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Managing the Multiple Symptoms of Benign Prostatic Hyperplasia — CME
Managing Type 2 Diabetes in Men
Meeting New Challenges with Antiplatelet Therapy in Primary Care
Dr. Kuritzky has nothing to disclose.
Dr. Díez has nothing to disclose.
SUPPORT
This program is sponsored by the PCEC and supported by funding from AstraZeneca. Dr. Kuritzky received no financial support for this article.
Introduction
The importance of acute coronary syndrome (ACS) (ie, patients with ST-segment elevation myocardial infarction [MI] [STEMI], non-ST segment elevation MI [NSTEMI], or unstable angina) in primary care is highlighted by its prevalence. Acute coronary syndrome was the primary or secondary discharge diagnosis in 1.19 million hospitalizations in the United States in 2009, a slight majority of which were in men.1 Platelet activation plays a central role in the pathophysiology of ACS. Despite well established benefits of antiplatelet therapy in both primary and secondary prevention of ACS, adverse events—particularly bleeding—require ongoing vigilance.2 Among the several classes of antiplatelet agents currently available, the thromboxane A2 inhibitor (ie, aspirin) and P2Y12 inhibitors (ie, clopidogrel, prasugrel, and ticagrelor) are those most commonly used; ticlopidine is not commonly used due to nausea/vomiting and bone marrow toxicity.3
Antiplatelet Agents
It is well established that hemostasis is protected by multilayered, overlapping, and sometimes redundant pathways. Even though currently available antiplatelet agents are highly efficacious in inhibiting 1 or more phases of platelet activity pertinent to coagulation (eg, activation, adhesion, and aggregation), because of the multiple backup pathways involved, no single antiplatelet agent is anticipated to totally eliminate platelet activity. In addition, every combination of antiplatelet agents—though potentially more efficacious because of multipathway activity—is also laden with greater bleeding risk. The 3 primary pathways of platelet activation for which pharmacologic antagonists have been developed are the thromboxane, adenosine diphosphonate (ADP)-P2Y12, and ADP-A2 pathways. While dual antiplatelet therapy with aspirin and clopidogrel may be the current standard of care, the focus of this review is on the ADP-P2Y12 inhibitors as the two newest agents, prasugrel and ticagrelor, are less familiar to family physicians. The second section addresses questions often encountered by family physicians when caring for patients who have recently experienced ACS.
P2Y12 Inhibitors
Two groups of agents exert their antiplatelet effects by inhibiting the platelet P2Y12 receptor: (1) thienopyridines (ie, ticlopidine, clopidogrel, and prasugrel) and (2) the cyclopentyltriazolopyrimidines (ie, ticagrelor). Both groups inhibit ADP-dependent platelet function but at different sites on the platelet P2Y12 receptor. Thienopyridine activity is mediated via short-lived active metabolites formed in the liver. Platelet exposure to the active metabolite of prasugrel is about 10-fold higher than to the active metabolite of clopidogrel, resulting in a higher level and less individual variation of platelet inhibition with prasugrel. Hepatic metabolism of clopidogrel makes it subject to genetic, as well as drug-induced, variation in activity; prasugrel is not affected by these same limitations. Recovery of platelet function following withdrawal of thienopyridine therapy occurs over 7 to 8 days as a function of platelet turnover.2,3 This slow recovery of platelet function has important implications when any surgical intervention is needed.
In contrast to the thienopyridines, ticagrelor does not require metabolic activation by the liver. Ticagrelor and its active metabolite display approximately equipotent antiplatelet activity and are direct P2Y12 inhibitors. Ticargrelor non-competitively antagonizes ADP-induced receptor activation. Ticagrelor is rapidly absorbed reaching its peak plasma concentration in 1.5 to 3 hours, thereby providing a rapid antiplatelet effect. Twice-daily administration is required because of its rapid offset of platelet inhibition.2,4,5
Prasugrel
Prasugrel is indicated by the US Food and Drug Administration (FDA) for reduction of thrombotic cardiovascular (CV) events (including stent thrombosis) in patients with ACS who are to be managed with percutaneous coronary intervention (PCI) as follows: (1) unstable angina or NSTEMI or (2) STEMI when managed with primary or delayed PCI.6
The efficacy and safety of prasugrel have been investigated in several clinical trials. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 is the largest and has many planned sub-analyses ( TABLE 1 ).7-9 TRITON TIMI 38 involved patients with moderate- to high-risk ACS scheduled for PCI
(N = 13,608).7 Patients were randomized to prasugrel 60 mg as a loading dose followed by 10 mg daily or clopidogrel 300 mg as a loading dose followed by 75 mg daily for 6 to 15 months. Aspirin 75 to 162 mg once daily was recommended, but was left up to the physician. The primary efficacy end point was a composite of CV death, nonfatal MI, or nonfatal stroke.
Findings from TRITON TIMI 38 show that, compared with clopidogrel, prasugrel was associated with significantly reduced rates of ischemic events, including nonfatal MI and stent thrombosis. The benefit with prasugrel was primarily due to a significant reduction in the rate of MI compared with clopidogrel. However, patients treated with prasugrel experienced a higher rate of major bleeding, including fatal and life-threatening bleeding. Prasugrel was found to be more effective than clopidogrel in preventing ischemic events without excess bleeding in patients with STEMI undergoing secondary PCI (treated between 12 hours and 14 days after symptom onset). In patients with ACS undergoing PCI without stent implantation, ischemic events occurred at similar rates in patients treated with prasugrel or clopidogrel; however, bleeding was more common with prasugrel.
Not all patients benefited from prasugrel therapy. Compared with clopidogrel, patients with previous stroke/transient ischemic attack (TIA) had net harm from prasugrel. In addition, no net benefit from prasugrel compared with clopidogrel was observed in patients age ≥75 years or body weight <60 kg. The results of TRITON TIMI 38 contributed to the boxed warnings regarding bleeding risk recommending that prasugrel not be used in patients age ≥75 years, in patients with active pathological bleeding or a history of TIA or stroke, or patients likely to undergo coronary artery bypass graft (CABG) surgery. In addition, patients with body weight < 60 kg are also at increased risk for bleeding.6
TABLE 1
Prasugrel: TRITON-TIMI 38 and subanalyses
| TRITON-TIMI 38 Cohort7 | TRITON-TIMI 38 Selected Subanalyses8,9 | ||
|---|---|---|---|
| Treatment | Pr 60 mg LD, then 10 mg QD or Cl 300 mg LD, then 75 mg QD plus Aspirin 75-162 mg QD for 6-15 mos (median 14.5 mos) | ||
| Population | Moderate/High-risk ACS scheduled for PCI (N = 13,608) | PCI for STEMI (N = 3534) | PCI without ST elevation (N = 569) |
| Efficacy Outcomes | Primary end point (CV death, nonfatal MI, or nonfatal stroke):
(P = .31) Nonfatal MI: Cl 9.5% vs Pr 7.3% (P < .001) Nonfatal stroke: Cl 1.0% vs Pr 1.0% (P = .93) Urgent target-vessel revascularization: Cl 3.7% vs Pr 2.5% (P < .001) Stent thrombosis: Cl 2.4% vs Pr 1.1% (P < .001) | Primary end point (CV death, nonfatal MI, or nonfatal stroke):
| Primary end point (CV death, nonfatal MI, or nonfatal stroke): Cl 17.1% vs Pr 14.2% (P = .27) Urgent target-vessel revascularization: Cl 8.2% vs Pr 3.6% (P = .04) |
| Safety Outcomes | Non-CABG TIMI major bleeding: Cl 1.8% vs Pr 2.4% (P = .03) Fatal bleeding: Cl 0.1% vs Pr 0.4% (P = .002) Life-threatening bleeding: Cl 0.9% vs Pr 1.4% (P = .01) Non-fatal bleeding: Cl 0.9% vs Pr 1.1% (P = .23) | TIMI major bleedinga unrelated to CABG:
| TIMI major bleedinga unrelated to CABG: Cl 0% vs Pr 2.1% (P = .03) |
| Key Findings | Prasugrel was associated with significantly reduced rates of ischemic events, including nonfatal MI and stent thrombosis, but with an increased risk of major bleeding, including fatal and life-threatening bleeding. Compared to clopidogrel, patients with previous stroke/TIA had net harm from prasugrel; patients with age ≥ 75 y had no net benefit from prasugrel; patients with BW < 60 kg had no net benefit from prasugrel. | Net clinical outcome All-cause death, MI, stroke, TIMI major bleeding unrelated to CABG:
| In patients with ACS undergoing PCI without stent implantation, ischemic events occurred at similar rates in patients treated with prasugrel or clopidogrel; however, bleeding was more common with prasugrel. |
| ACS, acute coronary syndrome; BW, body weight; CABG, coronary artery bypass graft; Cl, clopidogrel; CV, cardiovascular; LD, loading dose; MI, myocardial infarction; PCI, percutaneous coronary intervention; Pr, prasugrel; QD, once daily; STEMI, ST-segment elevation in myocardial infarction; TIA, transient ischemic attack; TIMI, thrombolysis in myocardial infarction. aTIMI major bleed (intracranial bleed or intrapericardial bleed with cardiac tamponade or a decline of 5.0 g/dL or more in hemoglobin after adjusting for red blood cell transfusions). | |||
Ticagrelor
Ticagrelor is the most recent antiplatelet agent to be approved by the US FDA. Ticagrelor is indicated to reduce the rate of thrombotic CV events in patients with ACS (eg, unstable angina, NSTEMI, or STEMI).10
The efficacy and safety of ticagrelor has been assessed in the Study of Platelet Inhibition and Patient Outcomes (PLATO) and several planned sub-analyses ( TABLE 2 ).11-16 PLATO was a 12-month, multicenter, double-blind, randomized trial that involved patients with ACS with or without ST-segment elevation (N = 18,624).11 Patients were randomized to ticagrelor 180 mg loading dose then 90 mg twice daily or clopidogrel 300 to 600 mg loading dose then 75 mg once daily for 12 months. The primary efficacy end point was a composite of death from vascular causes, MI, or stroke.
