. Pharmacotherapy. 2014;34(10):1061-1076.

12.       Plavix [package insert]. Bridgewater, NJ; 2015.

13.       Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College Of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2_suppl):e326S-e350S.

14.       Bhatt DL, Lincoff AM, Gibson CM, et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med. 2009;361(24):2330-2341.

15.       Kengreal [package insert]. Parsippany, NJ; 2015.

16.       Harrington RA, Stone GW, McNulty S, et al. Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med. 2009;361(24):2318-2329.

17.       Bhatt DL, Stone GW, Mahaffey KW, et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013;368(14):1303-1313.

18.       FDA briefing document for the Cardiovascular and Renal Drugs Advisory Committee. US Food and Drug Administration website. Published April 15, 2015. Accessed August 7, 2015.

19.       Angiolillo DJ, Firstenberg MS, Price MJ, et al. Bridging antiplatelet therapy with cangrelor in patients undergoing cardiac surgery: a randomized controlled trial. JAMA. 2012;307:265-274.

20.       Moussa ID, Klein LW, Shah B, et al. Consideration of a new definition of clinically relevant myocardial infarction after coronary revascularization: an expert consensus document from the Society for Cardiovascular Angiography and Interventions (SCAI). J Am Coll Cardiol. 2013;62(17):1563-1570.

September 2015

The information presented is current as of August 7, 2015. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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Is the recently updated cholesterol guideline cost-effective and better at identifying at-risk patients than the previous ATP III guideline?


On November 12, 2013, a revised guideline for the treatment of high blood cholesterol in adults was released by the American College of Cardiology-American Heart Association (ACC-AHA) Task Force on Practice Guidelines.1  The University of Illinois at Chicago Drug Information Group compiled a summary of the key features of this new guideline in January 2014 (  In contrast to previous guidelines, the expert panel in the ACC-AHA guideline relied heavily on data from randomized controlled trials involving fixed doses of statins in patients at risk for atherosclerotic cardiovascular disease (CVD) and identified 4 patient subgroups for which the benefits of statin therapy outweigh the risks.2  These subgroups included:

  • those with clinically evident atherosclerotic disease,
  • patients with low-density lipoprotein (LDL) cholesterol levels ≥ 190 mg/dL,
  • patients, 40 to 75 years of age, with diabetes and a LDL level of 70 to 189 mg/dL,
  • or those, 40 to 75 years of age, with a 10-year risk of atherosclerotic CVD of ≥ 7.5% and a LDL level of 70 to 189 mg/dL.

Fairly rapidly after the release of the ACC/AHA guideline, commentators expressed concern regarding this approach (primarily with the fourth clinical scenario above) stating that “we’re diluting the patient population who are now getting statins….we’re making people statin eligible who are not at higher risk”.3  In fact, Pencina and colleagues estimated that implementation of the ACC/AHA cholesterol guideline would result in 12.8 million more adults eligible for statin therapy.4  The majority of these individuals would be older adults without CVD.  In contrast to the National Cholesterol Education Program’s Updated Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) guideline, the new ACC/AHA guideline would recommend statin therapy for more adults who would be expected to have future cardiovascular events, but would also include many adults who would not have future events.  Potentially millions of American adults could be exposed to the costs and risks associated with statin therapy without any visible benefits.4,5  In response to these concerns, 2 recently published studies assessed guideline-based statin eligibility and cost-effectiveness of 10-year risk thresholds for initiation of statin therapy.6,7

Clinical Data

In order to determine whether the eligibility criteria for statin therapy in the ACC/AHA guideline improved the identification of individuals who develop incident CVD and/or have coronary artery calcification (CAC) in comparison to the ATP III guideline, Pursnani and colleagues conducted a longitudinal community-based cohort study.6  Coronary artery calcification was chosen as an additional marker to incident CVD because asymptomatic adults with a high CAC score (> 300) experience a nearly 10-fold higher incidence of coronary events.8

Subjects in this study were from the offspring and third-generation cohorts of patients in the Framingham Heart Study.6  All subjects had undergone multidetector computed tomography (MDCT) imaging between 2002 and 2005.  Additional inclusion criteria included men ³ 35 years of age, non-pregnant women ³ 40 years of age, and weight £ 157.5 kg.  Subjects with prevalent CVD and those receiving lipid lowering therapy at baseline were excluded.  For the ACC/AHA guideline, candidates for statin therapy were identified based on the 4 patient subgroups mentioned prior.  A pooled cohort calculator was utilized to estimate atherosclerotic CVD risk.  Framingham risk factors and LDL thresholds were used to determine statin eligibility via the ATP III guideline.

