Practical Knowledge in Antiplatelet Therapy

From Medscape Education Cardiology

John R. Fanikos, RPh, MBA

Authors and Disclosures

INTRODUCTION

Acute coronary syndrome (ACS) is a broad term describing the spectrum of clinical symptoms that reflect acute myocardial ischemia or reduced blood supply to the heart. Urgent revascularization is now recognized as the cornerstone of ACS management. Blood flow can be restored through a narrowed or obstructed blood vessel with either coronary artery bypass graft (CABG) surgery or, more commonly now, using a percutaneous coronary intervention (PCI) procedure. In patients stricken with myocardial infarction (MI), PCI reduces mortality, reinfarction, stroke, recurrent ischemia, and hospitalization when compared with conservative medical management strategies.^[1-3]

The introduction of drug-eluting stents, compared with bare-metal stents, has reduced the need for target vessel revascularization.^[4] However, these procedures and the devices, coupled with a persistent platelet hyperactive state associated with ACS, place patients at additional risk for ischemic events that extends long after clinical stabilization and hospital discharge. To combat this, the use of dual-antiplatelet therapy with complimentary mechanisms of action (most commonly aspirin and clopidogrel) is now a well-established strategy for improving outcomes in both short-term hospital-based invasive procedures^[5,6] as well as in the ambulatory setting^[7,8] for long-term prevention of secondary cardiovascular events. However, improvements in these therapies are needed because there are patients who will still develop atherothrombotic events while receiving currently available antiplatelet agents. The long-term morbidity and mortality after hospitalization remains significant. The recent introduction of prasugrel, as well as the promising investigational agents elinogrel and ticagrelor offer hope for improving care in patients suffering with cardiovascular disease. Pharmacists are uniquely positioned to interact with patients and their families to provide medication information, identify adverse reactions, and ensure compliance to optimize antiplatelet therapy.

Atherosclerosis is a systemic process in which lipids accumulate in the blood vessel walls and gradually develop into plaques that narrow the lumen and alter blood flow. Autopsy and ultrasound studies have shown that these atherosclerotic plaques are widely distributed throughout the body's blood vessels and become pathological in a variety of medical conditions (Figure 1).^[9]

Figure 1. Clinical manifestations of atherosclerotic plaques. From Meadows TA, et al. Circ Res. 2007;100:1261-1275.^[15]

In patients with heart disease, these plaques are located diffusely along the coronary arteries and consist of a lipid-rich core and a sclerotic, collagen-rich hard cap. The core is composed primarily of cholesterol and is normally not exposed to blood flow. However, if a plaque destabilizes and ruptures, the lipid components are exposed to blood, and thrombus formation ensues (Figure 2).^[10]

Figure 2. Rupture of atherosclerotic plaque. From Libby P, et al. Circulation. 2005;111:3481-3488.^[9]

Luminal thrombosis can obstruct blood flow totally or intermittently and gives rise to ACS with symptoms that patients often describe as chest pressure, squeezing, fullness, or pain. This discomfort may also radiate to the neck, jaw, shoulder, back, or arm.^[11] Along with symptoms of chest pain, the diagnosis of ACS is based on changes in the electrocardiogram (ECG) and the presence of biomarkers (creatine kinase-MB and troponin) in the blood that indicate heart muscle damage (Figure 3). An MI can be classified as an ST-elevation MI (STEMI) or a non-ST-elevation MI (non-STEMI) based on ECG changes. Ultimately the clinical presentation and outcome will depend on the severity and duration of myocardial ischemia generated by thrombosis around the culprit lesion.

Role of Platelets

Platelets play a pivotal role in hemostasis, the process of stopping bleeding. While platelets are key to physiologic blood vessel repair, they also have a prominent role in the development of ACS and stroke.^[12]Platelets are produced in the bone marrow and released, where they normally circulate in a disc-shaped resting state. A mature platelet has an expected lifespan of 7-10 days. In response to injury, platelets adhere, become activated, and aggregate with one another, producing a thrombus. The generation of a platelet-dependent thrombus requires 3 steps: (1) platelet adhesion; (2) activation, additional recruitment, and aggregation of platelets; and (3) thrombus stabilization.^[13]

Platelets roll, spread, and adhere over the damaged vessel wall to form a platelet monolayer. Adhesion results from the interaction of the glycoprotein (GP) receptors on the platelet surface with von Willebrand factor, a circulating plasma protein, and GP receptors and collagen at the site of vascular injury. Platelet activation occurs through 2 adenosine diphosphate (ADP) receptors, P2Y₁ and P2Y₁₂, on the platelet surface.^[13-15] ADP binding to the P2Y₁ receptor results in platelet shape change and rapid reversible platelet aggregation (Figure 5). ADP binding to the P2Y₁₂ receptor signals the release of platelet storage granules containing ADP, thromboxane A2 (TXA2), and other factors. This serves not only to recruit and activate additional platelets but also to amplify platelet aggregation induced by other agents, including thrombin, serotonin, and TXA2. These substances serve to heighten inflammation, attract other mediators to the local area, and enhance the adhesive properties of the vessel wall. Most important, this platelet procoagulant activity converts the GP IIb/IIIa receptor to an active form on the platelet surface. In the final step, activated platelets connect platelet to platelet, bridging via the GP IIb/IIIa receptors and fibrinogen, thereby stabilizing the thrombus.

Figure 5. Platelet surface interactions and thrombus formation. From Angiolillo DJ, et al. Circ J. 2010;74:597-607.^[13]

In summary, repeated episodes of platelet activation, subsequent thrombus formation, and fragmentation occur at the plaque rupture site.^[12] These hemostatic processes contribute to the development of ACS.

Antiplatelet Agents

Aspirin

Aspirin, or acetylsalicylic acid, blocks the platelet activation step of thrombus formation. Derived from the bark of the white willow tree, acetylsalicylic acid has been used pharmacologically since the middle of the 19th century.^[16] Aspirin irreversibly inhibits both forms of cyclooxygenase enzymes (COX-1 and COX-2), reducing the formation of prostaglandins and TXA2. The prostaglandin products of COX enzyme activity provide protection from gastrointestinal mucosal injury. Aspirin's irreversible antiplatelet effect lasts for the life of a platelet at doses as low as 30 mg.^[17] Larger doses (> 3000 mg daily) are required to inhibit COX-2 and produce systemic anti-inflammatory effects. Consequently, there is a 50- to 100-fold variation in the daily doses of aspirin required to suppress inflammation and inhibit platelet function.

In patients with cardiovascular disease, aspirin effectively reduces the risk for recurrent events by about 30%.^[18,19] When studies in patients with MI were combined, aspirin treatment reduced the relative risk for nonfatal MI by 28%, vascular death by 15%, and overall mortality by 11%. Aspirin is effective in a broad range of dosages, 75-325 mg daily. For treatment of ACS in patients undergoing PCI, it is recommended that a full dose (325 mg) of aspirin be given in the acute hospital setting for 1 month, and then the dose may be reduced to between 81 mg and 150 mg, taken indefinitely.^[5,6]

Aspirin, however, does not prevent all thrombotic events from recurring. This has led to the identification of patients with aspirin resistance, which may affect as many as 40% of patients.^[20] In clinical trials, aspirin resistance has been associated with an increased risk for death, ACS, or new cerebrovascular event.^[21] Aspirin resistance is the inability of aspirin to reduce platelet production of TXA2 and the steps of platelet activation and aggregation. Laboratory and platelet function tests measuring TXA2 production and TXA2 activity can detect this condition, but the diagnosis, definition, and testing have not been standardized. A number of potential causes of aspirin resistance have been hypothesized, including inadequate dose, drug interactions, genetic variation in COX-1 enzyme activity and TXA2 biosynthesis, and increased platelet turnover.