The results of PLATO and sub-analyses show that in patients with ACS and compared with clopidogrel, ticagrelor significantly reduced the primary efficacy end point with a similar rate of major bleeding
( TABLE 1 ). These safety results contributed to the boxed warnings regarding bleeding risk that ticagrelor not be used in patients with active pathological bleeding or a history of intracranial hemorrhage, or in patients planned to undergo urgent CABG surgery. In addition, maintenance aspirin therapy at a dose above 100 mg reduces the effectiveness of ticagrelor and should be avoided.10
Consistent with the general PLATO population, in patients intended for non-invasive management, ticagrelor significantly reduced the rate of death from vascular causes, MI, or stroke compared with clopidogrel with a similar rate of major bleeding. In patients with ACS and ST elevation or left bundle branch block planned for PCI, ticagrelor reduced CV and all-cause death, MI, stent thrombosis, and improved survival compared with clopidogrel, with a similar rate of major bleeding. Ticagrelor, compared with clopidogrel, reduced all-cause and CV death without excess risk of CABG-related bleeding in patients with ACS undergoing CABG within 7 days of the last dose of clopidogrel or ticagrelor. Finally, in ACS with chronic kidney disease (estimated creatinine clearance < 60 mL/minute), ticagrelor compared with clopidogrel significantly reduced ischemic end points and mortality without a significant increase in major bleeding and with a similar rate of non–CABG-related bleeding.
TABLE 2
Ticagrelor: PLATO and subanalyses
| PLATO Cohort9,12 | PLATO Selected Subanalyses13-16 | ||||
|---|---|---|---|---|---|
| Treatment | Ti 180 mg LD, then 90 mg BID or Cl 300-600 mg LD then 75 mg QD plus Aspirin 75-325 mg QD for 12 months | ||||
| Population | ACS with/without ST elevation (N = 18,624) | ACS planned for non-invasive management (N = 5216) | ACS with ST elevation or left bundle branch block planned for PCI (N = 7544) | ACS with/without ST elevation managed with CABG (N = 1261) | ACS with/without ST elevation but with chronic kidney disease (eCrCl < 60 mL/min) (n = 3237) |
| Efficacy Outcomes | Primary end point (death from vascular causes, MI, or stroke): Cl 11.7% vs Ti 9.8% (P < .001) Death from any cause, MI, or stroke: Cl 12.3% vs Ti 10.2% (P < .001) Death from any cause, MI, stroke, severe recurrent ischemia, recurrent ischemia, TIA, or other arterial thrombotic event: Cl 16.7% vs Ti 14.6% (P < .001) Death from nonvascular causes: Cl 0.8% vs Ti 0.5% (P = .08) | Primary end point (death from vascular causes, MI, or stroke): Cl 14.3% vs. Ti 12.0% (P = .045) CV death: Cl 7.2% vs Ti 5.5% (P = .019) | Primary end point (death from vascular causes, MI, or stroke): Cl 10.8% vs Ti 9.4% (P = .07) CV death, MI (excluding silent): Cl 10.2% vs Ti 8.4% (P = .01) All cause death, MI (excluding silent), stroke: Cl 11.3% vs Ti 9.8% (P = .05) CV death, total MI, stroke, severe recurrent cardiac ischemia, recurrent cardiac ischemia, TIA, arterial thrombotic events: Cl 15.0% vs Ti 13.3% (P = .03) MI (excluding silent): Cl 5.8% vs Ti 4.7% (P = .03) Stroke: Cl 1.0% vs Ti 1.7% (P = .02) All-cause mortality: Cl 6.1% vs Ti 5.0% (P = .05) Definite, probable, or possible stent thrombosis: Cl 4.3% vs Ti 3.3% (P = .04) | Primary end point (death from vascular causes, MI, or stroke): Cl 13.1% vs Ti 10.6% (P = .29) All-cause death: Cl 9.7% vs Ti 4.7% (P < .01) CV death: Cl 7.9% vs Ti 4.1% (P < .01) Non-CV death: Cl 2.0% vs Ti 0.7% (P = .07) Stroke: Cl 2.1% vs Ti 2.1% (P = .70) | Primary end point (death from vascular causes, MI, or stroke): Cl 22.0% vs Ti 17.3% All-cause death: Cl 14.0% vs Ti 10.0% |
| Safety Outcomes | TIMI major bleedinga: Cl 7.7% vs Ti 7.9% (P = .57) TIMI major bleedinga unrelated to CABG: Cl 2.2% vs Ti 2.8% (P = .03) PLATO major bleedingb: Cl 11.2% vs Ti 11.6% (P = .43) PLATO major bleedingb unrelated to CABG: Cl 3.8% vs Ti 4.5% (P = .03) Dyspnea requiring discontinuation: Cl 0.1% vs Ti 0.9% (P < .001) | PLATO major bleedingb: Cl 10.3% vs Ti 11.9% (P = .079) Life-threatening/fatal bleeding: Cl 5.6% vs Ti 5.5% (P= . 911) Major/Minor bleeding unrelated to CABG: Cl 6.7% vs Ti 8.3% (P = .0182) | PLATO major bleeding: Cl 9.2% vs Ti 9.0% (P = .76) TIMI major bleeding: Cl 6.4% vs Ti 6.1% (P = .66) PLATO non-procedure-related major/ minor bleeding: Cl 3.7% vs Ti 5.1% (P = .02) PLATO minor bleeding: Cl 3.8% vs Ti 4.9% (P = .05) Dyspnea requiring discontinuation: Cl 0.1% vs Ti 0.5% (P = .0004) | Major/Life-threatening CABG-related bleeding causing death within 7 d after CABG: Cl 3.0% vs Ti 1.3% (P = .052) Major CABG bleeding: Cl 80.1% vs Ti 81.2% (P = .669) TIMI major CABG bleeding: Cl 57.6% vs Ti 59.3% (P = .53) | PLATO major bleeding: Cl 14.3% vs Ti 15.1% PLATO fatal major bleeding: Cl 0.77% vs Ti 0.34% PLATO non-CABG major bleeding: Cl 7.3% vs Ti 8.5% Dyspnea: Cl 11.5% vs Ti 16.4% |
| Key Findings | Ticagrelor significantly reduced the rate of CV death, MI, or stroke compared to clopidogrel with a similar rate of major bleeding; ticagrelor led to increased major bleeding unrelated to CABG. Fatal bleeding was low and did not differ between groups. | Consistent with the general PLATO population, ticagrelor significantly reduced the rate of CV death, MI, or stroke compared to clopidogrel with a similar rate of major bleeding. | Consistent with the general PLATO population, compared with clopidogrel, ticagrelor reduced CV and all-cause death, MI, stent thrombosis and improved survival without increasing major bleeding. Ticagrelor resulted in a higher rate of stroke. | Ticagrelor compared with clopidogrel reduced all-cause and CV death without excess risk of CABG-related bleeding in patients with ACS undergoing CABG within 7 days of the last dose of clopidogrel or ticagrelor. | In ACS with CKD, ticagrelor compared with clopidogrel significantly reduced ischemic end points and mortality without a significant increase in major bleeding and with a similar rate of non-procedure- related bleeding. |
| ACS, acute coronary syndrome; BID, twice daily; CABG, coronary artery bypass graft; Cl, clopidogrel; CKD, chronic kidney disease; CV, cardiovascular; eCrCL, estimated creatinine clearance; LD, loading dose; MI, myocardial infarction; PCI, percutaneous coronary intervention; QD, once daily; Ti, ticagrelor; TIA, transient ischemic attack; TIMI, thrombolysis in myocardial infarction. aTIMI major bleed (intracranial bleed or intrapericardial bleed with cardiac tamponade or a decline of 5.0 g/dL or more in hemoglobin after adjusting for red blood cell transfusions). bPLATO major bleed (fatal bleeding, intrapericardial bleeding with cardiac tamponade, intracranial bleeding, severe hypotension, or hypovolemic shock due to bleeding and requiring either vasopressors or surgical intervention, a decline in hemoglobin of 5.0 g/dL or more after adjusting for red blood cell transfusions, or the need for transfusion of 4 or more units of packed red blood cells) | |||||
Common Questions Regarding Antiplatelet Therapy in Primary Care
The preceding discussion confirms that many patients with ACS benefit from antiplatelet therapy. However, the use of antiplatelet agents in primary care can be challenging. The following are some of the evolving issues and questions regarding antiplatelet therapy faced by family physicians.
If a patient has experienced gastrointestinal bleeding while taking low-dose aspirin in the past and has an acute coronary syndrome, what course of action should be taken?
Dual antiplatelet therapy is still recommended in this setting, but therapy with a proton pump inhibitor (PPI) for gastrointestinal (GI) protection is recommended.2,3,17 For patients at low risk of upper GI bleeding, routine PPI prophylaxis is not recommended. Currently available data do not demonstrate the prophylactic superiority of one PPI over another, but do show that PPI therapy is more effective in decreasing GI bleeding associated with aspirin and is, therefore, preferred over a histamine H2 receptor antagonist.17 For instance, high-dose famotidine has been shown to be less effective than pantoprazole in patients with aspirin-related peptic ulcers/erosions.18
Can a proton pump inhibitor be used for gastrointestinal protection in conjunction with clopidogrel?
Yes, although the evidence is conflicting about whether specific PPIs should be avoided because of reduced clinical efficacy of clopidogrel. The results of a meta-analysis of 23 studies demonstrated a clinically significant interaction that reduces the antiplatelet effectiveness of clopidogrel when combined with some PPIs.19 The results of 4 prospective, crossover pharmacokinetic studies in healthy subjects (N = 282) also suggest an interaction between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.20 A subanalysis of PLATO showed that the use of a PPI was independently associated with a higher rate of CV events in patients with ACS treated with clopidogrel or ticagrelor.21 The observed effect with both agents, as well as a higher rate of major bleeding among PPI vs non-PPI users suggests that PPI use may be more of a marker for rather than a cause of higher rates of CV events. In fact, data from the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) found that in patients treated with clopidogrel and aspirin, the addition of omeprazole reduced the rate of a GI event, compared with placebo at 180 days (1.1% vs. 2.9%, respectively;
P < .001).22 Overt upper GI bleeding occurred less frequently in the omeprazole group (hazard ratio, 0.13; 95% confidence interval, 0.03 to 0.56; P = .001). A CV event was observed in 4.9% of patients treated with omeprazole and 5.7% of placebo patients (P = .96). While limited, these prospective data do not suggest a detriment to clopidogrel efficacy when used in combination with a PPI. The dose of PPI to use for GI protection is not well-established; the following drugs and doses have been used: omeprazole 20 to 40 mg once daily; esomeprazole 20 mg once or twice daily; pantoprazole 20 mg once daily; or lansoprazole 30 mg once daily.18,23-28
Should I avoid starting clopidogrel in patients with acute coronary syndrome because of concerns about “poor metabolizers”?