Of the 7,634 participants in the offspring and third-generation Framingham Heart Study cohort, the study population consisted of 2,435 statin-naïve subjects.6  At baseline, subjects had a mean age of 51.3 years, LDL level of 121 mg/dL , Framingham risk score of 6.6%, and CAC score of 93.3.  The vast majority of subjects were Caucasian and the mean age of enrollees was 51.3 years.  Median follow-up was over a period of 9.4 years.  During follow-up there was a total of 74 (3%) incident cardiovascular events (40 nonfatal myocardial infarctions, 31 nonfatal strokes, and 3 with fatal coronary heart disease (CHD)).  Overall, significantly more subjects were eligible for statin therapy when applying the ACC/AHA guideline versus the ATP III guideline (39% [941/2435] vs. 14% [348/2435]; p<0.001).  Among those eligible for statin therapy per the ATP III guideline, 6.9% (24 subjects) experienced incident CVD versus 2.4% (50 subjects) of those who were not eligible (HR 3.1; 95% CI: 1.9 to 5.0; p<0.001).  For those eligible for statin therapy per the ACC/AHA guideline, 6.3% (59 subjects) developed incident CVD versus 1% (15 subjects) of those deemed not eligible (HR 6.8; 95% CI: 3.8 to 11.9; p<0.001).  The hazard ratio of experiencing incident CVD among statin-eligible versus noneligible subjects was significantly higher when applying the ACC/AHA guideline criteria as compared to the ATP III guideline criteria (p<0.001).  Similar results were seen for subjects at intermediate CVD risk and for incident CHD (myocardial infarction and death due to CHD).  In addition, subjects with CAC were significantly more likely to be eligible for statin therapy via the ACC/AHA guideline versus ATP III (p<0.001 for those with a CAC score > 0, > 100, or > 300).  Based on these results, the authors concluded that the ACC/AHA guideline for determining statin eligibility is associated with greater accuracy and efficiency in identifying an increased risk of incident CVD and presence of subclinical coronary artery disease as compared to ATP III.  This was most pronounced among subjects at intermediate CVD risk.

In the same issue of JAMA, Pandya and colleagues estimated the cost-effectiveness of various 10-year risk thresholds for initiation of statin therapy for primary prevention of CVD using a microsimulation model.7 This model incorporated lifetime treatment and health outcomes in a population of 1 million hypothetical adults (40 to 75 years of age) in the United States. Within this hypothetical model, adults were administered statin therapy, experienced atherosclerotic CVD events, and died from CVD and non-CVD causes.  Data sources for information within the model included National Health and Nutrition Examination Surveys (NHANES), large clinical trials/meta-analyses involving statin therapy, and other publications. 

Within this analysis, the authors evaluated the cost-effectiveness of 12 different 10-year atherosclerotic CVD risk thresholds that could be utilized in the ACC/AHA guideline (>=30%, >=20%, >=15%, >=10%, >=7.5%, >=5%, >=4%, >=3%, >=2%, >=1% plus treating all patients and not using an atherosclerotic CVD risk-based treatment strategy).7  In their model, the atherosclerotic CVD threshold of >=7.5%, which is currently recommended in the ACC/AHA guideline, estimated that 48% of adults would be eligible for statin therapy.  At this risk threshold, the incremental cost-effective ratio (ICER) is $37,000 per quality-adjusted life year (QALY) gained compared with a threshold of 10% or higher.  At the atherosclerotic CVD thresholds of >=5%, >= 4%, and >= 3%, respectively, the ICER was $57,000/QALY, $81,000/QALY, and $140,000/QALY gained compared with a 10% atherosclerotic CVD treatment threshold.  The authors concluded that initiation of statin therapy is cost-effective at the current >= 7.5% threshold seen in the ACC/AHA guideline and may be cost-effective at even more lenient 10-year atherosclerotic CVD risk thresholds. 


The recent introduction of the new ACC/AHA cholesterol guideline, which focuses on appropriate use of statin therapy in certain subgroups, created concern among healthcare providers.  Some providers felt that the recommendations in the new guideline would unnecessarily increase the number of patients exposed to statin therapy.  These patients could potentially experience the risks and costs of statin therapy without any benefits.  Two new published studies have evaluated these concerns and concluded that not only is the ACC/AHA guideline more accurate and efficient at identifying those at an increased risk of incident CVD and presence of subclinical coronary artery disease as compared to ATP III, but that the ³ 7.5% risk threshold utilized by the guideline is a cost-effective approach for initiation of statin therapy.


1.  Stone NJ, Robinson J, Lichtenstein AH, et al.  2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. J Am Coll Cardiol. 2014;63(25 Pt B):2889-2934.

2.  Keaney JF, Curfman GD, Jarcho JA.  A pragmatic view of the new cholesterol treatment guidelines.  N Engl J Med. 2014;370(3):275-278.

3.  O’Riordan M.  ACC/AHA cholesterol guidelines better at identifying at-risk patients, are cost-effective.  Accessed August 7, 2015.

4.  Pencina MJ, Navar-Boggar AM, D’Agostino RB, et al.  Application of new cholesterol guidelines to a population-based sample.  N Engl J Med. 2014;370(15):1422-1431.

5.  Greenland P, Lauer MS. Cholesterol lowering in 2015.  Still answering questions about how and in whom.  JAMA. 2015;314(2):127-128.

6.  Pursnani A, Massaro JM, D’Agostino RB, O’Donnell CJ, Hoffmann U.  Guideline-based statin eligibility, coronary artery calcification, and cardiovascular events.  JAMA. 2015;314(2):134-141.

7.  Pandya A, Sy S, Cho S, Weinstein MC, Gaziano TA.  Cost-effectiveness of 10-year risk thresholds for initiation of statin therapy for primary prevention of cardiovascular disease.  JAMA. 2015;314(2):142-150.

8.  Detrano R, Guerci AD, Carr J, et al.  Coronary calcium as a predictor of coronary events in four racial or ethnic groups.  N Engl J Med. 2008;358(13):1336-1345.

September 2015

The information presented is current as of August 7, 2015. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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