Aspirin's most common adverse effects are gastrointestinal (GI) (indigestion, nausea, heartburn, and constipation). These events are usually dose related and can be minimized by using enteric-coated, buffered formulations or taking aspirin with meals.^[22] Bleeding is the most serious adverse effect of long-term aspirin therapy, with cerebral bleeding (hemorrhagic stroke, intracranial hemorrhage) and GI bleeding considered major adverse events. Combined trial results suggest these complications are infrequent, with GI bleeding events (about 1 event in 100 patients) occurring more often compared with cerebral bleeding (about 1 event per 1000 patients).^[23,24]

P2Y₁₂ Antagonists

ADP receptor antagonists exert their pharmacologic action by inhibiting the P2Y₁₂ receptor on the platelet surface, preventing ADP-induced fibrinogen binding to platelets, a necessary step in the platelet aggregation process. There are 3 FDA-approved P2Y₁₂ antagonists (ticlopidine, clopidogrel, and prasugrel) and 2 agents in clinical development (ticagrelor, elinogrel) (Table 1). While these agents have similar mechanisms of action, they vary widely in their structure, receptor site action, and pharmacokinetics.

Table 1. Pharmacokinetic and Pharmacodynamic Properties of P2Y₁₂ Inhibitors

	Ticlopidine	Clopidogrel	Prasugrel	Ticagrelora
Trade name	Ticlid®	Plavix®	Effient®	Brilinta®
Route	Oral	Oral	Oral	Oral
Chemical structure	Thienopyridine	Thienopyridine	Thienopyridine	Cyclopentyl-triazolo-pyrimidine
Receptor binding	Irreversible	Irreversible	Irreversible	Reversible
Pro-drug	Yes	Yes	Yes	No
Cytochrome P450 metabolism	CYP 3A4	CYP 1A2, 2B6, 2C19, 2C9, 3A4, 3A5	CYP 3A4, 2B6, 2C9, 2C19	CYP 3A4
Clearance	Renal 60% Fecal 23%	Renal 50% Fecal 46%	Renal 68% Fecal 27%	Fecal 99% Renal <1%
Enteral bioavailability	80%	50%	80%	Not reported
Time to peak plasma concentration	1-3 hrs	1 hr	30-60 mins	1.5-3 hrs
Time to peak platelet inhibition	2-5 days	300 mg LD: 6 hrs 600 mg LD: 2 hrs	1-2 hrs	2 hrs
Plasma half life	12 hrs	30 minsb	3.7 hrsb	6-12 hrs
Time to steady state	2-5 days	3-7 days	2-4 days	2-3 days
Duration of antiplatelet effect	7-10 days	7-10 days	7-10 days	1 day
Significant drug interactions or genetic polymorphisms	Yes	Yes	No	No
FDA indication	1. To reduce the risk for thrombotic stroke (fatal or nonfatal) in patients who have experienced stroke precursors, and in patients who have had a completed thrombotic stroke 2. As adjunctive therapy with aspirin to reduce the incidence of subacute stent thrombosis in patients undergoing successful coronary stent implantation	1. For patients with ACS, including patients who are to be managed medically and those who are to be managed with coronary revascularization 2. Recent MI, recent stroke, or established peripheral arterial disease	1. To reduce the rate of thrombotic cardiovascular events (including stent thrombosis) in patients with ACS who are to be managed with PCI	Not approved for use in the United States
ACS = acute coronary syndromes; CYP = cytochrome P; FDA = US Food and Drug Administration; LD = loading dose; MI = myocardial infarction; PCI = percutaneous coronary intervention a. Investigational agent b. Active metabolite half-life Ticlid®: Roche Laboratories; Plavix®: sanofi aventis/Bristol-Myers Squibb; Effient®: Daiichi Sankyo, Inc./Lilly USA; Brilinta®: AstraZeneca.

Ticlopidine

Ticlopidine, a first-generation thienopyridine, played an important historical role in patients undergoing PCI and coronary artery stenting for management of coronary artery disease. With early use of these stents, thrombosis was a common complication, occurring in as many as 20% of patients.^[25] Several studies evaluated the use of aspirin alone, anticoagulant therapy, and ticlopidine with and without aspirin.^[25,26] The important findings showed that antiplatelet therapy reduced cardiovascular complications (death, MI, and stent thrombosis) with less bleeding than anticoagulation with warfarin. Furthermore, dual antiplatelet therapy with aspirin and a P2Y₁₂antagonist acts synergistically, reducing cardiovascular events greater than either agent alone. Ticlopidine, however, was associated with a rare but life-threatening blood disorder, thrombotic thrombocytopenic purpura (TTP).^[27] Subsequent clinical and registry studies showed clopidogrel was better tolerated, produced fewer side effects, and had better efficacy.^[28] Clopidogrel therefore replaced ticlopidine as the standard antiplatelet regimen.

Clopidogrel

Clopidogrel has a long history of providing benefit in patients with cardiovascular disease. The CAPRIE (Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events) study compared clopidogrel vs aspirin therapy in patients with recent MI, ischemic stroke, or symptomatic peripheral arterial disease with the intent of preventing recurrent cardiovascular events. Compared with aspirin, clopidogrel was associated with an 8.7% relative risk reduction in the combined events of vascular death, MI, or ischemic stroke (intent-to-treat analysis).^[29]Clopidogrel also reduced the risk for rehospitalization for ischemic events vs aspirin with no major differences in adverse events between the 2 therapies. The results from CAPRIE supported clopidogrel as the alternative antiplatelet agent of choice for patients with aspirin intolerance.

The CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) study was performed in patients with ACS without ST-segment elevation.^[30] Patients received clopidogrel (300 mg immediately followed by 75 mg once daily) plus aspirin or aspirin alone daily. Over 12 months there was a relative risk reduction of 20% in the composite outcome of nonfatal MI, stroke, or cardiovascular death in clopidogrel plus aspirin-treated patients. In the substudy of patients treated with PCI (PCI-CURE), there was a 30% relative risk reduction in the composite of cardiovascular death, MI, or urgent target-vessel revascularization (within 30 days of PCI) and a 31% relative risk reduction in cardiovascular death or MI overall (before and after PCI) in patients who received clopidogrel plus aspirin.^[31] Findings from the CREDO (Clopidogrel for the Reduction of Events During Observation) trial supported the beneficial effect of clopidogrel plus aspirin therapy in the long-term management of patients undergoing planned PCI.^[32] At 1 year, clopidogrel plus aspirin reduced the relative risk for death, MI, or stroke by 27%. CREDO also provided insight into the most appropriate timing of clopidogrel administration prior to PCI. The COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) and CLARITY-TIMI 28 (CLopidogrel as Adjunctive ReperfusIon TherapY-Thrombolysis In Myocardial Infarction 28) studies focused on the early medical management of MI in the hospital, combining clopidogrel and aspirin with thrombolysis.^[33,34] In both studies, clopidogrel and aspirin reduced the combined adverse cardiovascular outcomes of death, MI, stroke, or occluded infarct-related coronary vessels.