Clopidogrel is a prodrug, requiring CYP450 metabolism to its active metabolite. Because of genetic CYP450 variations, as many as one-third of patients lack fully active CYP450 pathways, resulting in reduced (or even absent) conversion from the parent drug to the active metabolite, with a corresponding diminution of antiplatelet effects.3,29 Recent recommendations about dealing with these genetic polymorphisms include direct measurement of CYP450 pathway status and selection of alternative pharmacologic agents which are not dependent upon similar CYP pathway activation. There are, unfortunately, no prospective clinical trials based upon CYP2C19 genotyping confirming that patient selection based upon genotyping is associated with improved outcomes.
In terms of alternative antiplatelet therapy in clopidogrel nonresponders, the Response to Ticagrelor in Clopidogrel Nonresponders and Responders (RESPOND) study shows ticagrelor to be beneficial, at least as measured in vitro.30 Following laboratory assessment of patients’ responsiveness to clopidogrel, both responders and nonresponders were randomized to clopidogrel or ticagrelor. After 14 days, all clopidogrel nonresponders and half of the responders switched treatment. The antiplatelet effects of ticagrelor were similar whether the patient was a clopidogrel responder or not. The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) showed higher inhibition of platelet aggregation (IPA) with prasugrel 60 mg compared with clopidogrel 600 mg 6 hours after initiation.31 Following crossover, IPA was higher in subjects receiving prasugrel 10 mg/d compared with clopidogrel 150 mg/d (61% vs 46%, respectively; P < .0001). While not measuring clopidogrel responsiveness, this suggests that prasugrel might be effective in clopidogrel nonresponders. Not all patients treated with prasugrel achieve optimal inhibition of platelet reactivity. In patients who underwent successful PCI for ACS (N = 301) 25.2% were observed to have high on-treatment platelet reactivity following a 60 mg loading dose of prasugrel.32 Such patients had a significantly higher risk for a major adverse cardiovascular event after PCI. The clinical trials which demonstrate improved clinical outcomes when clopidogrel is compared with other antiplatelet agents suggest that the above-mentioned in vitro metrics are clinically relevant.
I’ve heard a lot about testing platelet aggregability. Should I be considering that for my patients?
Not at the present time. One prospective study evaluated the capability of platelet function tests to predict clinical outcome in patients taking clopidogrel undergoing elective stent implantation.33 On-treatment platelet reactivity was measured using: light transmittance aggregometry, VerifyNow P2Y12, Plateletworks, and the IMPACT-R and the platelet function analysis system (PFA-100) (with the Dade PFA collagen/ADP cartridge and Innovance PFA P2Y). After 1 year of follow-up, only the light transmittance aggregometry, VerifyNow, Plateletworks, and Innovance PFA P2Y tests were significantly associated with patient outcome, but had only modest predictive accuracy. Also, none of the tests studied provided accurate prognostic information to identify patients at higher risk of bleeding following stent implantation.
How concerning are the findings on ticagrelor and dyspnea?
The occurrence of dyspnea associated with ticagrelor was observed during its clinical development. While the mechanism is not known, dyspnea is a transient phenomenon, and there is no suggestion that ticagrelor is associated with an increased incidence of heart failure.
The incidence and characterization of dyspnea has been investigated in subanalyses of 2 large clinical trials of ticagrelor. Prospective analysis of the ONSET/OFFSET study (N = 123) showed that dyspnea was experienced by more patients treated with ticagrelor than clopidogrel or placebo over 6 weeks (38.6% vs 9.3% vs 8.3%, respectively; P < .001).34 Episodes of dyspnea were generally mild, lasted <24 hours, and easily tolerated. Moderate dyspnea that led to study discontinuation occurred in 3 patients (5.3%) treated with ticagrelor. Dyspnea occurred within the first 24 hours in 8 of 22 patients (36.4%) and within the first week in 17 of 22 patients (77.3%) of the ticagrelor-treated patients who experienced dyspnea. Dyspnea persisted through the study follow-up (10 days after the 6 week study) in 3 of 22 patients (13.6%) treated with ticagrelor. Dyspnea was not associated with any significant adverse change in cardiac or pulmonary function tests.34
In a subanalysis of the PLATO study to investigate the occurrence of dyspnea (N = 18,421), dyspnea occurred in 14.5% of patients treated with ticagrelor and 8.7% of patients treated with clopidogrel.35 Severe dyspnea occurred in 0.4% and 0.3% of patients, respectively. Dyspnea had no impact on the composite end point after excluding dyspnea that occurred after the secondary end point of MI. The mechanism whereby ticagrelor induces dyspnea is not certain, but may be mediated via an adenosine-related mechanism.36
Conclusion
Aspirin and clopidogrel have been the predominant antiplatelet agents used in the management of patients with ACS, yet their use can be challenging. Differences in the clinical pharmacology of prasugrel and ticagrelor provide the opportunity to address some of these challenges and better enable antiplatelet therapy to be individualized.
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21. Goodman SG, Clare R, Pieper KS, et al. Association of proton pump inhibitor use on cardiovascular outcomes with clopidogrel and ticagrelor: insights from the platelet inhibition and patient outcomes trial. Circulation. 2012;125(8):978-986.
22. Bhatt DL, Cryer BL, Contant CF, et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med. 2010;363(20):1909-1917.
23. Chan FK, Chung SC, Suen BY, et al. Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med. 2001;344(13):967-973.
24. Hawkey CJ, Karrasch JA, Szczepañski L, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group. N Engl J Med. 1998;338(11):727-734.
25. Yeomans ND, Tulassay Z, Juhász L, et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group. N Engl J Med. 1998;338(11):719-726.
26. Lai KC, Chu KM, Hui WM, et al. Esomeprazole with aspirin versus clopidogrel for prevention of recurrent gastrointestinal ulcer complications. Clin Gastroenterol Hepatol. 2006;4(7):860-865.
27. Chan FK, Ching JY, Hung LC, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med. 2005;352(3):238-244.
28. Lai KC, Lam SK, Chu KM, et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med. 2002;346(26):2033-2038.
29. Plavix [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; 2011.
30. Gurbel PA, Bliden KP, Butler K, et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study. Circulation. 2010;121(10):1188-1199.
31. Wiviott SD, Trenk D, Frelinger AL, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation. 2007;116(25):2923-2932.
32. Bonello L, Pansieri M, Mancini J, et al. High on-treatment platelet reactivity after prasugrel loading dose and cardiovascular events after percutaneous coronary intervention in acute coronary syndromes. J Am Coll Cardiol 2011;58(5):467-473.
33. Breet NJ, van Werkum JW, Bouman HJ, et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA. 2010;303(8):754-762.
34. Storey RF, Bliden KP, Patil SB, et al. Incidence of dyspnea and assessment of cardiac and pulmonary function in patients with stable coronary artery disease receiving ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET study. J Am Coll Cardiol. 2010;56(3):185-193.
35. Storey RF, Becker RC, Harrington RA, et al. Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J. 2011;32(23):2945-2953.
36. Gan L-M, Wittfeldt A, Emanuelsson H, Nylander S, Jonasson J. Adenosine may mediate ticagrelor-induced dyspnea. J Am Coll Cardiol 2012;59(13):E344-
Managing the Multiple Symptoms of Benign Prostatic Hyperplasia — CME
Managing Type 2 Diabetes in Men
Meeting New Challenges with Antiplatelet Therapy in Primary Care
Dr. Kuritzky has nothing to disclose.
Dr. Díez has nothing to disclose.
SUPPORT
This program is sponsored by the PCEC and supported by funding from AstraZeneca. Dr. Kuritzky received no financial support for this article.
Introduction
The importance of acute coronary syndrome (ACS) (ie, patients with ST-segment elevation myocardial infarction [MI] [STEMI], non-ST segment elevation MI [NSTEMI], or unstable angina) in primary care is highlighted by its prevalence. Acute coronary syndrome was the primary or secondary discharge diagnosis in 1.19 million hospitalizations in the United States in 2009, a slight majority of which were in men.1 Platelet activation plays a central role in the pathophysiology of ACS. Despite well established benefits of antiplatelet therapy in both primary and secondary prevention of ACS, adverse events—particularly bleeding—require ongoing vigilance.2 Among the several classes of antiplatelet agents currently available, the thromboxane A2 inhibitor (ie, aspirin) and P2Y12 inhibitors (ie, clopidogrel, prasugrel, and ticagrelor) are those most commonly used; ticlopidine is not commonly used due to nausea/vomiting and bone marrow toxicity.3
Antiplatelet Agents
It is well established that hemostasis is protected by multilayered, overlapping, and sometimes redundant pathways. Even though currently available antiplatelet agents are highly efficacious in inhibiting 1 or more phases of platelet activity pertinent to coagulation (eg, activation, adhesion, and aggregation), because of the multiple backup pathways involved, no single antiplatelet agent is anticipated to totally eliminate platelet activity. In addition, every combination of antiplatelet agents—though potentially more efficacious because of multipathway activity—is also laden with greater bleeding risk. The 3 primary pathways of platelet activation for which pharmacologic antagonists have been developed are the thromboxane, adenosine diphosphonate (ADP)-P2Y12, and ADP-A2 pathways. While dual antiplatelet therapy with aspirin and clopidogrel may be the current standard of care, the focus of this review is on the ADP-P2Y12 inhibitors as the two newest agents, prasugrel and ticagrelor, are less familiar to family physicians. The second section addresses questions often encountered by family physicians when caring for patients who have recently experienced ACS.
P2Y12 Inhibitors
Two groups of agents exert their antiplatelet effects by inhibiting the platelet P2Y12 receptor: (1) thienopyridines (ie, ticlopidine, clopidogrel, and prasugrel) and (2) the cyclopentyltriazolopyrimidines (ie, ticagrelor). Both groups inhibit ADP-dependent platelet function but at different sites on the platelet P2Y12 receptor. Thienopyridine activity is mediated via short-lived active metabolites formed in the liver. Platelet exposure to the active metabolite of prasugrel is about 10-fold higher than to the active metabolite of clopidogrel, resulting in a higher level and less individual variation of platelet inhibition with prasugrel. Hepatic metabolism of clopidogrel makes it subject to genetic, as well as drug-induced, variation in activity; prasugrel is not affected by these same limitations. Recovery of platelet function following withdrawal of thienopyridine therapy occurs over 7 to 8 days as a function of platelet turnover.2,3 This slow recovery of platelet function has important implications when any surgical intervention is needed.
