Physical Address

304 North Cardinal St.
Dorchester Center, MA 02124

Interventional pharmacology


Key points

  • Anticoagulant and antiplatelet medications are required for the safe percutaneous coronary intervention (PCI).

  • Recent studies have demonstrated that shorter durations of dual antiplatelet therapy (DAPT) are safe.

  • Vasodilators and vasopressors may often be necessary in some complicated or critical in-lab scenarios.

This chapter will describe common medications used in the cardiac catheterization laboratory for interventional procedures. It is not intended to be all inclusive, and the reader is referred elsewhere for a comprehensive review of the doses, indications, contraindications, and side effect of these important drugs. A list of the medications commonly used in the cath lab is provided in Table 3.1 .

Table 3.1
Medications Commonly Used in the Cardiac Catheterization Laboratory a
Inotropic Agents

  • Digoxin 0.125–0.25 mg IV >4 hr apart

  • Dobutamine 2–10 μg/kg/min IV drip

  • Dopamine 2–10 μg/kg/min IV drip

  • Epinephrine 1:10,000 IV

Antiarrhythmic Agents, Anticholinergic Agents, β-Blockers, Calcium Blockers

  • Adenosine 5–12 mg IV bolus

  • Amiodarone 150 mg IV × 10 min (15 mg/min)

  • Atropine 0.6–1.2 mg IV

  • Diltiazem 10 mg IV

  • Esmolol 4–24 mg/kg IV drip

  • Lidocaine 50–100 mg IV bolus; 2–4 mg/min IV drip

  • Propranolol 1 mg bolus; 0.1 mg/kg in three divided doses

  • Verapamil 2–5 mg IV, may repeat dose to 10 mg

Analgesic Agents, Sedatives

  • Diazepam 2–5 mg IV

  • Diphenhydramine 25–50 mg IV

  • Meperidine 12.5–50 mg IV

  • Morphine sulfate 2.5 mg IV

  • Naloxone 0.5 mg IV

Anticoagulants

  • Heparin 2000–5000 U IV; 1000 U/hr IV drip; 40–70 U/kg for PCI

  • Low-molecular-weight heparin (LMWH; See Table 3.6 )

  • Bivalirudin, bolus: 0.75 mg/kg with infusion of 1.75 mg/kg/h

Antiplatelet Agents
O ral A gents

  • Clopidogrel – 600 mg loading with 75 mg daily PO

  • Prasugrel - 60-mg loading dose with 10 mg daily PO

  • Ticagrelor - Loading dose 180 mg with 90 mg q12hr PO

I ntravenous A gents

  • IV abciximab – A 0.25 mg/kg IV bolus given 10–60 minutes before PCI with a continuous infusion of 0.125 μg/kg/min (to a maximum of 10 μg/min) for 12 hours

  • IV eptifibatide – 180 mcg/kg intravenous bolus administered immediately before the initiation of PCI followed by a continuous infusion of 2 mcg/kg/min and a second 180 mcg/kg bolus 10 minutes after the first bolus. Patients >120 kg, given maximum bolus of 22.6 mg with infusion of 15 mg/h.

  • Patients with renal impairment (CrCl <50 mL/min) should receive the standard 180 mcg/kg loading dose followed by infusion at 1 mcg/kg/min.

  • IV tirofiban – A high-dose bolus 25 mcg/kg over 3 minutes with 0.15 mcg/kg/min for up to 18 hours. In patients with creatinine clearance ≤60 mL/min, give 25 mcg/kg over 3 minutes and then 0.075 mcg/kg/min.

  • IV cangrelor – In patients who have not been treated with a P2Y12 platelet inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor

    • 30 mcg/kg IV bolus infused over 1 minute before PCI, immediately follow bolus injection with 4 mcg/kg/min IV infusion; continue for at least 2 hr or duration of PCI, whichever is longer

Vasodilators

  • Nitroglycerin 0.4 mg sublingual; intracoronary 100–300 μg

  • Nitroprusside 5–50 μg/kg/min IV

Vasoconstrictors

  • Metaraminol 10 mg in 100 mL saline, 1 mL IV

  • Epinephrine, for weight >50 kg; 0.5 mg (0.5 mL of epinephrine 1 mg/mL)

  • Phenylephrine 0.1–0.5 mg bolus, 100–180 μg/min IV drip

  • Norepinephrine 1:10,000 IV, 1-mL doses IV

IC , Intracoronary; IV , intravenous; PCI , percutaneous coronary intervention; PO , per os.

a The list is not meant to be all-inclusive or to exclude emergency life support techniques or standards.