There have been recent trials, however, in which the benefit of clopidogrel has not been universal. In the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) study, outcomes were compared in patients with stable cardiovascular disease or asymptomatic patients with multiple cardiovascular risk factors.^[35] The combination of aspirin plus clopidogrel did not reduce adverse cardiovascular outcomes when compared with aspirin alone and was associated with an increased risk for bleeding. The CURRENT-OASIS 7 (Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions 7) demonstrated no difference in adverse cardiovascular events at 30 days between patients with ACS who received double-dose clopidogrel vs standard-dose clopidogrel.^[36] In patients in whom platelet function is studied, those with a high residual platelet reactivity have a higher risk for cardiovascular events after stent implantation. In the GRAVITAS trial (Gauging Responsiveness With A VerifyNow Assay – Impact on Thrombosis and Safety), patients were treated with either high-dose clopidogrel (150 mg daily) or standard-dose clopidogrel (75 mg daily). The composite endpoint of death, MI, and stent thrombosis was the same (2.3%) in both groups at 6 months. This study suggests alternative treatment strategies to clopidogrel may be necessary to improve patient outcomes.^[37]

In addition to factors such as dosing and timing of intervention, the potential benefit of clopidogrel treatment is related to its metabolism. The phenomenon of "clopidogrel resistance" has led to efforts investigating reasons for the wide variability in patient response including the pharmacodynamics of this agent.^[38]

Clopidogrel, a second-generation thienopyridine, is a prodrug for which hepatic metabolism is essential to the generation of its active metabolite. Approximately 85% of a clopidogrel dose is metabolized by blood esterases into an inactive metabolite. The remaining clopidogrel undergoes a 2-step process involving multiple cytochrome P450 enzymes. In the first metabolic step, clopidogrel is catalyzed by 3 enzymes (CYP1A2, CYP2B6, and CYP2C19) and leads to an inactive metabolite (2-oxo-clopidogrel). The second step requires 4 enzymes (CYP2B6, CYP2C9, CYP2C19, and CYP3A4) and produces an active metabolite.^[39] Variations or polymorphisms in the gene that codes for CYP2C19 appears to be the most important. A reduced function gene, which is present in 15%-30% of ACS patients, is associated with reduced concentrations of active drug, a 50% higher risk for death, MI, and stroke, as well as a 3-fold higher risk for stent thrombosis.^[40] An enhanced function gene is associated with rapid metabolism, heightened antiplatelet activity, and an increased bleeding risk.^[41] In response, the US Food and Drug Administration (FDA) has incorporated a boxed warning alerting clinicians of the "diminished effectiveness in poor metabolizers" and recommendations to consider alternative agents.

P-glycoprotein, a membrane-associated protein responsible for drug transport, affects clopidogrel absorption. Genetic variants can alter clopidogrel concentrations, reduce platelet inhibition, and compromise efficacy. A recent study has shown ACS patients with this specific genotype undergoing PCI are at higher risk for death, MI, and stroke.^[42]

Drug interactions may affect clopidogrel efficacy. When coadministered, statins that are metabolized by CYP450 enzymes, such as atorvastatin or simvastatin, may compete with clopidogrel, reducing its activation and attenuating its antiplatelet effect.^[43] With a similar mechanism to statins, proton-pump inhibitors, which are the preferred agents for aspirin-associated GI injury, have been shown to reduce the antiplatelet effect and efficacy of clopidogrel.^[44,45] While trials have not confirmed these interactions clinically,^[43,46] the FDA issued a public health advisory warning, and reissued a reminder warning in October 2010, that concomitant use of clopidogrel and omeprazole can significantly reduce antiplatelet activity.^[47]

While genetic testing is available, controversy exists over its value and role.^[48] Point-of-care genetic testing with a rapid turnaround (3-8 hours) has been limited to research studies. Furthermore, identifying the CYP2C19 gene only explains about 10% of the variation in clopidogrel response.^[49] Other environmental and clinical factors can affect clopidogrel metabolism and platelet function (Figure 6). Recognizing that one dose may not fit all, clinicians are faced with implementing untested strategies such as increasing the clopidogrel daily dose or adding additional weak-acting antiplatelet medications like dipyridamole or cilostazol. An alternative option is to consider the use of novel P2Y₁₂ receptor inhibitors.

Figure 6. Factors affecting clopidogrel response.

Prasugrel

Prasugrel, like clopidogrel, is a thienopyridine but with 10-fold greater anti-P2Y₁₂ receptor inhibitory activity.^[50,51]Prasugrel has a more rapid onset, irreversibly binds to the P2Y₁₂ receptor, and inhibits platelet activity more consistently and extensively than do standard and higher doses of clopidogrel (Table 1).^[52-54] Prasugrel is a prodrug, metabolized in one step via the CYP450 system, and is not susceptible to genetic polymorphisms and drug-drug interactions that are associated with adverse cardiovascular outcomes (Table 1).^[55]

In the Trial to Assess Improvement in TRITON-TIMI 38 (Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction) study, ACS patients scheduled for PCI were treated with either clopidogrel (300 mg loading dose, then 75 mg daily) or prasugrel (60 mg loading dose, then 10 mg daily) and followed over the subsequent 6-15 months.^[56] In the prasugrel-treated patients, there was a 19% relative risk reduction in the primary efficacy endpoint (death from cardiovascular causes, nonfatal MI, and nonfatal stroke) compared with clopidogrel (Figure 7). Additionally, the frequency of both early and late stent thrombosis was reduced by 52%. This benefit was magnified in high-risk groups, such as patients with diabetes mellitus or STEMI, and was apparent as early as day 3.^[56,57] The benefit of prasugrel vs clopidogrel was consistent across subsets of diabetes patients (insulin- and non-insulin-dependent).

Figure 7. TRITON-TIMI 38 patient outcomes. RRR = relative risk reduction; NS = not significant. From Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.^[56]

There was, however, a sacrifice in that prasugrel was associated with a statistically significant increase in non-CABG-related TIMI major bleeding, TIMI major bleeding and minor bleeding, and fatal bleeding.^[56] The risk for bleeding was related to diabetes status with statistically significant excess risk with prasugrel vs clopidogrel in patients without diabetes, but not in patients with diabetes.^[57] Some groups appeared to have less clinical efficacy and were particularly susceptible to bleeding. These groups included the elderly (age ≥ 75 years), the underweight (< 60 kg), and patients with a previous cerebrovascular event (stroke or transient ischemic attack). In the small number of patients with a previous stroke or transient ischemic attack, prasugrel significantly increased the rate of intracranial hemorrhage.