In contrast to the thienopyridines, ticagrelor does not require metabolic activation by the liver. Ticagrelor and its active metabolite display approximately equipotent antiplatelet activity and are direct P2Y12 inhibitors. Ticargrelor non-competitively antagonizes ADP-induced receptor activation. Ticagrelor is rapidly absorbed reaching its peak plasma concentration in 1.5 to 3 hours, thereby providing a rapid antiplatelet effect. Twice-daily administration is required because of its rapid offset of platelet inhibition.2,4,5
Prasugrel
Prasugrel is indicated by the US Food and Drug Administration (FDA) for reduction of thrombotic cardiovascular (CV) events (including stent thrombosis) in patients with ACS who are to be managed with percutaneous coronary intervention (PCI) as follows: (1) unstable angina or NSTEMI or (2) STEMI when managed with primary or delayed PCI.6
The efficacy and safety of prasugrel have been investigated in several clinical trials. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 is the largest and has many planned sub-analyses ( TABLE 1 ).7-9 TRITON TIMI 38 involved patients with moderate- to high-risk ACS scheduled for PCI
(N = 13,608).7 Patients were randomized to prasugrel 60 mg as a loading dose followed by 10 mg daily or clopidogrel 300 mg as a loading dose followed by 75 mg daily for 6 to 15 months. Aspirin 75 to 162 mg once daily was recommended, but was left up to the physician. The primary efficacy end point was a composite of CV death, nonfatal MI, or nonfatal stroke.
Findings from TRITON TIMI 38 show that, compared with clopidogrel, prasugrel was associated with significantly reduced rates of ischemic events, including nonfatal MI and stent thrombosis. The benefit with prasugrel was primarily due to a significant reduction in the rate of MI compared with clopidogrel. However, patients treated with prasugrel experienced a higher rate of major bleeding, including fatal and life-threatening bleeding. Prasugrel was found to be more effective than clopidogrel in preventing ischemic events without excess bleeding in patients with STEMI undergoing secondary PCI (treated between 12 hours and 14 days after symptom onset). In patients with ACS undergoing PCI without stent implantation, ischemic events occurred at similar rates in patients treated with prasugrel or clopidogrel; however, bleeding was more common with prasugrel.
Not all patients benefited from prasugrel therapy. Compared with clopidogrel, patients with previous stroke/transient ischemic attack (TIA) had net harm from prasugrel. In addition, no net benefit from prasugrel compared with clopidogrel was observed in patients age ≥75 years or body weight <60 kg. The results of TRITON TIMI 38 contributed to the boxed warnings regarding bleeding risk recommending that prasugrel not be used in patients age ≥75 years, in patients with active pathological bleeding or a history of TIA or stroke, or patients likely to undergo coronary artery bypass graft (CABG) surgery. In addition, patients with body weight < 60 kg are also at increased risk for bleeding.6
TABLE 1
Prasugrel: TRITON-TIMI 38 and subanalyses
| TRITON-TIMI 38 Cohort7 | TRITON-TIMI 38 Selected Subanalyses8,9 | ||
|---|---|---|---|
| Treatment | Pr 60 mg LD, then 10 mg QD or Cl 300 mg LD, then 75 mg QD plus Aspirin 75-162 mg QD for 6-15 mos (median 14.5 mos) | ||
| Population | Moderate/High-risk ACS scheduled for PCI (N = 13,608) | PCI for STEMI (N = 3534) | PCI without ST elevation (N = 569) |
| Efficacy Outcomes | Primary end point (CV death, nonfatal MI, or nonfatal stroke):
(P = .31) Nonfatal MI: Cl 9.5% vs Pr 7.3% (P < .001) Nonfatal stroke: Cl 1.0% vs Pr 1.0% (P = .93) Urgent target-vessel revascularization: Cl 3.7% vs Pr 2.5% (P < .001) Stent thrombosis: Cl 2.4% vs Pr 1.1% (P < .001) | Primary end point (CV death, nonfatal MI, or nonfatal stroke):
| Primary end point (CV death, nonfatal MI, or nonfatal stroke): Cl 17.1% vs Pr 14.2% (P = .27) Urgent target-vessel revascularization: Cl 8.2% vs Pr 3.6% (P = .04) |
| Safety Outcomes | Non-CABG TIMI major bleeding: Cl 1.8% vs Pr 2.4% (P = .03) Fatal bleeding: Cl 0.1% vs Pr 0.4% (P = .002) Life-threatening bleeding: Cl 0.9% vs Pr 1.4% (P = .01) Non-fatal bleeding: Cl 0.9% vs Pr 1.1% (P = .23) | TIMI major bleedinga unrelated to CABG:
| TIMI major bleedinga unrelated to CABG: Cl 0% vs Pr 2.1% (P = .03) |
| Key Findings | Prasugrel was associated with significantly reduced rates of ischemic events, including nonfatal MI and stent thrombosis, but with an increased risk of major bleeding, including fatal and life-threatening bleeding. Compared to clopidogrel, patients with previous stroke/TIA had net harm from prasugrel; patients with age ≥ 75 y had no net benefit from prasugrel; patients with BW < 60 kg had no net benefit from prasugrel. | Net clinical outcome All-cause death, MI, stroke, TIMI major bleeding unrelated to CABG:
| In patients with ACS undergoing PCI without stent implantation, ischemic events occurred at similar rates in patients treated with prasugrel or clopidogrel; however, bleeding was more common with prasugrel. |
| ACS, acute coronary syndrome; BW, body weight; CABG, coronary artery bypass graft; Cl, clopidogrel; CV, cardiovascular; LD, loading dose; MI, myocardial infarction; PCI, percutaneous coronary intervention; Pr, prasugrel; QD, once daily; STEMI, ST-segment elevation in myocardial infarction; TIA, transient ischemic attack; TIMI, thrombolysis in myocardial infarction. aTIMI major bleed (intracranial bleed or intrapericardial bleed with cardiac tamponade or a decline of 5.0 g/dL or more in hemoglobin after adjusting for red blood cell transfusions). | |||
Ticagrelor
Ticagrelor is the most recent antiplatelet agent to be approved by the US FDA. Ticagrelor is indicated to reduce the rate of thrombotic CV events in patients with ACS (eg, unstable angina, NSTEMI, or STEMI).10
The efficacy and safety of ticagrelor has been assessed in the Study of Platelet Inhibition and Patient Outcomes (PLATO) and several planned sub-analyses ( TABLE 2 ).11-16 PLATO was a 12-month, multicenter, double-blind, randomized trial that involved patients with ACS with or without ST-segment elevation (N = 18,624).11 Patients were randomized to ticagrelor 180 mg loading dose then 90 mg twice daily or clopidogrel 300 to 600 mg loading dose then 75 mg once daily for 12 months. The primary efficacy end point was a composite of death from vascular causes, MI, or stroke.
The results of PLATO and sub-analyses show that in patients with ACS and compared with clopidogrel, ticagrelor significantly reduced the primary efficacy end point with a similar rate of major bleeding
( TABLE 1 ). These safety results contributed to the boxed warnings regarding bleeding risk that ticagrelor not be used in patients with active pathological bleeding or a history of intracranial hemorrhage, or in patients planned to undergo urgent CABG surgery. In addition, maintenance aspirin therapy at a dose above 100 mg reduces the effectiveness of ticagrelor and should be avoided.10
Consistent with the general PLATO population, in patients intended for non-invasive management, ticagrelor significantly reduced the rate of death from vascular causes, MI, or stroke compared with clopidogrel with a similar rate of major bleeding. In patients with ACS and ST elevation or left bundle branch block planned for PCI, ticagrelor reduced CV and all-cause death, MI, stent thrombosis, and improved survival compared with clopidogrel, with a similar rate of major bleeding. Ticagrelor, compared with clopidogrel, reduced all-cause and CV death without excess risk of CABG-related bleeding in patients with ACS undergoing CABG within 7 days of the last dose of clopidogrel or ticagrelor. Finally, in ACS with chronic kidney disease (estimated creatinine clearance < 60 mL/minute), ticagrelor compared with clopidogrel significantly reduced ischemic end points and mortality without a significant increase in major bleeding and with a similar rate of non–CABG-related bleeding.