Anticoagulation and antiplatelet agents

Antithrombotic and antiplatelet agents for percutaneous coronary intervention (PCI) are summarized in Table 3.2 . Fig. 3.1 depicts the mechanism of action of these agents. Recommendations from the American College of Cardiology (ACC)/American Heart Association (AHA) for pharmacology during acute coronary syndromes (ACS) are summarized in Table 3.3 . Fig. 3.2 diagrams the mechanism of action of available anticoagulant drugs.

Table 3.2
Antithrombotic, Antiplatelet, and Anticoagulant Drugs
Antithrombotic Therapy

  • Heparin (unfractionated)

  • Low-molecular-weight heparin (enoxaparin [Lovenox], dalteparin [Fragmin], tinzaparin [Innohep])

  • Direct thrombin inhibitor—Polypeptide inhibitor (bivalirudin [Angiomax])

  • Low-molecular-weight inhibitor (argatroban [Acova])

Antiplatelet Therapy

  • Cyclooxygenase inhibitors (aspirin)

  • Adenosine diphosphate (ADP) receptor inhibitors (clopidogrel [Plavix], prasugrel [Effient], ticlopidine [Ticlid], ticagrelor [Brilinta], cangrelor [Kengreal])

  • Phosphodiesterase inhibitors (cilostazol [Pletal])

  • Glycoprotein IIb/IIIa receptor inhibitors (abciximab [ReoPro], eptifibatide [Integrilin], tirofiban [Aggrastat])

  • Adenosine reuptake inhibitors (dipyridamole [Persantine])

  • Platelet activating receptor (PAR-1) antagonist [vorapaxar (Zontivity)]

Figure 3.1, Acute coronary syndromes and targets of antiplatelet and antithrombotic agents.

Table 3.3
ACC/AHA Recommendations for Pharmacologic Management of Patients Undergoing PCI for Acute Coronary Syndromes
From O’Gara et al, J Am Coll Cardiol. 2013 Jan61(4):485-510, and Amsterdam et al, J Am Coll Cardiol. 2014 Dec 23;64(24):e139-228.
Drug Unstable Angina/NSTEMI STEMI Comments
Aspirin I (LOE A) I (LOE B) 162–325 mcg loading, 81 mg maintenance
Clopidogrel I (LOE B) I (LOE B) Loading dose of 600 mg recommended as early as possible
Prasugrel I (LOE B) I (LOE B) Contraindicated in patients with prior stroke or TIA. Not recommended before PCI.
Ticagrelor I (LOE B) I (LOE B) IIa recommendation to use in preference to clopidogrel in PCI patients.
Unfractionated heparin I (LOE B) I (LOE C)
Low-molecular-weight heparin I (LOE A) I (LOE A) only for postlytic patient Not recommended for primary PCI.
Bivalirudin I (LOE B) I (LOE B) Especially for patients at high risk for bleeding.
Fondaparinux I (LOE B) III (LOE B) for use as sole anticoagulant Requires an additional antithrombin during PCI. Preferred for conservative strategy.
Glycoprotein IIb/IIIa inhibitors I (LOE A) in patients not pretreated with P2Y12 inhibitor, IIa (LOE B) when pretreated IIa (LOE A-B)
IIb for intracoronary or prehospital use
ACC, American College of Cardiology; AHA, American Heart Association; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction.

Figure 3.2, Mechanism of action of unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), fondaparinux, and bivaliruden.

Unfractionated heparin

Unfractionated heparin (UFH), the most common anticoagulation for PCI, accelerates the activity of antithrombin III (AT III), a molecule that breaks down the procoagulant factor IIa (thrombin) and factor Xa by forming a complex with AT III and thrombin. Because heparin has a variable effect, it requires monitoring of its activity during a procedure with a goal of an activated partial thromboplastin time (aPTT) of 50 to 75 seconds for most non-PCI applications, or 1.5 to 2.5 times the upper limit of normal. For PCI, anticoagulation is measured using the whole blood activated clotting time (ACT), with a goal of 250 to 350 seconds, or 200 to 250 seconds if using a GP IIb/IIIa inhibitor.