The prolonged, irreversible antiplatelet effect is of concern when patients need urgent surgery, such as CABG, that cannot be postponed. Treatment-related hemorrhagic complications have been strongly linked to subsequent mortality in patients with cardiovascular disease.^[58] Overall, the increase in prasugrel-related bleeding may partially offset the benefits from prevention of MI and stent thrombosis. As a result, there were no statistical differences between prasugrel and clopidogrel in all-cause mortality (3.0% vs 3.2%) at 15 months. However, stratifying by diabetes status showed a statistically greater net clinical benefit (composite cardiovascular death, nonfatal MI, stroke, nonfatal TIMI major bleed not related to CABG) with prasugrel among patients with diabetes.^[57]

Prasugrel was approved by the FDA in July 2009 with a boxed warning incorporated into its labeling alerting clinicians that it is contraindicated in patients with prior cerebrovascular events and to avoid its use in those at a high risk for bleeding (age ≥ 75 years, body weight < 60 kg, those taking concomitant medications that increase bleeding risk, and those likely to undergo CABG surgery). The dosing instructions also include recommendations to consider reducing the maintenance dose to 5 mg daily.^[59]

Ticagrelor

Ticagrelor, unlike clopidogrel and prasugrel, is a reversible, direct-acting, oral antagonist of the P2Y₁₂ receptor. It is a new class of agents, the cyclo-pentyl-triazolo-pyrimidines. Ticagrelor provides faster, greater, and more consistent P2Y₁₂ inhibition than clopidogrel (Figure 8).^[60-63]

Figure 8. Antiplatelet agent pharmacokinetics inhibition of platelet activity: ticagrelor vs clopidogrel vs placebo. a.P<.0001; b. P<.005; c. P<.05. From Gurbel PA, et al. Circulation. 2009;120;2577-2585.^[62]

Peak platelet inhibition, as measured by inhibition of platelet aggregation, is seen within 2 hours after ticagrelor administration as compared with 24 hours with clopidogrel. A greater platelet inhibition is sustained with maintenance dosing. After 14 and 28 days of dosing, ticagrelor inhibited 90%-95% of platelet activity as compared with 60% with clopidogrel. Ticagrelor's offset is faster than clopidogrel with a significantly lower platelet inhibition seen 72 hours after the last dose. The unique feature of reversible receptor binding is evident at 24 hours. This decrease in platelet aggregation necessitates every-12-hours dosing. Despite this reduction, platelet inhibition is still greater with ticagrelor than with clopidogrel, suggesting omitted doses may not have dire consequences.

Ticagrelor is metabolized by the CYP450 system to an equipotent active metabolite, which is further metabolized via glucuronidation. Since less than 1% of the ticagrelor dose is found in the urine, dose adjustments may be warranted in hepatic but not in renal dysfunction.^[63,64] Studies have confirmed that the genetic polymorphisms that affect clopidogrel absorption and active metabolite generation do not affect ticagrelor pharmacodynamics.^[65]Nearly all patients who do not respond to clopidogrel, when switched to ticagrelor had a reduction in the platelet activity level that is associated with ischemic risk.^[66]

In the PLATO (PLATelet inhibition and patient Outcomes) study, patients with ACS were treated with either clopidogrel (300 mg loading dose with an additional 300 mg for patients undergoing PCI, then 75 mg daily) or ticagrelor (180 mg loading dose with an additional 90 mg for patients undergoing PCI, then 90 mg twice daily) and followed over the subsequent 12 months.^[67] In the ticagrelor-treated patients, there was a 16% relative risk reduction in the primary efficacy endpoint (death from cardiovascular causes, MI, and stroke) (Figure 9).

Figure 9. PLATO patient outcomes. RRR = relative risk reduction; NS = not significant. From Wallentin L, et al.N Engl J Med. 2009;361:1045-1057.^[67]

There was a 22% relative risk reduction in all-cause mortality, and the risk for definite stent thrombosis was reduced by 33%. These benefits were maintained in patients managed with PCI, where there was no significant difference in the primary safety endpoint of major bleeding or the combination endpoint of major and minor bleeding between the ticagrelor and clopidogrel groups.^[68] However ticagrelor was associated with a higher rate of major or minor bleeding not related to CABG. Renal dysfunction in ACS patients is associated with a worse prognosis and an increased bleeding risk.^[69] Ticagrelor was more effective in reducing cardiovascular events than clopidogrel regardless of renal function, with greater benefit in those with poor renal function, and without any need for dose reduction to prevent major bleeding.^[64]

Bradycardia and transient dyspnea, not associated with adverse changes in cardiac or pulmonary function, are common side effects associated with ticagrelor administration, occurring in 4.4% and 13.8% of patients enrolled in the PLATO study, respectively. Results from the small, 6-week ONSET/OFFSET study indicated that drug discontinuation due to adverse events occurred only slightly more frequently with ticagrelor (7.4%) than with clopidogrel (6.0%).^[70] Of the 57 patients taking ticagrelor, 22 (38.6%) experienced dyspnea, compared with 5 taking clopidogrel (9.3%) and 1 in the placebo group (8.3%). Of the 22 patients who developed dyspnea while taking ticagrelor, 3 patients had to discontinue the medication (5.3%). Most of the sustained episodes of dyspnea with the ticagrelor group resolved upon cessation of treatment.

The major PLATO study finding that ticagrelor reduced all-cause mortality has led experts to speculate about possible reasons.^[71,72] Some believe it is related to the rapid offset of activity and the ability to transition patients to CABG surgery or better manage bleeding episodes. Because adenosine is involved in numerous biological activities, others have hypothesized that adenosine inhibition may improve myocardial performance, microcirculatory coronary blood flow, cardioprotection from reperfusion injury, and myocyte regeneration. Dyspnea and bradyarrhythmias could be related to the inhibition of adenosine as well.

Ticagrelor is not yet approved in the United States; however, the FDA Cardiovascular and Renal Drugs Advisory Committee voted to recommend its approval for preventing thrombotic events in patients with ACS in July 2010.^[73]

Role of the Pharmacist

The pharmacist's role has changed dramatically over the past 30 years, becoming more patient oriented, increasingly providing medication therapy management as part of their professional practices, and integrating into the healthcare delivery team. Because pharmacists are highly accessible and skilled in medication counseling and education, they can play a much needed role in improving access to care, patient satisfaction, clinical outcomes, and reducing costs. Community and clinic-based pharmacists have successfully participated in disease state management including diabetes and hypertension,^[74,75] as well as in drug class management such as anticoagulation, immunosuppressive, and antibiotic therapy.^[76-78] Similar to these initiatives, a simple 5-step action plan for pharmacists can assist in improving outcomes in those patients requiring antiplatelet therapy (Table 2).

Table 2. Pharmacist Action Plan for Antiplatelet Therapy

Step	Pharmacist Setting	Pharmacist Action
1	Transition	Provide patients and family with their antiplatelet therapy treatment plan (medications, doses, duration) at hospital discharge
2	Continuum	Eliminate delays in prescription filling, ensure prescription is picked up and available for administration, prevent premature discontinuation
3	Community -- Initiation	Educate patient and family about the medication, compliance, drug-food interactions, and adverse events
4	Community -- Maintenance	Monitor comorbidities, medication use, refill intervals, and over-the-counter medication purchases and detect drug-related problems
5	Community -- Outcomes	Critically evaluate with the patient the outcomes of treatment for safety and efficacy and the need for therapy changes

Hospitalization and subsequent discharge is a hectic, confusing period for many patients that often results in new medications or changes in existing regimens. In this transition, pharmacists can provide patients and their family with the antiplatelet therapy treatment plan (medications, doses, and duration) at hospital discharge. This education is now a requirement with oral anticoagulation and makes sense to extend to antiplatelet therapy whenever possible.^[79]

Surprisingly, 1 out of 6 patients will delay filling their antiplatelet medication prescription after stent insertion.^[80]Even with a prescription benefit, as many as 1% of patients will abandon their index prescription for an antiplatelet agent.^[81] Recent registry data show that only 79% of patients with risk factors for atherothrombosis or established cardiovascular disease received any form of antiplatelet therapy.^[82]

These delays are associated with an increased risk for death and MI. Physicians have been alerted to the importance of premature discontinuation of dual antiplatelet therapy and stent thrombosis.^[83] While other prescriptions were not associated with adverse outcomes, this problem demonstrates the discontinuity of care among care providers. It also highlights a role for pharmacists to ensure patients have access to medications. Pharmacists can facilitate continuity by providing the prescription at discharge or by having selected a pharmacy care provider that has the prescription waiting and, probably most important, making sure the medication is taken home and available for administration.