TABLE 2
Ticagrelor: PLATO and subanalyses
| PLATO Cohort9,12 | PLATO Selected Subanalyses13-16 | ||||
|---|---|---|---|---|---|
| Treatment | Ti 180 mg LD, then 90 mg BID or Cl 300-600 mg LD then 75 mg QD plus Aspirin 75-325 mg QD for 12 months | ||||
| Population | ACS with/without ST elevation (N = 18,624) | ACS planned for non-invasive management (N = 5216) | ACS with ST elevation or left bundle branch block planned for PCI (N = 7544) | ACS with/without ST elevation managed with CABG (N = 1261) | ACS with/without ST elevation but with chronic kidney disease (eCrCl < 60 mL/min) (n = 3237) |
| Efficacy Outcomes | Primary end point (death from vascular causes, MI, or stroke): Cl 11.7% vs Ti 9.8% (P < .001) Death from any cause, MI, or stroke: Cl 12.3% vs Ti 10.2% (P < .001) Death from any cause, MI, stroke, severe recurrent ischemia, recurrent ischemia, TIA, or other arterial thrombotic event: Cl 16.7% vs Ti 14.6% (P < .001) Death from nonvascular causes: Cl 0.8% vs Ti 0.5% (P = .08) | Primary end point (death from vascular causes, MI, or stroke): Cl 14.3% vs. Ti 12.0% (P = .045) CV death: Cl 7.2% vs Ti 5.5% (P = .019) | Primary end point (death from vascular causes, MI, or stroke): Cl 10.8% vs Ti 9.4% (P = .07) CV death, MI (excluding silent): Cl 10.2% vs Ti 8.4% (P = .01) All cause death, MI (excluding silent), stroke: Cl 11.3% vs Ti 9.8% (P = .05) CV death, total MI, stroke, severe recurrent cardiac ischemia, recurrent cardiac ischemia, TIA, arterial thrombotic events: Cl 15.0% vs Ti 13.3% (P = .03) MI (excluding silent): Cl 5.8% vs Ti 4.7% (P = .03) Stroke: Cl 1.0% vs Ti 1.7% (P = .02) All-cause mortality: Cl 6.1% vs Ti 5.0% (P = .05) Definite, probable, or possible stent thrombosis: Cl 4.3% vs Ti 3.3% (P = .04) | Primary end point (death from vascular causes, MI, or stroke): Cl 13.1% vs Ti 10.6% (P = .29) All-cause death: Cl 9.7% vs Ti 4.7% (P < .01) CV death: Cl 7.9% vs Ti 4.1% (P < .01) Non-CV death: Cl 2.0% vs Ti 0.7% (P = .07) Stroke: Cl 2.1% vs Ti 2.1% (P = .70) | Primary end point (death from vascular causes, MI, or stroke): Cl 22.0% vs Ti 17.3% All-cause death: Cl 14.0% vs Ti 10.0% |
| Safety Outcomes | TIMI major bleedinga: Cl 7.7% vs Ti 7.9% (P = .57) TIMI major bleedinga unrelated to CABG: Cl 2.2% vs Ti 2.8% (P = .03) PLATO major bleedingb: Cl 11.2% vs Ti 11.6% (P = .43) PLATO major bleedingb unrelated to CABG: Cl 3.8% vs Ti 4.5% (P = .03) Dyspnea requiring discontinuation: Cl 0.1% vs Ti 0.9% (P < .001) | PLATO major bleedingb: Cl 10.3% vs Ti 11.9% (P = .079) Life-threatening/fatal bleeding: Cl 5.6% vs Ti 5.5% (P= . 911) Major/Minor bleeding unrelated to CABG: Cl 6.7% vs Ti 8.3% (P = .0182) | PLATO major bleeding: Cl 9.2% vs Ti 9.0% (P = .76) TIMI major bleeding: Cl 6.4% vs Ti 6.1% (P = .66) PLATO non-procedure-related major/ minor bleeding: Cl 3.7% vs Ti 5.1% (P = .02) PLATO minor bleeding: Cl 3.8% vs Ti 4.9% (P = .05) Dyspnea requiring discontinuation: Cl 0.1% vs Ti 0.5% (P = .0004) | Major/Life-threatening CABG-related bleeding causing death within 7 d after CABG: Cl 3.0% vs Ti 1.3% (P = .052) Major CABG bleeding: Cl 80.1% vs Ti 81.2% (P = .669) TIMI major CABG bleeding: Cl 57.6% vs Ti 59.3% (P = .53) | PLATO major bleeding: Cl 14.3% vs Ti 15.1% PLATO fatal major bleeding: Cl 0.77% vs Ti 0.34% PLATO non-CABG major bleeding: Cl 7.3% vs Ti 8.5% Dyspnea: Cl 11.5% vs Ti 16.4% |
| Key Findings | Ticagrelor significantly reduced the rate of CV death, MI, or stroke compared to clopidogrel with a similar rate of major bleeding; ticagrelor led to increased major bleeding unrelated to CABG. Fatal bleeding was low and did not differ between groups. | Consistent with the general PLATO population, ticagrelor significantly reduced the rate of CV death, MI, or stroke compared to clopidogrel with a similar rate of major bleeding. | Consistent with the general PLATO population, compared with clopidogrel, ticagrelor reduced CV and all-cause death, MI, stent thrombosis and improved survival without increasing major bleeding. Ticagrelor resulted in a higher rate of stroke. | Ticagrelor compared with clopidogrel reduced all-cause and CV death without excess risk of CABG-related bleeding in patients with ACS undergoing CABG within 7 days of the last dose of clopidogrel or ticagrelor. | In ACS with CKD, ticagrelor compared with clopidogrel significantly reduced ischemic end points and mortality without a significant increase in major bleeding and with a similar rate of non-procedure- related bleeding. |
| ACS, acute coronary syndrome; BID, twice daily; CABG, coronary artery bypass graft; Cl, clopidogrel; CKD, chronic kidney disease; CV, cardiovascular; eCrCL, estimated creatinine clearance; LD, loading dose; MI, myocardial infarction; PCI, percutaneous coronary intervention; QD, once daily; Ti, ticagrelor; TIA, transient ischemic attack; TIMI, thrombolysis in myocardial infarction. aTIMI major bleed (intracranial bleed or intrapericardial bleed with cardiac tamponade or a decline of 5.0 g/dL or more in hemoglobin after adjusting for red blood cell transfusions). bPLATO major bleed (fatal bleeding, intrapericardial bleeding with cardiac tamponade, intracranial bleeding, severe hypotension, or hypovolemic shock due to bleeding and requiring either vasopressors or surgical intervention, a decline in hemoglobin of 5.0 g/dL or more after adjusting for red blood cell transfusions, or the need for transfusion of 4 or more units of packed red blood cells) | |||||
Common Questions Regarding Antiplatelet Therapy in Primary Care
The preceding discussion confirms that many patients with ACS benefit from antiplatelet therapy. However, the use of antiplatelet agents in primary care can be challenging. The following are some of the evolving issues and questions regarding antiplatelet therapy faced by family physicians.
If a patient has experienced gastrointestinal bleeding while taking low-dose aspirin in the past and has an acute coronary syndrome, what course of action should be taken?
Dual antiplatelet therapy is still recommended in this setting, but therapy with a proton pump inhibitor (PPI) for gastrointestinal (GI) protection is recommended.2,3,17 For patients at low risk of upper GI bleeding, routine PPI prophylaxis is not recommended. Currently available data do not demonstrate the prophylactic superiority of one PPI over another, but do show that PPI therapy is more effective in decreasing GI bleeding associated with aspirin and is, therefore, preferred over a histamine H2 receptor antagonist.17 For instance, high-dose famotidine has been shown to be less effective than pantoprazole in patients with aspirin-related peptic ulcers/erosions.18
Can a proton pump inhibitor be used for gastrointestinal protection in conjunction with clopidogrel?
Yes, although the evidence is conflicting about whether specific PPIs should be avoided because of reduced clinical efficacy of clopidogrel. The results of a meta-analysis of 23 studies demonstrated a clinically significant interaction that reduces the antiplatelet effectiveness of clopidogrel when combined with some PPIs.19 The results of 4 prospective, crossover pharmacokinetic studies in healthy subjects (N = 282) also suggest an interaction between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.20 A subanalysis of PLATO showed that the use of a PPI was independently associated with a higher rate of CV events in patients with ACS treated with clopidogrel or ticagrelor.21 The observed effect with both agents, as well as a higher rate of major bleeding among PPI vs non-PPI users suggests that PPI use may be more of a marker for rather than a cause of higher rates of CV events. In fact, data from the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) found that in patients treated with clopidogrel and aspirin, the addition of omeprazole reduced the rate of a GI event, compared with placebo at 180 days (1.1% vs. 2.9%, respectively;
P < .001).22 Overt upper GI bleeding occurred less frequently in the omeprazole group (hazard ratio, 0.13; 95% confidence interval, 0.03 to 0.56; P = .001). A CV event was observed in 4.9% of patients treated with omeprazole and 5.7% of placebo patients (P = .96). While limited, these prospective data do not suggest a detriment to clopidogrel efficacy when used in combination with a PPI. The dose of PPI to use for GI protection is not well-established; the following drugs and doses have been used: omeprazole 20 to 40 mg once daily; esomeprazole 20 mg once or twice daily; pantoprazole 20 mg once daily; or lansoprazole 30 mg once daily.18,23-28
Should I avoid starting clopidogrel in patients with acute coronary syndrome because of concerns about “poor metabolizers”?
Clopidogrel is a prodrug, requiring CYP450 metabolism to its active metabolite. Because of genetic CYP450 variations, as many as one-third of patients lack fully active CYP450 pathways, resulting in reduced (or even absent) conversion from the parent drug to the active metabolite, with a corresponding diminution of antiplatelet effects.3,29 Recent recommendations about dealing with these genetic polymorphisms include direct measurement of CYP450 pathway status and selection of alternative pharmacologic agents which are not dependent upon similar CYP pathway activation. There are, unfortunately, no prospective clinical trials based upon CYP2C19 genotyping confirming that patient selection based upon genotyping is associated with improved outcomes.
In terms of alternative antiplatelet therapy in clopidogrel nonresponders, the Response to Ticagrelor in Clopidogrel Nonresponders and Responders (RESPOND) study shows ticagrelor to be beneficial, at least as measured in vitro.30 Following laboratory assessment of patients’ responsiveness to clopidogrel, both responders and nonresponders were randomized to clopidogrel or ticagrelor. After 14 days, all clopidogrel nonresponders and half of the responders switched treatment. The antiplatelet effects of ticagrelor were similar whether the patient was a clopidogrel responder or not. The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) showed higher inhibition of platelet aggregation (IPA) with prasugrel 60 mg compared with clopidogrel 600 mg 6 hours after initiation.31 Following crossover, IPA was higher in subjects receiving prasugrel 10 mg/d compared with clopidogrel 150 mg/d (61% vs 46%, respectively; P < .0001). While not measuring clopidogrel responsiveness, this suggests that prasugrel might be effective in clopidogrel nonresponders. Not all patients treated with prasugrel achieve optimal inhibition of platelet reactivity. In patients who underwent successful PCI for ACS (N = 301) 25.2% were observed to have high on-treatment platelet reactivity following a 60 mg loading dose of prasugrel.32 Such patients had a significantly higher risk for a major adverse cardiovascular event after PCI. The clinical trials which demonstrate improved clinical outcomes when clopidogrel is compared with other antiplatelet agents suggest that the above-mentioned in vitro metrics are clinically relevant.
I’ve heard a lot about testing platelet aggregability. Should I be considering that for my patients?
Not at the present time. One prospective study evaluated the capability of platelet function tests to predict clinical outcome in patients taking clopidogrel undergoing elective stent implantation.33 On-treatment platelet reactivity was measured using: light transmittance aggregometry, VerifyNow P2Y12, Plateletworks, and the IMPACT-R and the platelet function analysis system (PFA-100) (with the Dade PFA collagen/ADP cartridge and Innovance PFA P2Y). After 1 year of follow-up, only the light transmittance aggregometry, VerifyNow, Plateletworks, and Innovance PFA P2Y tests were significantly associated with patient outcome, but had only modest predictive accuracy. Also, none of the tests studied provided accurate prognostic information to identify patients at higher risk of bleeding following stent implantation.
How concerning are the findings on ticagrelor and dyspnea?
The occurrence of dyspnea associated with ticagrelor was observed during its clinical development. While the mechanism is not known, dyspnea is a transient phenomenon, and there is no suggestion that ticagrelor is associated with an increased incidence of heart failure.