Typically, bolus intravenous (IV) UFH doses in the catheterization laboratory are 70 to 100 units (U)/kg. ACT values measured using the Hemochron tend to run higher than with the I-Stat ACT (Abbott). Repeated ACT measurements should be made approximately every 20 to 30 minutes. Contamination of the blood sample with heparin or contrast from within the guide catheter may artefactually prolong ACT measurements. Continuing heparinization after a successful PCI procedure increases the risk for bleeding without ischemic benefit and is not recommended.

The half-life of IV UFH is 1.5 hours, resulting in normalization of the clotting cascade a few hours after UFH discontinuation. If there is a need to reverse the anticoagulant effect of UFH, protamine sulfate can be given because it binds to the negatively charged heparin molecule, neutralizing it. Protamine dosage for UFH reversal is 1 mg IV per 100 units of remaining active UFH (max 50 mg/dose at 5 mg/min). The routine use of protamine after elective PCI or catheter ablation is not required from the radial approach but may be useful (and safe) to facilitate early femoral sheath removal. Protamine is unnecessary with femoral vascular closure devices.

Protamine allergic reactions include hypotension and bronchoconstriction caused by the histamine released. Reactions can be mitigated with a slow IV infusion. Although most of the protamine sulfate used today is recombinant, caution should be taken in patients with fish allergies because some proportion may still be derived from fish sperm. Patients taking protamine-containing insulin preparations (e.g., NPH insulin) are at increased risk for severe protamine reactions.

Heparin-induced thrombocytopenia

Heparin can cause an immune-mediated thrombocytopenia that can lead to thrombosis, stroke, loss of limb, or other ischemic events (e.g., heparin-induced thrombocytopenia with thrombosis [HITT]). Although relatively rare after brief heparin exposures, heparin-induced thrombocytopenia (HIT) should be of concern if platelets fall below 100,000 or by more than 50%.

There are two types of HIT ( Table 3.4 ). Type I HIT (HIT-1) is caused by direct (non–immune-mediated) platelet activation, with mild thrombocytopenia and a benign clinical course. Type II HIT (HIT-2) is caused by immune-mediated platelet activation, with moderate or severe thrombocytopenia and serious thromboembolic complications.

Table 3.4
Heparin-Induced Thrombocytopenia
Type I Heparin-Induced Thrombocytopenia Type II Heparin-Induced Thrombocytopenia
Incidence 10% Rare (0.2%)
Mechanism Direct platelet aggregating effect of heparin Autoantibody (IgG) directed against platelet factor IV–heparin complex
Onset Early (within 2 days) Later (4–10 days)
Platelet count 50,000–150,000/mm 3 <50,000/mm 3
Duration Transient; often improves even if heparin is continued Requires discontinuation of all heparin; gradual recovery in platelet count in most patients
Clinical Benign Recalcitrant venous and arterial course thromboses and thromboembolism; may be fatal
Heparin Unfractionated or low-molecular-weight heparin may be continued Argatroban for longer treatment. Bivalirudin for PCI or short-term treatment Danaparoid and lipirudin not available in USA.
IgG , Immunoglobulin G; IV , intravenous; PCI , percutaneous coronary intervention

Anticoagulation to prevent thrombosis is the main treatment of HIT-2 patients; typical drugs are the direct-acting thrombin antagonists argatroban or bivalirudin. Patients presenting to the catheterization laboratory with a history of potential HIT should have procedures with heparin-free saline and bivalirudin for anticoagulation.

Low-molecular-weight heparin

Low-molecular-weight heparins (LMWHs; enoxaparin, tinzaparin, dalteparin) are fractionated heparins with molecular weights between 3000 and 7000 daltons (UFH is 3000–30,000 daltons). Like UFH, LMWH binds to antithrombin, causing inhibition of factor Xa and thrombin. Because of improved subcutaneous absorption, LMWH can be administered either subcutaneously (SQ) or IV. LMWHs have features distinct from UFH, including:

  • 1.