With initiation of therapy, community pharmacists can provide additional counseling on the antiplatelet medication, the importance of compliance, drug-drug and drug-food interactions, and adverse events. Pharmacist medication and medication profile review, patient counseling, and follow-up patient contact 3-5 days after hospital discharge facilitates clarifying medication regimens, reviewing indications, directions, and potential side effects. It also provides an opportunity to provide physician feedback when necessary. This intervention has been associated with a reduction in adverse events 30 days after hospital discharge.^[84]

While it is easy to point to genetic causes, genetic variation may explain only 50% of the variation in response to clopidogrel. There are multiple influences on a medication's response including genetics, concomitant disease processes, other medications, foods, age, and lifestyle. All will affect clopidogrel metabolism and platelet function. Similarly, a number of comorbidities including ACS, left ventricular dysfunction, diabetes mellitus, and renal insufficiency will independently alter platelet function. Furthermore, nonadherence may be the major cause of clopidogrel resistance. The overall nonadherence rate with clopidogrel therapy is about 22% of treated patients.^[85]Through their interactions, pharmacists are in a position to monitor symptoms associated with comorbidities and lifestyle changes. Routine direct measurements of platelet activity to detect antiplatelet therapy regimen adherence would be expensive and burdensome to the patient.^[86] Indirect measurements of adherence such as asking the patient directly; performing tablet counts; providing questionnaires, diaries, or calendars; or engaging caregiver or family support are all effective methods. Pharmacy computer systems and refill records can assist in monitoring medication compliance rather than escalating therapy to more aggressive combination antiplatelet regimens. Interventions to improve adherence include patient education, simplified or cued dosing schedules that surround daily activities (sleep, meals, hygiene, etc.), medication pill boxes or dose organizers, and constant communication to and between providers. Because many factors contribute to medication adherence, a single intervention may not be enough or work for all patients.

Finally, the pharmacist must critically evaluate with the patient the outcomes of treatment for safety, efficacy, and the need for therapy changes. Symptomatic events should be reported back to the physician. The availability of 3 antiplatelet agents provides additional options and makes it possible to individualize antiplatelet therapy. Prasugrel use should be discouraged in patients with, or who have developed, or are faced with, a high bleeding risk. Ticagrelor therapy may be preferred in patients for whom a CABG procedure is deemed probable or for those who are receiving clopidogrel or prasugrel and need elective surgery. Ticagrelor therapy should be discouraged in patients who have restrictive airway disease, cardiac arrhythmias, or compliance issues with a twice-a-day regimen. The pharmacists can assist in tailoring antiplatelet therapy to meet the patient's needs or existing conditions.

Case Study

WL is a 51-year-old white woman who was shoveling snow when she suddenly developed severe chest pain and shortness of breath. Her husband dialed 911, activating the local emergency response system, and an ambulance arrived in 15 minutes. An ECG was interpreted as showing acute ST-segment elevations indicative of MI (Figure 3).

Figure 3. ECG tracings.

WL was transferred to a hospital where coronary angiography showed a 90% occlusion in the right coronary artery. There were also 30% lesions in the left coronary and circumflex arteries. PCI was performed on the right coronary artery with a drug-eluting stent, and blood flow was restored (Figure 4). WL was discharged on a regimen of metoprolol (sustained release) 100 mg daily, aspirin 325 mg daily, clopidogrel 75 mg daily, and atorvastatin 80 mg daily.

Figure 4. Pre- and post-PCI images.

Six weeks later, WL presented to the emergency department complaining of increasing anginal pain over the last 3 weeks with minimal exertion. She perceived the pain as indigestion and self treated with over-the-counter omeprazole. Today the pain radiated to both arms and shoulders without relief with sublingual nitroglycerin.

An ECG showed ST-depression and T-wave inversions. She admits she has had difficulty in maintaining adherence to her medication regimens. Intravenous nitroglycerin was initiated in the emergency department, and she was transferred to the cath lab. No new lesions were found, but a thrombus was detected in the stent in the right coronary artery. She was transferred to the coronary care unit where a platelet reactivity test revealed that she was resistant to clopidogrel. Omeprazole was ceased, and she was transitioned to prasugrel 10 mg once daily. She was then transferred to a step-down cardiology unit, where a pharmacist provided:

• Medication counseling including verbal and written information about the use of the medications, including how long to take them and what to do if side effects occurred or a dose was missed; and
• Medications organized into a calendar pill box with directions to take them before brushing her teeth every morning.

WL provided feedback that she understood the information and directions, and a time and date for a follow-up phone call was scheduled in 2 weeks to check on the adherence.

Conclusions

Cardiovascular disease, in the form of atherosclerotic plaques, leads to ACS. Antiplatelet therapy is a key component of hospital care, supporting early invasive management, and extends to the home setting to prevent recurrent events. Clopidogrel is hampered by a variable patient response that is related to both genetic and environmental factors. Novel antiplatelet agents represent an advance in pharmacotherapy with more favorable pharmacodynamics and potential improvement in patient outcomes. Prasugrel and ticagrelor may obviate the need for genetic testing that may be necessary with clopidogrel. Pharmacists can play a key role in ensuring prescriptions are filled and compliance to regimens is maintained. They can assist in patient education and be vigilant for and help manage side effects and adverse reactions.

Supported by an independent educational grant from AstraZeneca

PHARMACY TECHNICIAN SERVICE INNOVATION

Kepada semua PPF Malaysia,

Sila baca artikel di bawah berkaitan Inovasi Perkhidmatan di antara Pharmacist dan Pharmacy Technician di USA di mana "expanded role" di berikan kepada Pharmacy Technician oleh Pharmacist di sana supaya semua Pharmacist dapat menumpukan dan meningkatkan perhatian kepada aktiviti "Patient Care" serta clinical duty. Delegasi perkhidmatan adalah sangat penting dalam membina satu "Positive Team Work" di antara Pegawai Farmasi dan Penolong Pegawai Farmasi dan semua Pegawai Farmasi Malaysia harus mempunyai sikap profesional seperti di New York ini dengan memberi peluang dalam expanded role serta mencipta inovasi perkhidmatan dengan tujuan murni supaya para pelanggan atau pesakit mendapat manfaat kesihatan yang maksima. Sila baca...

Winners of Innovations in Pharmaceutical Care Award Announced

New York (MedscapeWire) Dec 13 — Five teams of pharmacists and certified pharmacy technicians were declared the winners of this year's Innovations in Pharmaceutical Care Award on December 4th at the American Society of Health-System Pharmacists (ASHP) Midyear Conference in Las Vegas, Nevada.