The incidence and characterization of dyspnea has been investigated in subanalyses of 2 large clinical trials of ticagrelor. Prospective analysis of the ONSET/OFFSET study (N = 123) showed that dyspnea was experienced by more patients treated with ticagrelor than clopidogrel or placebo over 6 weeks (38.6% vs 9.3% vs 8.3%, respectively; P < .001).34 Episodes of dyspnea were generally mild, lasted <24 hours, and easily tolerated. Moderate dyspnea that led to study discontinuation occurred in 3 patients (5.3%) treated with ticagrelor. Dyspnea occurred within the first 24 hours in 8 of 22 patients (36.4%) and within the first week in 17 of 22 patients (77.3%) of the ticagrelor-treated patients who experienced dyspnea. Dyspnea persisted through the study follow-up (10 days after the 6 week study) in 3 of 22 patients (13.6%) treated with ticagrelor. Dyspnea was not associated with any significant adverse change in cardiac or pulmonary function tests.34
In a subanalysis of the PLATO study to investigate the occurrence of dyspnea (N = 18,421), dyspnea occurred in 14.5% of patients treated with ticagrelor and 8.7% of patients treated with clopidogrel.35 Severe dyspnea occurred in 0.4% and 0.3% of patients, respectively. Dyspnea had no impact on the composite end point after excluding dyspnea that occurred after the secondary end point of MI. The mechanism whereby ticagrelor induces dyspnea is not certain, but may be mediated via an adenosine-related mechanism.36
Conclusion
Aspirin and clopidogrel have been the predominant antiplatelet agents used in the management of patients with ACS, yet their use can be challenging. Differences in the clinical pharmacology of prasugrel and ticagrelor provide the opportunity to address some of these challenges and better enable antiplatelet therapy to be individualized.
Managing the Multiple Symptoms of Benign Prostatic Hyperplasia — CME
Managing Type 2 Diabetes in Men
Meeting New Challenges with Antiplatelet Therapy in Primary Care
Dr. Kuritzky has nothing to disclose.
Dr. Díez has nothing to disclose.
SUPPORT
This program is sponsored by the PCEC and supported by funding from AstraZeneca. Dr. Kuritzky received no financial support for this article.
Introduction
The importance of acute coronary syndrome (ACS) (ie, patients with ST-segment elevation myocardial infarction [MI] [STEMI], non-ST segment elevation MI [NSTEMI], or unstable angina) in primary care is highlighted by its prevalence. Acute coronary syndrome was the primary or secondary discharge diagnosis in 1.19 million hospitalizations in the United States in 2009, a slight majority of which were in men.1 Platelet activation plays a central role in the pathophysiology of ACS. Despite well established benefits of antiplatelet therapy in both primary and secondary prevention of ACS, adverse events—particularly bleeding—require ongoing vigilance.2 Among the several classes of antiplatelet agents currently available, the thromboxane A2 inhibitor (ie, aspirin) and P2Y12 inhibitors (ie, clopidogrel, prasugrel, and ticagrelor) are those most commonly used; ticlopidine is not commonly used due to nausea/vomiting and bone marrow toxicity.3
Antiplatelet Agents
It is well established that hemostasis is protected by multilayered, overlapping, and sometimes redundant pathways. Even though currently available antiplatelet agents are highly efficacious in inhibiting 1 or more phases of platelet activity pertinent to coagulation (eg, activation, adhesion, and aggregation), because of the multiple backup pathways involved, no single antiplatelet agent is anticipated to totally eliminate platelet activity. In addition, every combination of antiplatelet agents—though potentially more efficacious because of multipathway activity—is also laden with greater bleeding risk. The 3 primary pathways of platelet activation for which pharmacologic antagonists have been developed are the thromboxane, adenosine diphosphonate (ADP)-P2Y12, and ADP-A2 pathways. While dual antiplatelet therapy with aspirin and clopidogrel may be the current standard of care, the focus of this review is on the ADP-P2Y12 inhibitors as the two newest agents, prasugrel and ticagrelor, are less familiar to family physicians. The second section addresses questions often encountered by family physicians when caring for patients who have recently experienced ACS.
P2Y12 Inhibitors
Two groups of agents exert their antiplatelet effects by inhibiting the platelet P2Y12 receptor: (1) thienopyridines (ie, ticlopidine, clopidogrel, and prasugrel) and (2) the cyclopentyltriazolopyrimidines (ie, ticagrelor). Both groups inhibit ADP-dependent platelet function but at different sites on the platelet P2Y12 receptor. Thienopyridine activity is mediated via short-lived active metabolites formed in the liver. Platelet exposure to the active metabolite of prasugrel is about 10-fold higher than to the active metabolite of clopidogrel, resulting in a higher level and less individual variation of platelet inhibition with prasugrel. Hepatic metabolism of clopidogrel makes it subject to genetic, as well as drug-induced, variation in activity; prasugrel is not affected by these same limitations. Recovery of platelet function following withdrawal of thienopyridine therapy occurs over 7 to 8 days as a function of platelet turnover.2,3 This slow recovery of platelet function has important implications when any surgical intervention is needed.
In contrast to the thienopyridines, ticagrelor does not require metabolic activation by the liver. Ticagrelor and its active metabolite display approximately equipotent antiplatelet activity and are direct P2Y12 inhibitors. Ticargrelor non-competitively antagonizes ADP-induced receptor activation. Ticagrelor is rapidly absorbed reaching its peak plasma concentration in 1.5 to 3 hours, thereby providing a rapid antiplatelet effect. Twice-daily administration is required because of its rapid offset of platelet inhibition.2,4,5
Prasugrel
Prasugrel is indicated by the US Food and Drug Administration (FDA) for reduction of thrombotic cardiovascular (CV) events (including stent thrombosis) in patients with ACS who are to be managed with percutaneous coronary intervention (PCI) as follows: (1) unstable angina or NSTEMI or (2) STEMI when managed with primary or delayed PCI.6
The efficacy and safety of prasugrel have been investigated in several clinical trials. The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 is the largest and has many planned sub-analyses ( TABLE 1 ).7-9 TRITON TIMI 38 involved patients with moderate- to high-risk ACS scheduled for PCI
(N = 13,608).7 Patients were randomized to prasugrel 60 mg as a loading dose followed by 10 mg daily or clopidogrel 300 mg as a loading dose followed by 75 mg daily for 6 to 15 months. Aspirin 75 to 162 mg once daily was recommended, but was left up to the physician. The primary efficacy end point was a composite of CV death, nonfatal MI, or nonfatal stroke.
Findings from TRITON TIMI 38 show that, compared with clopidogrel, prasugrel was associated with significantly reduced rates of ischemic events, including nonfatal MI and stent thrombosis. The benefit with prasugrel was primarily due to a significant reduction in the rate of MI compared with clopidogrel. However, patients treated with prasugrel experienced a higher rate of major bleeding, including fatal and life-threatening bleeding. Prasugrel was found to be more effective than clopidogrel in preventing ischemic events without excess bleeding in patients with STEMI undergoing secondary PCI (treated between 12 hours and 14 days after symptom onset). In patients with ACS undergoing PCI without stent implantation, ischemic events occurred at similar rates in patients treated with prasugrel or clopidogrel; however, bleeding was more common with prasugrel.
Not all patients benefited from prasugrel therapy. Compared with clopidogrel, patients with previous stroke/transient ischemic attack (TIA) had net harm from prasugrel. In addition, no net benefit from prasugrel compared with clopidogrel was observed in patients age ≥75 years or body weight <60 kg. The results of TRITON TIMI 38 contributed to the boxed warnings regarding bleeding risk recommending that prasugrel not be used in patients age ≥75 years, in patients with active pathological bleeding or a history of TIA or stroke, or patients likely to undergo coronary artery bypass graft (CABG) surgery. In addition, patients with body weight < 60 kg are also at increased risk for bleeding.6
TABLE 1
Prasugrel: TRITON-TIMI 38 and subanalyses
| TRITON-TIMI 38 Cohort7 | TRITON-TIMI 38 Selected Subanalyses8,9 | ||
|---|---|---|---|
| Treatment | Pr 60 mg LD, then 10 mg QD or Cl 300 mg LD, then 75 mg QD plus Aspirin 75-162 mg QD for 6-15 mos (median 14.5 mos) | ||
| Population | Moderate/High-risk ACS scheduled for PCI (N = 13,608) | PCI for STEMI (N = 3534) | PCI without ST elevation (N = 569) |
| Efficacy Outcomes | Primary end point (CV death, nonfatal MI, or nonfatal stroke):
(P = .31) Nonfatal MI: Cl 9.5% vs Pr 7.3% (P < .001) Nonfatal stroke: Cl 1.0% vs Pr 1.0% (P = .93) Urgent target-vessel revascularization: Cl 3.7% vs Pr 2.5% (P < .001) Stent thrombosis: Cl 2.4% vs Pr 1.1% (P < .001) | Primary end point (CV death, nonfatal MI, or nonfatal stroke):
| Primary end point (CV death, nonfatal MI, or nonfatal stroke): Cl 17.1% vs Pr 14.2% (P = .27) Urgent target-vessel revascularization: Cl 8.2% vs Pr 3.6% (P = .04) |
| Safety Outcomes | Non-CABG TIMI major bleeding: Cl 1.8% vs Pr 2.4% (P = .03) Fatal bleeding: Cl 0.1% vs Pr 0.4% (P = .002) Life-threatening bleeding: Cl 0.9% vs Pr 1.4% (P = .01) Non-fatal bleeding: Cl 0.9% vs Pr 1.1% (P = .23) | TIMI major bleedinga unrelated to CABG:
| TIMI major bleedinga unrelated to CABG: Cl 0% vs Pr 2.1% (P = .03) |
| Key Findings | Prasugrel was associated with significantly reduced rates of ischemic events, including nonfatal MI and stent thrombosis, but with an increased risk of major bleeding, including fatal and life-threatening bleeding. Compared to clopidogrel, patients with previous stroke/TIA had net harm from prasugrel; patients with age ≥ 75 y had no net benefit from prasugrel; patients with BW < 60 kg had no net benefit from prasugrel. | Net clinical outcome All-cause death, MI, stroke, TIMI major bleeding unrelated to CABG:
| In patients with ACS undergoing PCI without stent implantation, ischemic events occurred at similar rates in patients treated with prasugrel or clopidogrel; however, bleeding was more common with prasugrel. |
| ACS, acute coronary syndrome; BW, body weight; CABG, coronary artery bypass graft; Cl, clopidogrel; CV, cardiovascular; LD, loading dose; MI, myocardial infarction; PCI, percutaneous coronary intervention; Pr, prasugrel; QD, once daily; STEMI, ST-segment elevation in myocardial infarction; TIA, transient ischemic attack; TIMI, thrombolysis in myocardial infarction. aTIMI major bleed (intracranial bleed or intrapericardial bleed with cardiac tamponade or a decline of 5.0 g/dL or more in hemoglobin after adjusting for red blood cell transfusions). | |||
Ticagrelor
Ticagrelor is the most recent antiplatelet agent to be approved by the US FDA. Ticagrelor is indicated to reduce the rate of thrombotic CV events in patients with ACS (eg, unstable angina, NSTEMI, or STEMI).10
The efficacy and safety of ticagrelor has been assessed in the Study of Platelet Inhibition and Patient Outcomes (PLATO) and several planned sub-analyses ( TABLE 2 ).11-16 PLATO was a 12-month, multicenter, double-blind, randomized trial that involved patients with ACS with or without ST-segment elevation (N = 18,624).11 Patients were randomized to ticagrelor 180 mg loading dose then 90 mg twice daily or clopidogrel 300 to 600 mg loading dose then 75 mg once daily for 12 months. The primary efficacy end point was a composite of death from vascular causes, MI, or stroke.