    More predictable anticoagulation effect

  • 2.

    Lack of inhibition by platelet factor 4

  • 3.

    Lack of need for monitoring

  • 4.

    Lower risk for HIT

  • 5.

    SQ or IV bolus administration

Table 3.5 compares features of LMWHs with UFH.

Table 3.5
Comparison of Low-Molecular-Weight and Unfractionated Heparin
Modified from Safian R, Grines C, Freed M. The new manual of interventional cardiology. Physicians’ Press, 1999.
Characteristic Unfractionated Heparin Low-Molecular-Weight Heparin
Composition Heterogeneous mix of polysaccharides; molecular weight 3000–30,000 Homogeneous glycosaminoglycans; molecular weight 4000–6000
Mechanisms Activates antithrombin III* a ; equivalent activity against factor Xa and thrombin; releases TFPI from endothelium; unable to inactivate clot-bound thrombin or FDP; inactivates fluid phase thrombin Less activation of antithrombin III; greater activity against factor Xa than thrombin; releases TFPI for endothelium; unable to inactivate clot-bound thrombin or FDP; weaker inactivation of fluid-phase thrombin
Pharmacokinetics Variable binding to plasma proteins, endothelial cells, and macrophages leads to unpredictable anticoagulant effects (less available to interact with antithrombin III); short half-life Minimal binding to plasma proteins, endothelial cells, and macrophages leads to predictable anticoagulation; longer half-life
Laboratory monitoring Unpredictable anticoagulant effects; use aPTT or ACT Unable to use aPTT or ACT except in renal failure to body weight <50 kg or >80 kg; use antifactor-Xa levels
Clinical uses Venous thrombosis; unstable angina, acute myocardial infarction, ischemic stroke, PCI Venous thrombosis in surgery and trauma patients, unstable angina, ischemic stroke. No advantage during PCI
Reversal Protamine neutralizes antithrombin activity Protamine neutralizes antithrombin activity but only partially reverses antifactor-Xa activity
History of HIT-2 Should not be used in patients with a history of HIT-2 Should not be used in patients with a history of HIT-2
Cost Inexpensive 10–20 times more expensive than unfractionated heparin
ACT, Activated clotting time; aPTT, activated partial thromboplastin time; FDP, fibrin degradation product; HIT, heparin-induced thrombocytopenia; PCI, percutaneous coronary intervention; TFPI, tissue factor pathway inhibitor.

a Antithrombin III is now commonly referred to as antithrombin.

Absorption and clearance

Peak plasma anti-Xa levels are achieved 3 to 4 hours after subcutaneous dosing and are detectable for up to 12 hours. LMWH is eliminated via the kidneys and should be used with caution in patients with creatinine clearance of less than 30 mL/min. LMWH has a half-life of 2 to 4 hours longer than UFH.

Monitoring

The ACT assay does not reliably measure the LMWH effect. LMWH activity is measured using blood anti-Xa levels. Routine monitoring is not readily available in many catheterization laboratories and not necessary in most cases. LMWHs have very predictable antithrombotic effects; monitoring and dose adjustment is necessary only in obese patients (body mass index [BMI] > 40) or patients with renal insufficiency.

Clinical use

Enoxaparin, the best studied among the LMWH, is used mainly for precatheterization treatment of ACS. The therapeutic dose is 1 mg/kg SQ every 12 hours or 0.75 to 1 mg/kg IV for elective PCI where no other anticoagulant has been given. To optimize anti-Xa activity for PCI, an additional IV booster dose of 0.3 mg/kg is given if PCI is performed 8 to 12 hours after the prior SQ dose, particularly if fewer than three previous SQ doses have been received by the patient. Table 3.6 provides dosing of enoxaparin for PCI.