Winners included a team at Duke University Medical Center that reengineered pharmacy work functions to allow pharmacists more time to focus on patient care. Another winning team, from North Mississippi Medical Center - Department of Pharmacy Services, uses a certified pharmacy technician in the medication error tracking and reporting process, giving pharmacists and other health professionals more time to implement new patient care programs.

The award, founded in 1998 by the Pharmacy Technician Certification Board (PTCB), recognizes innovations in pharmaceutical care by teams of pharmacists and certified pharmacy technicians in any practice setting. Each of the five winning teams received a cash award of $1,000 to be shared equally by the pharmacist and certified pharmacy technician and a framed certificate to be displayed in their respective practice settings.

"We take great pride in the Innovations Award Program," said Melissa M. Murer, RPh, PTCB Executive Director. "Efforts to enhance patient care, reduce medication errors and manage patient's chronic diseases serve as best practices for the over 70,800 certified pharmacy technicians nationwide."

The global pharmacy workforce: a systematic review of the literature

Nicola Hawthorne and Claire Anderson

Division of Social Research in Medicines and Health, School of Pharmacy, University of Nottingham, Nottingham, UK

Human Resources for Health 2009, 7:48doi:10.1186/1478-4491-7-48

The electronic version of this article is the complete one and can be found online at: http://www.human-resources-health.com/content/7/1/48

Received:	22 September 2008
Accepted:	19 June 2009
Published:	19 June 2009

© 2009 Hawthorne and Anderson; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The importance of health workforce provision has gained significance and is now considered one of the most pressing issues worldwide, across all health professions. Against this background, the objectives of the work presented here were to systematically explore and identify contemporary issues surrounding expansion of the global pharmacy workforce in order to assist the International Pharmaceutical Federation working group on the workforce.

International peer and non-peer-reviewed literature published between January 1998 and February 2008 was analysed. Articles were collated by performing searches of appropriate databases and reference lists of relevant articles; in addition, key informants were contacted. Information that met specific quality standards and pertained to the pharmacy workforce was extracted to matrices and assigned an evidence grade.

Sixty-nine papers were identified for inclusion (48 peer reviewed and 21 non-peer-reviewed). Evaluation of evidence revealed the global pharmacy workforce to be composed of increasing numbers of females who were working fewer hours; this decreased their overall full-time equivalent contribution to the workforce, compared to male pharmacists. Distribution of pharmacists was uneven with respect to location (urban/rural, less-developed/more-developed countries) and work sector (private/public). Graduates showed a preference for completing pre-registration training near where they studied as an undergraduate; this was of considerable importance to rural areas. Increases in the number of pharmacy student enrolments and pharmacy schools occurred alongside an expansion in the number and roles of pharmacy technicians. Increased international awareness and support existed for the certification, registration and regulation of pharmacy technicians and accreditation of training courses. The most common factors adding to the demand for pharmacists were increased feminization, clinical governance measures, complexity of medication therapy and increased prescriptions.

To maintain and expand the future pharmacy workforce, increases in recruitment and retention will be essential, as will decreases in attrition, where possible. However, scaling up the global pharmacy workforce is a complex, multifactorial responsibility that requires coordinated action. Further research by means of prospective and comparative methods, not only surveys, is needed into feminization; decreasing demand for postgraduate training; graduate trends; job satisfaction and the impact of pharmacy technicians; and how effective existing interventions are at expanding the pharmacy workforce. More coordinated monitoring and modelling of the pharmacy workforce worldwide (particularly in developing countries) is required.

Introduction

Shortages of pharmacists have been reported in specific countries since the early 1990s. Reports of shortages of the health workforce had surfaced in the 1970s but it was not until the following decade, and in particular the publishing of the World health report in 2006 [1], that health workforce issues gained sufficient momentum to merit widespread investigation and international action to bring about changes. That report was a major driving force for expansion of the international health workforce in order to meet the health-related Millennium Development Goals. The Global Health Workforce Alliance was established to accelerate progress towards these goals by identifying and implementing solutions to the shortages [2]. The international shortage of health care professionals exists in different severities and has different root causes, depending on the particular health profession and the country of origin. Health care priorities therefore change between countries: a universal health system would invariably not provide the required health care efficiently to all those who need it. The Global pharmacy workforce and migration report was the first of its kind to investigate specific workforce issues affecting the international pharmacy profession as a whole [3].

This review focuses upon the issues facing the expansion of the global pharmacy workforce; by gathering together past and present literature, it provides a platform for discussion, planning and action to enable the management of current problems and the foresight of future challenges worldwide. The main objectives of this report are to systematically identify and review the contemporary issues surrounding the global pharmacy workforce and, more specifically, to explore the published methods used to expand the workforce. The review was produced for the International Pharmaceutical Federation's working group on the pharmacy workforce.

Methods

Relevant peer-reviewed and non-peer-reviewed international literature was initially identified via searches on electronic databases. The databases searched included MEDLINE, EMBASE, International Pharmaceutical Abstracts, PubMed and The Cochrane Library. The search terms used were "pharmacy workforce", "pharmacy manpower", "human resources for health AND pharmacy", "human resources AND pharmacy" and "pharmacist shortage". Members of the International Pharmaceutical Federation working group on the pharmacy workforce provided country-specific literature on Canada and the United States of America. In addition, reference lists of relevant articles were searched. Copies of all the evidence included in the review were obtained.

The criteria for inclusion were that the literature related to pharmacists, pharmacy technicians or pharmacy assistants from any country worldwide; was published between January 1998 and February 2008; and that it satisfied the Health Development Agency Evidence Base 2000 standards [4] (with some noted exceptions). The review excluded workforce imbalances within pharmacy specialties (such as the mental health pharmacy workforce); literature published relating to historical data; non-English language literature; human resource matters concerned with delivering therapy for specific diseases (for example HIV and AIDS); and workforce issues surrounding emergency situations (such as natural disasters, conflict and epidemics). Once the relevant papers and reports were identified for inclusion, each document was ascribed an evidence grade used by the Department of Health in National Service Frameworks [5] and key data relating to the pharmacy workforce were extracted to matrices (see Additional files 1 and 2, which were independently checked by the second author). The evidence that did not meet all the Evidence Base 2000 standards was clearly annotated in the matrices.

Results

In total, 69 papers were identified for inclusion in the review: 48 peer-reviewed papers and 21 non-peer-reviewed reports. Most of the evidence gathered was in the B3 category (individual, well-designed, non-experimental studies; well-designed qualitative studies; and well-designed analytical studies, including secondary analysis), which was also the highest evidence grade achieved in this review. The papers and reports revealed several key areas important in workforce planning and expansion; these are detailed below.

Demographics

The proportion of females within the pharmacy workforce was found to either predominate, as observed in the United Kingdom [6], Canada [7], New Zealand [8] and Ireland [9], or be increasing, as seen in the United States between 2000 and 2004 [10,11]. The age of practising pharmacists was another important demographic issue presented in the national pharmacist workforce data from these countries. In general, the largest proportion of pharmacists was aged between 30 and 45 years [6,11-16] and the majority of male pharmacists tended to be older than the females; this was the case in New Zealand [8], the United Kingdom [6], the United States [11], Ireland [9], Australia [14] and Canada [7]. Generally male pharmacists predominated above the age of 50.