The results of PLATO and sub-analyses show that in patients with ACS and compared with clopidogrel, ticagrelor significantly reduced the primary efficacy end point with a similar rate of major bleeding
( TABLE 1 ). These safety results contributed to the boxed warnings regarding bleeding risk that ticagrelor not be used in patients with active pathological bleeding or a history of intracranial hemorrhage, or in patients planned to undergo urgent CABG surgery. In addition, maintenance aspirin therapy at a dose above 100 mg reduces the effectiveness of ticagrelor and should be avoided.10
Consistent with the general PLATO population, in patients intended for non-invasive management, ticagrelor significantly reduced the rate of death from vascular causes, MI, or stroke compared with clopidogrel with a similar rate of major bleeding. In patients with ACS and ST elevation or left bundle branch block planned for PCI, ticagrelor reduced CV and all-cause death, MI, stent thrombosis, and improved survival compared with clopidogrel, with a similar rate of major bleeding. Ticagrelor, compared with clopidogrel, reduced all-cause and CV death without excess risk of CABG-related bleeding in patients with ACS undergoing CABG within 7 days of the last dose of clopidogrel or ticagrelor. Finally, in ACS with chronic kidney disease (estimated creatinine clearance < 60 mL/minute), ticagrelor compared with clopidogrel significantly reduced ischemic end points and mortality without a significant increase in major bleeding and with a similar rate of non–CABG-related bleeding.
TABLE 2
Ticagrelor: PLATO and subanalyses
| PLATO Cohort9,12 | PLATO Selected Subanalyses13-16 | ||||
|---|---|---|---|---|---|
| Treatment | Ti 180 mg LD, then 90 mg BID or Cl 300-600 mg LD then 75 mg QD plus Aspirin 75-325 mg QD for 12 months | ||||
| Population | ACS with/without ST elevation (N = 18,624) | ACS planned for non-invasive management (N = 5216) | ACS with ST elevation or left bundle branch block planned for PCI (N = 7544) | ACS with/without ST elevation managed with CABG (N = 1261) | ACS with/without ST elevation but with chronic kidney disease (eCrCl < 60 mL/min) (n = 3237) |
| Efficacy Outcomes | Primary end point (death from vascular causes, MI, or stroke): Cl 11.7% vs Ti 9.8% (P < .001) Death from any cause, MI, or stroke: Cl 12.3% vs Ti 10.2% (P < .001) Death from any cause, MI, stroke, severe recurrent ischemia, recurrent ischemia, TIA, or other arterial thrombotic event: Cl 16.7% vs Ti 14.6% (P < .001) Death from nonvascular causes: Cl 0.8% vs Ti 0.5% (P = .08) | Primary end point (death from vascular causes, MI, or stroke): Cl 14.3% vs. Ti 12.0% (P = .045) CV death: Cl 7.2% vs Ti 5.5% (P = .019) | Primary end point (death from vascular causes, MI, or stroke): Cl 10.8% vs Ti 9.4% (P = .07) CV death, MI (excluding silent): Cl 10.2% vs Ti 8.4% (P = .01) All cause death, MI (excluding silent), stroke: Cl 11.3% vs Ti 9.8% (P = .05) CV death, total MI, stroke, severe recurrent cardiac ischemia, recurrent cardiac ischemia, TIA, arterial thrombotic events: Cl 15.0% vs Ti 13.3% (P = .03) MI (excluding silent): Cl 5.8% vs Ti 4.7% (P = .03) Stroke: Cl 1.0% vs Ti 1.7% (P = .02) All-cause mortality: Cl 6.1% vs Ti 5.0% (P = .05) Definite, probable, or possible stent thrombosis: Cl 4.3% vs Ti 3.3% (P = .04) | Primary end point (death from vascular causes, MI, or stroke): Cl 13.1% vs Ti 10.6% (P = .29) All-cause death: Cl 9.7% vs Ti 4.7% (P < .01) CV death: Cl 7.9% vs Ti 4.1% (P < .01) Non-CV death: Cl 2.0% vs Ti 0.7% (P = .07) Stroke: Cl 2.1% vs Ti 2.1% (P = .70) | Primary end point (death from vascular causes, MI, or stroke): Cl 22.0% vs Ti 17.3% All-cause death: Cl 14.0% vs Ti 10.0% |
| Safety Outcomes | TIMI major bleedinga: Cl 7.7% vs Ti 7.9% (P = .57) TIMI major bleedinga unrelated to CABG: Cl 2.2% vs Ti 2.8% (P = .03) PLATO major bleedingb: Cl 11.2% vs Ti 11.6% (P = .43) PLATO major bleedingb unrelated to CABG: Cl 3.8% vs Ti 4.5% (P = .03) Dyspnea requiring discontinuation: Cl 0.1% vs Ti 0.9% (P < .001) | PLATO major bleedingb: Cl 10.3% vs Ti 11.9% (P = .079) Life-threatening/fatal bleeding: Cl 5.6% vs Ti 5.5% (P= . 911) Major/Minor bleeding unrelated to CABG: Cl 6.7% vs Ti 8.3% (P = .0182) | PLATO major bleeding: Cl 9.2% vs Ti 9.0% (P = .76) TIMI major bleeding: Cl 6.4% vs Ti 6.1% (P = .66) PLATO non-procedure-related major/ minor bleeding: Cl 3.7% vs Ti 5.1% (P = .02) PLATO minor bleeding: Cl 3.8% vs Ti 4.9% (P = .05) Dyspnea requiring discontinuation: Cl 0.1% vs Ti 0.5% (P = .0004) | Major/Life-threatening CABG-related bleeding causing death within 7 d after CABG: Cl 3.0% vs Ti 1.3% (P = .052) Major CABG bleeding: Cl 80.1% vs Ti 81.2% (P = .669) TIMI major CABG bleeding: Cl 57.6% vs Ti 59.3% (P = .53) | PLATO major bleeding: Cl 14.3% vs Ti 15.1% PLATO fatal major bleeding: Cl 0.77% vs Ti 0.34% PLATO non-CABG major bleeding: Cl 7.3% vs Ti 8.5% Dyspnea: Cl 11.5% vs Ti 16.4% |
| Key Findings | Ticagrelor significantly reduced the rate of CV death, MI, or stroke compared to clopidogrel with a similar rate of major bleeding; ticagrelor led to increased major bleeding unrelated to CABG. Fatal bleeding was low and did not differ between groups. | Consistent with the general PLATO population, ticagrelor significantly reduced the rate of CV death, MI, or stroke compared to clopidogrel with a similar rate of major bleeding. | Consistent with the general PLATO population, compared with clopidogrel, ticagrelor reduced CV and all-cause death, MI, stent thrombosis and improved survival without increasing major bleeding. Ticagrelor resulted in a higher rate of stroke. | Ticagrelor compared with clopidogrel reduced all-cause and CV death without excess risk of CABG-related bleeding in patients with ACS undergoing CABG within 7 days of the last dose of clopidogrel or ticagrelor. | In ACS with CKD, ticagrelor compared with clopidogrel significantly reduced ischemic end points and mortality without a significant increase in major bleeding and with a similar rate of non-procedure- related bleeding. |
| ACS, acute coronary syndrome; BID, twice daily; CABG, coronary artery bypass graft; Cl, clopidogrel; CKD, chronic kidney disease; CV, cardiovascular; eCrCL, estimated creatinine clearance; LD, loading dose; MI, myocardial infarction; PCI, percutaneous coronary intervention; QD, once daily; Ti, ticagrelor; TIA, transient ischemic attack; TIMI, thrombolysis in myocardial infarction. aTIMI major bleed (intracranial bleed or intrapericardial bleed with cardiac tamponade or a decline of 5.0 g/dL or more in hemoglobin after adjusting for red blood cell transfusions). bPLATO major bleed (fatal bleeding, intrapericardial bleeding with cardiac tamponade, intracranial bleeding, severe hypotension, or hypovolemic shock due to bleeding and requiring either vasopressors or surgical intervention, a decline in hemoglobin of 5.0 g/dL or more after adjusting for red blood cell transfusions, or the need for transfusion of 4 or more units of packed red blood cells) | |||||
Common Questions Regarding Antiplatelet Therapy in Primary Care
The preceding discussion confirms that many patients with ACS benefit from antiplatelet therapy. However, the use of antiplatelet agents in primary care can be challenging. The following are some of the evolving issues and questions regarding antiplatelet therapy faced by family physicians.
If a patient has experienced gastrointestinal bleeding while taking low-dose aspirin in the past and has an acute coronary syndrome, what course of action should be taken?
Dual antiplatelet therapy is still recommended in this setting, but therapy with a proton pump inhibitor (PPI) for gastrointestinal (GI) protection is recommended.2,3,17 For patients at low risk of upper GI bleeding, routine PPI prophylaxis is not recommended. Currently available data do not demonstrate the prophylactic superiority of one PPI over another, but do show that PPI therapy is more effective in decreasing GI bleeding associated with aspirin and is, therefore, preferred over a histamine H2 receptor antagonist.17 For instance, high-dose famotidine has been shown to be less effective than pantoprazole in patients with aspirin-related peptic ulcers/erosions.18
Can a proton pump inhibitor be used for gastrointestinal protection in conjunction with clopidogrel?
Yes, although the evidence is conflicting about whether specific PPIs should be avoided because of reduced clinical efficacy of clopidogrel. The results of a meta-analysis of 23 studies demonstrated a clinically significant interaction that reduces the antiplatelet effectiveness of clopidogrel when combined with some PPIs.19 The results of 4 prospective, crossover pharmacokinetic studies in healthy subjects (N = 282) also suggest an interaction between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.20 A subanalysis of PLATO showed that the use of a PPI was independently associated with a higher rate of CV events in patients with ACS treated with clopidogrel or ticagrelor.21 The observed effect with both agents, as well as a higher rate of major bleeding among PPI vs non-PPI users suggests that PPI use may be more of a marker for rather than a cause of higher rates of CV events. In fact, data from the Clopidogrel and the Optimization of Gastrointestinal Events Trial (COGENT) found that in patients treated with clopidogrel and aspirin, the addition of omeprazole reduced the rate of a GI event, compared with placebo at 180 days (1.1% vs. 2.9%, respectively;
P < .001).22 Overt upper GI bleeding occurred less frequently in the omeprazole group (hazard ratio, 0.13; 95% confidence interval, 0.03 to 0.56; P = .001). A CV event was observed in 4.9% of patients treated with omeprazole and 5.7% of placebo patients (P = .96). While limited, these prospective data do not suggest a detriment to clopidogrel efficacy when used in combination with a PPI. The dose of PPI to use for GI protection is not well-established; the following drugs and doses have been used: omeprazole 20 to 40 mg once daily; esomeprazole 20 mg once or twice daily; pantoprazole 20 mg once daily; or lansoprazole 30 mg once daily.18,23-28
Should I avoid starting clopidogrel in patients with acute coronary syndrome because of concerns about “poor metabolizers”?
Clopidogrel is a prodrug, requiring CYP450 metabolism to its active metabolite. Because of genetic CYP450 variations, as many as one-third of patients lack fully active CYP450 pathways, resulting in reduced (or even absent) conversion from the parent drug to the active metabolite, with a corresponding diminution of antiplatelet effects.3,29 Recent recommendations about dealing with these genetic polymorphisms include direct measurement of CYP450 pathway status and selection of alternative pharmacologic agents which are not dependent upon similar CYP pathway activation. There are, unfortunately, no prospective clinical trials based upon CYP2C19 genotyping confirming that patient selection based upon genotyping is associated with improved outcomes.
In terms of alternative antiplatelet therapy in clopidogrel nonresponders, the Response to Ticagrelor in Clopidogrel Nonresponders and Responders (RESPOND) study shows ticagrelor to be beneficial, at least as measured in vitro.30 Following laboratory assessment of patients’ responsiveness to clopidogrel, both responders and nonresponders were randomized to clopidogrel or ticagrelor. After 14 days, all clopidogrel nonresponders and half of the responders switched treatment. The antiplatelet effects of ticagrelor were similar whether the patient was a clopidogrel responder or not. The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 (PRINCIPLE-TIMI 44) showed higher inhibition of platelet aggregation (IPA) with prasugrel 60 mg compared with clopidogrel 600 mg 6 hours after initiation.31 Following crossover, IPA was higher in subjects receiving prasugrel 10 mg/d compared with clopidogrel 150 mg/d (61% vs 46%, respectively; P < .0001). While not measuring clopidogrel responsiveness, this suggests that prasugrel might be effective in clopidogrel nonresponders. Not all patients treated with prasugrel achieve optimal inhibition of platelet reactivity. In patients who underwent successful PCI for ACS (N = 301) 25.2% were observed to have high on-treatment platelet reactivity following a 60 mg loading dose of prasugrel.32 Such patients had a significantly higher risk for a major adverse cardiovascular event after PCI. The clinical trials which demonstrate improved clinical outcomes when clopidogrel is compared with other antiplatelet agents suggest that the above-mentioned in vitro metrics are clinically relevant.
I’ve heard a lot about testing platelet aggregability. Should I be considering that for my patients?
Not at the present time. One prospective study evaluated the capability of platelet function tests to predict clinical outcome in patients taking clopidogrel undergoing elective stent implantation.33 On-treatment platelet reactivity was measured using: light transmittance aggregometry, VerifyNow P2Y12, Plateletworks, and the IMPACT-R and the platelet function analysis system (PFA-100) (with the Dade PFA collagen/ADP cartridge and Innovance PFA P2Y). After 1 year of follow-up, only the light transmittance aggregometry, VerifyNow, Plateletworks, and Innovance PFA P2Y tests were significantly associated with patient outcome, but had only modest predictive accuracy. Also, none of the tests studied provided accurate prognostic information to identify patients at higher risk of bleeding following stent implantation.
How concerning are the findings on ticagrelor and dyspnea?
The occurrence of dyspnea associated with ticagrelor was observed during its clinical development. While the mechanism is not known, dyspnea is a transient phenomenon, and there is no suggestion that ticagrelor is associated with an increased incidence of heart failure.
The incidence and characterization of dyspnea has been investigated in subanalyses of 2 large clinical trials of ticagrelor. Prospective analysis of the ONSET/OFFSET study (N = 123) showed that dyspnea was experienced by more patients treated with ticagrelor than clopidogrel or placebo over 6 weeks (38.6% vs 9.3% vs 8.3%, respectively; P < .001).34 Episodes of dyspnea were generally mild, lasted <24 hours, and easily tolerated. Moderate dyspnea that led to study discontinuation occurred in 3 patients (5.3%) treated with ticagrelor. Dyspnea occurred within the first 24 hours in 8 of 22 patients (36.4%) and within the first week in 17 of 22 patients (77.3%) of the ticagrelor-treated patients who experienced dyspnea. Dyspnea persisted through the study follow-up (10 days after the 6 week study) in 3 of 22 patients (13.6%) treated with ticagrelor. Dyspnea was not associated with any significant adverse change in cardiac or pulmonary function tests.34
In a subanalysis of the PLATO study to investigate the occurrence of dyspnea (N = 18,421), dyspnea occurred in 14.5% of patients treated with ticagrelor and 8.7% of patients treated with clopidogrel.35 Severe dyspnea occurred in 0.4% and 0.3% of patients, respectively. Dyspnea had no impact on the composite end point after excluding dyspnea that occurred after the secondary end point of MI. The mechanism whereby ticagrelor induces dyspnea is not certain, but may be mediated via an adenosine-related mechanism.36
Conclusion
Aspirin and clopidogrel have been the predominant antiplatelet agents used in the management of patients with ACS, yet their use can be challenging. Differences in the clinical pharmacology of prasugrel and ticagrelor provide the opportunity to address some of these challenges and better enable antiplatelet therapy to be individualized.
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25. Yeomans ND, Tulassay Z, Juhász L, et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group. N Engl J Med. 1998;338(11):719-726.
26. Lai KC, Chu KM, Hui WM, et al. Esomeprazole with aspirin versus clopidogrel for prevention of recurrent gastrointestinal ulcer complications. Clin Gastroenterol Hepatol. 2006;4(7):860-865.
27. Chan FK, Ching JY, Hung LC, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med. 2005;352(3):238-244.
28. Lai KC, Lam SK, Chu KM, et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med. 2002;346(26):2033-2038.
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30. Gurbel PA, Bliden KP, Butler K, et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study. Circulation. 2010;121(10):1188-1199.
31. Wiviott SD, Trenk D, Frelinger AL, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation. 2007;116(25):2923-2932.
32. Bonello L, Pansieri M, Mancini J, et al. High on-treatment platelet reactivity after prasugrel loading dose and cardiovascular events after percutaneous coronary intervention in acute coronary syndromes. J Am Coll Cardiol 2011;58(5):467-473.
33. Breet NJ, van Werkum JW, Bouman HJ, et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA. 2010;303(8):754-762.
34. Storey RF, Bliden KP, Patil SB, et al. Incidence of dyspnea and assessment of cardiac and pulmonary function in patients with stable coronary artery disease receiving ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET study. J Am Coll Cardiol. 2010;56(3):185-193.
35. Storey RF, Becker RC, Harrington RA, et al. Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J. 2011;32(23):2945-2953.
36. Gan L-M, Wittfeldt A, Emanuelsson H, Nylander S, Jonasson J. Adenosine may mediate ticagrelor-induced dyspnea. J Am Coll Cardiol 2012;59(13):E344-
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23. Chan FK, Chung SC, Suen BY, et al. Preventing recurrent upper gastrointestinal bleeding in patients with Helicobacter pylori infection who are taking low-dose aspirin or naproxen. N Engl J Med. 2001;344(13):967-973.
24. Hawkey CJ, Karrasch JA, Szczepañski L, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group. N Engl J Med. 1998;338(11):727-734.
25. Yeomans ND, Tulassay Z, Juhász L, et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group. N Engl J Med. 1998;338(11):719-726.
26. Lai KC, Chu KM, Hui WM, et al. Esomeprazole with aspirin versus clopidogrel for prevention of recurrent gastrointestinal ulcer complications. Clin Gastroenterol Hepatol. 2006;4(7):860-865.
27. Chan FK, Ching JY, Hung LC, et al. Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding. N Engl J Med. 2005;352(3):238-244.
28. Lai KC, Lam SK, Chu KM, et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med. 2002;346(26):2033-2038.
29. Plavix [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; 2011.
30. Gurbel PA, Bliden KP, Butler K, et al. Response to ticagrelor in clopidogrel nonresponders and responders and effect of switching therapies: the RESPOND study. Circulation. 2010;121(10):1188-1199.
31. Wiviott SD, Trenk D, Frelinger AL, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation. 2007;116(25):2923-2932.
32. Bonello L, Pansieri M, Mancini J, et al. High on-treatment platelet reactivity after prasugrel loading dose and cardiovascular events after percutaneous coronary intervention in acute coronary syndromes. J Am Coll Cardiol 2011;58(5):467-473.
33. Breet NJ, van Werkum JW, Bouman HJ, et al. Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation. JAMA. 2010;303(8):754-762.
34. Storey RF, Bliden KP, Patil SB, et al. Incidence of dyspnea and assessment of cardiac and pulmonary function in patients with stable coronary artery disease receiving ticagrelor, clopidogrel, or placebo in the ONSET/OFFSET study. J Am Coll Cardiol. 2010;56(3):185-193.
35. Storey RF, Becker RC, Harrington RA, et al. Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J. 2011;32(23):2945-2953.
36. Gan L-M, Wittfeldt A, Emanuelsson H, Nylander S, Jonasson J. Adenosine may mediate ticagrelor-induced dyspnea. J Am Coll Cardiol 2012;59(13):E344-