Education

One response to the shortage of pharmacists was found to be a planned expansion of the number of pharmacy graduates, which occurred or was recommended in the United Kingdom [17], the United States [14], Australia [12], Canada [15], Ireland [9] and Northern Ireland [16]. Expansion was indicated by an increase in the number of pharmacy schools or increases in enrolments at existing schools or increased numbers of entrants to the profession. However, this expansion presented many concerns regarding quality of teaching, the number of available pharmacy-trained faculty and the academic standard of applicants. In addition, alignment of pharmacy curricula with pharmacy practice was considered important for job satisfaction [18-22] and hence retention of pharmacists.

Distribution

Four important types of distribution became apparent within the pharmacy workforce: urban and rural; private sector and public sector; international migration; and movement between workplace sectors. Distribution of pharmacists was found to be uneven, with fewer pharmacists employed relative to population in rural or remote locations, compared with urban environments [8,22,23]; public or federal sector posts were less likely to be filled, compared with private sector positions [24-26]; and there was greater migration from less-developed countries to more-developed countries The pharmacist workforce of African countries was disproportionately affected by these trends [22]. Graduates also showed a preference for completing pre-registration training near where they studied as an undergraduate[27,28]; this was of considerable importance when planning recruitment to rural areas in Australia [23].

Pharmacy technicians

The relative importance of pharmacy technicians within the contemporary pharmacy workforce has been amplified, largely as a reaction to pharmacist shortages. As such, their numbers and responsibilities have been increased [29-31]. There was also found to be increased international awareness and support for the certification, registration and regulation of pharmacy technicians, and accreditation of the relevant training courses [32-34].

Feminization

The aforementioned increased proportion of female pharmacists in many countries brought to light specific issues surrounding their work patterns, particularly workforce participation. The prevalence of part-time work among female pharmacists was found to be much greater than that of their male counterparts in several countries [35,36], and as a result the full-time equivalent contribution of females was lower than that of males [36]. Females were found to be overrepresented in the hospital sector [11,9,20,35] and underrepresented in higher-status roles such as management in the United States [11] and the United Kingdom [35]. The number of female pharmacy students graduating was also noted to have increased, thus giving weight to the fact that female workforce issues will become increasingly important in the future. Reports of females comprising approximately two thirds of all pharmacy graduates were not uncommon[7,9,25,37,38].

Graduate trends

Graduate trends were important to investigate, as they may be used to predict and prepare for future workforce planning issues. A large proportion of pharmacy graduates in the United Kingdom intended to take a career break [39], and as mentioned earlier, graduates also showed a preference to complete pre-registration training near where they studied as an undergraduate. The university at which undergraduate training was completed in the United Kingdom was also revealed to potentially influence in which sector of pharmacy graduates decided to pursue their future careers [40]. Growing numbers of young pharmacists and pharmacy graduates originated from ethnic minorities in the United Kingdom [41].

Job satisfaction

Job satisfaction was viewed as an important indicator of staff turnover and retention. Factors identified as increasing pharmacist retention in the United States were good remuneration, good relationships with co-workers and flexible schedules. Factors increasing staff turnover included high stress, insufficient or unqualified staff and poor salary [42].

Supply and demand factors

Increased demand or limited supply of pharmacists constrains the ability of the workforce to expand. Many different supply and demand factors that influenced the pharmacy profession were identified, the majority of which were common to most countries. The most common factors increasing demand for pharmacists were increased feminization, increased clinical governance measures through continually reviewing and improving the quality of patient care, increased numbers of prescriptions and increased complexity of medication therapy. The most common factors mitigating demand for pharmacists included increased use of technology, expansion in the numbers and roles of pharmacy technicians and increased numbers of pharmacy graduates [9,20,15,21,39-41].

Discussion

Most of the papers identified for inclusion were judged to be of sound methodological quality and each added value to understanding the factors surrounding the expansion of the pharmacy workforce. The issues surrounding planning and expansion of the pharmacy workforce elucidated from the literature will be discussed in relation to recruitment, retention and attrition.

Recruitment

There are four relatively distinct areas of recruitment, as seen in Figure 1, which may be relied upon as routes to expand the pharmacy workforce: undergraduate, postgraduate, re-entry and foreign pharmacy graduates. The first of these, undergraduate recruitment, is the only process that will lead to expansion of the overall number of qualified pharmacists. The literature suggested that the main methods used to increase the number of qualified pharmacists was to expand the number of students enrolled in current pharmacy courses and increase the overall number of pharmacy courses.

Figure 1. Potential areas of recruitment to the pharmacist workforce.

Maintaining the quality and prestige of the pharmacy profession by retaining high-quality applicants was viewed with great importance; measures should be undertaken to increase the applicant pool in order to select the best candidates for pharmacy. Nevertheless, it seems inevitable that if enrolments increase significantly, a lower academic standard of pharmacists will result, since if student intake keeps increasing but the pool of potential students does not, schools may have to take applicants with lower entrance qualifications. The academic standards at which the course is set will probably not be achieved by less capable individuals (unless these standards are lowered), increasing the possible numbers who drop out of the course or those unable to pass a licensing exam where one exists.

Also, a United Kingdom report noted that pharmacy enrolments may be adversely affected by the increase in the number of medical school positions, with the medical profession similarly trying to increase enrolments to redress shortages [17]. Therefore, expansions in the number of alternative science-based degree courses may also be a factor limiting the expansion of suitable applicants to pharmacy.

Another important issue in the recruitment of pharmacists was the lack of male students entering the pharmacy degree course; the workforce implications of having a high female component have been extensively relayed. However, the reasons why males and females choose to study pharmacy or choose not to study pharmacy remain unknown.

There was a lack of pharmacy students choosing to undertake postgraduate pharmacy education. As academics are usually required to hold a postgraduate degree, this may worsen the pharmacy faculty shortages identified in both the United Kingdom and United States literature. A decline in the pharmacist-to-student ratio or a reduced rate of expansion may result if more pharmacist faculty were not recruited.

Another valuable area for pharmacy recruitment is the current inactive or part-time workforce. However, the literature indicates that the capacity for increasing the participation of this proportion of the workforce is minimal, either because of the high proportion of female pharmacists with family responsibilities, the high desirability of career breaks and part-time hours or the increasingly early age of (phased) retirement.

The final route of increasing the size of one particular country's pharmacy workforce is to recruit from another country's pool of pharmacy graduates, which can be inherently controversial. The increasing migratory flow of the health care workforce was of particular concern in developing countries, as the majority of migrating pharmacists moved to more-developed countries. While this was seen to benefit the individual for a variety of reasons, when emigration occurred disproportionately it severely hampered the provision of adequate health care to the home nation. Nevertheless, despite the human resource crisis in developing countries the opinion acknowledged by this investigation was not to prevent the flow of migration (partly due to the importance of remittances received by the families of expatriates) but instead to emphasize the need for exchange of professional expertise.

Retention

Retention was frequently reported as being a problem and a number of reasons, illustrated in Figure 2, were identified as being partly responsible for these difficulties. The first to be discussed is the effect of job satisfaction on retention. A theme echoed throughout the literature studied was that alignment of career expectations, aptitude and the pharmacy course content with the actual realities of practising pharmacy was imperative to ensure career satisfaction. Another key issue revealed by the literature regarding pharmacy curricula was that the curricula taught in developing countries were similar to those of developed countries. While this produced highly competent individuals, it did not necessarily prepare them for the realities of a career in their own country, thus disillusionment and frustration may result in increased emigration to more-developed countries, facilitated by the similarity of the degree course. In order to model the demands for pharmacists, it is very important to define needs-based roles for all cadres in the pharmacy workforce in any particular country. In addition, evolving, new and emerging technologies and innovative practice models and their impact on the workforce must be described for particular country and health systems.

Figure 2. Factors affecting pharmacist retention.

Training and career advancement were also predominant in the literature, especially surrounding the retention of female pharmacists and pharmacy technicians. Female pharmacists, although making up the majority of the workforce, were underrepresented in management positions, which was shown to be a result of their personal choices influenced by family responsibilities in the United Kingdom [42]. In terms of the pharmacy technician workforce, the lack of a "career ladder" or opportunities for career progression was the most frequent cause of dissatisfaction.

While wider roles were generally welcomed by pharmacists as a chance to make use of a greater breadth of their training, it may also be prudent to mention the potential of role overload, which may result due to high expectations for service delivery, unless sufficient resources and staffing occur simultaneously or a shifting of roles and responsibilities occurs.

Working conditions and workload were also shown to have a significant impact on retention, encompassing a wide range of intrinsic and extrinsic factors. Only a limited number of factors adversely affecting working conditions and workload can be tackled by individual employers, but wider-ranging alterations may call for changes in government legislation or company policy.

Attrition

The loss of participating pharmacists from the workforce needs to be taken into account to obtain a more accurate understanding about the net change in size of the workforce. As seen in Figure 3, three broad forms of attrition were identified from the literature as temporary, temporary or permanent, and permanent loss.

Figure 3. Forms of attrition in the pharmacy workforce.

In the case of temporary removal from active participation in the workforce, the most significant factor seemed to be the high preference for career breaks within the pharmacy profession. The reasons for this should be explored further. However, it may be postulated that with increasing proportions of female pharmacists present in the workforce, more females will take time off to raise a family. This may even be facilitated by the growing numbers of chain pharmacies, as they are likely to have greater capacity to support maternity or paternity leave, compared to independent owner/manager pharmacies.

Another factor involved in temporary attrition of the workforce is involvement in training courses. When pharmacists, pharmacy technicians or pharmacy assistants are engaged in a training course, they are not providing a service; unless these courses take place outside the hours of normal work, they reduce the capacity of the workforce to expand, as substitutes will be required to fill the temporarily vacant positions. This factor is likely to grow in significance with the sustained emphasis on continuing professional development, continuing education and risk management measures.

Factors affecting the loss of participation in the pharmacy workforce that may be either temporary or permanent were classified as part-time working and migration. The increasing trend of part-time working was largely due to the increased proportion of female pharmacists, but it was noted in the United States that the number of male pharmacists working part-time also increased between 2000 and 2004. This may not be part of a growing trend, but nonetheless this situation should be monitored.

A possible reason for increased part-time working among males may be increased salaries due to pharmacist shortages, making part-time working more economically viable. But perhaps the most likely reason may have been the self-implementation of phased retirement, as the majority of male pharmacists were in the older age groups. Nevertheless, increased part-time working, whether undertaken by male or female pharmacists, is a concern for workforce expansion, as more pharmacists will be needed to maintain current levels of service provision due to reduced pharmacist full-time-equivalent contributions.

International migration of pharmacists can result in a net loss or gain of pharmacists. The exchange of knowledge and skills is valuable, but large or continuous net losses can have serious detrimental effects on the source workforce. In order to minimize the potential damage while maximizing the advantages, a sound understanding of pharmacist migration must be achieved.

Migration is being accelerated by workforce shortages. When there are shortages, pharmacists are pushed back into the dispensaries and away from direct patient care – for which they are prepared by undergraduate courses – towards largely supply roles. The relevance of continuing education courses is then questionable because of the lack of capacity to integrate new knowledge and skills into the workplace. These circumstances accelerate the move from the public sector to the private sector and to emigration.

Permanent loss from the workforce – true attrition – was attributed to changing employment to a field outside pharmacy, retirement or death. Not much was known about the numbers of qualified pharmacists working outside pharmacy, as unless they remain registered there is no way of tracking them. However, a factor increasing the demand for pharmacists was the movement of pharmacists into non-traditional areas of work. The identification of this trend clearly meant that pharmacists involved in these fields remained registered. Nevertheless, if this set of circumstances changes, leakage of pharmacists to "other" employment sectors may go unnoticed.

Retirement can also only be estimated, as retired, inactive pharmacists do not legally have to remain registered. However, those who do and are over the state pension age have provided very interesting information about the pharmacy workforce. A development of concern was that male pharmacists were generally predominant in the workforce by a considerable margin after the age of 50; considering that male pharmacists in the overall workforce were in the minority, it appears that female pharmacists leave the profession much younger than their male counterparts. Despite this, the majority of pharmacists were found to be aged between 30 and 45 years. Therefore, as long as adequate numbers of newly qualified pharmacists and pharmacy technicians enter the workforce to maintain the high proportion of the workforce in younger age groups, pharmacy should not be expected to become an ageing profession.

Finally, the death of pharmacists was another factor in the permanent attrition of pharmacists from the workforce. Although the death of pharmacists was not reported to be a problem in any of the literature included in the review, most of the literature was from developed countries with relatively low death rates compared to less-developed countries. However, the World health report in 2006 revealed that deaths due to HIV/AIDS were alarmingly numerous within the health workforce in several African countries [1]. This raises the question: If health care professionals cannot get access to effective treatment, what hope does the rest of the population have?

Limitations

This review of literature found a significant amount of information detailing the characteristics of the pharmacy workforce in developed countries. However, there were significant shortfalls of published information regarding the pharmacist workforce in developing nations and also that relating to the effectiveness of any interventions used to expand the pharmacy workforce. Although this does limit the generalizability of this review, it does not devalue its usefulness. It also provides several comparators for additional research in the excluded countries. There was also a shortfall of literature relating specifically to the global pharmacist workforce as a whole: the only other international report on the pharmacy workforce was the Global Pharmacy Workforce Report [3] commissioned by the International Pharmaceutical Federation, the second edition of which is currently being produced.

Research implications

Most of the evidence included in this review is derived from surveys and is rated at a relatively low level. Future prospective and comparative research might use observational methodologies for certain aspects such as graduate trends, job satisfaction and the impact of pharmacy technicians. Further research into why males are increasingly choosing not to study pharmacy and a more coordinated monitoring of the pharmacy workforce worldwide (particularly in developing countries) are needed. Also, research into why pharmacy students are increasingly not pursuing postgraduate education and what measures can be taken to encourage careers in academia should be undertaken.

Conclusion

This review adds significantly to the current understanding of the international pharmacy workforce by bringing together and evaluating the relevant literature from around the world. To maintain and expand the future pharmacy workforce, increases in recruitment and retention will be essential, as will decreases in attrition where possible. However, scaling up the global pharmacy workforce is a complex, multifactorial responsibility that requires coordinated action. The repercussions of any changes made to the pharmacy workforce need to be considered carefully and optimal use of the current workforce should be made.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

NH carried out this study as part of her MPharm degree. CA independently reviewed all the papers and commented on each draft of the paper.

Acknowledgements

The authors would like to thank Craig Pederson and Janet Cooper, who supplied information regarding the pharmacy workforce in the United States and Canada, respectively.

For a copy of the full review, please contact Professor Claire Anderson: (claire.anderson@nottingham.ac.uk).

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