Table 3.6
Dosing of Enoxaparin Before Percutaneous Coronary Intervention
Preprocedural Enoxaparin IV Bolus Enoxaparin Dose at Time of PCI
No prior enoxaparin 0.75 mg/kg IV
Prophylactic doses of enoxaparin only 0.5 mg/kg IV
1–2 1 mg/kg SQ doses, last <8 hrs before 0.3 mg/kg IV
1–2 SQ doses, last 8–12 hrs before 0.3–0.5 mg/kg IV
Adequate (>3) SQ doses, last <8 hrs before No additional enoxaparin
Adequate (>3) SQ doses, last 8–12 hrs before 0.3 mg/kg IV
Any doses, >12 hours Can use alternative antithrombin
IV, Intravenous; PCI , percutaneous coronary intervention; SQ, subcutaneous.

Switching from one anticoagulant strategy to another (i.e., LMWH to UFH) is associated with increased bleeding risk and is discouraged.

Overall, LMWH is considered equivalent to UFH for ACS and PCI. Its advantages include a predictable dosing, ease of administration, and lower risk for HIT. LMWH has primarily been used in ACS in Europe and Canada, whereas it is only occasionally used in the US.

Fondaparinux

The heparinoid fondaparinux is a synthetic pentasaccharide that is derived from the binding regions of UFH and LWH. It inhibits factor Xa with antithrombin at high potency, with a SQ dose of 2.5 mg daily. Unexpected episodes of catheter thrombosis were noted with fondaparinux (0.9% vs. 0.4%), and therefore, this agent should not be used for anticoagulation during PCI. Operators should routinely use a standard bolus of UFH at the time of PCI for patients pretreated with fondaparinux.

Direct thrombin inhibitors

Direct thrombin inhibitors are polypeptide or low-molecular-weight inhibitors of thrombin that do not require antithrombin for anticoagulant effect ( Table 3.7 ). Low-molecular-weight inhibitors inactivate circulating thrombin at the active binding site but do not inactivate clot-bound thrombin.

Table 3.7
Direct Thrombin Inhibitors
Polypeptide Inhibitors
Hirudin (lepirudin b , desirudin b )
Bivalirudin
Low-Molecular-Weight Inhibitors
Argatroban a
Dabigatran

a Approved for use in patients with heparin-induced thrombocytopenia (HIT).

b Discontinued in the US.

Bivalirudin is a 20-amino acid polypeptide with a chemical structure like hirudin that is frequently used in PCI. It binds bivalently (at both the active site and exosite-1) and reversibly to both circulating and clot-bound thrombin with prompt recovery of thrombin function after drug discontinuation. This specific pharmacology potentially leads to reductions in bleeding complications and increased efficacy against thrombus.

Bivalirudin is given as an IV bolus of 0.75 mg/kg, with an infusion of 1.75 mg/kg/hr. It has a rapid onset of action of 5 minutes. Bivalirudin is excreted by the kidney and has a short half-life of 25 minutes in patients with normal renal function. The infusion should be dose-adjusted in renal insufficiency, but PCI procedures may be so brief that dose adjustment may be unnecessary unless the infusion is continued post-PCI.

Clinical use

Compared with UFH with glycoprotein inhibitors, bivalirudin demonstrates equal efficacy with a reduced risk for bleeding in patients with unstable angina/non–ST-segment elevation myocardial infarction (UA/NSTEMI; see the REPLACE-2, ACUITY, MATRIX trials) and in ST-segment elevation myocardial infarction (STEMI; the HORIZONS-AMI trial). In the absence of glycoprotein IIb/IIIa receptor inhibitors (GPI) and particularly with radial access, bleeding is not necessarily reduced (VALIDATE-SWEDEHEART trial).

Bivalirudin is associated with an increased risk for acute stent thrombosis because the drug’s short duration of action may not sufficiently protect against thrombosis while the dual antiplatelet medications take effect. The bivalirudin infusion may be extended at full dose for up to 4 hours after the procedure if antiplatelet agents are delayed, although the benefit of this approach on stent thrombosis rates remains unclear (MATRIX trial). Patients with femoral access, planned PCI, preprocedural P2Y12 inhibition, and high bleeding risk may benefit from bivalirudin.

IV infusion of argatroban is approved for treatment of HIT, with limited case reports of its use in PCI.

Table 3.8 compares UFH with direct thrombin inhibitors.

Table 3.8
Comparison of Unfractionated Heparin and Bivalirudin
Unfractionated Heparin Bivalirudin
Effect on clot-bound thrombin None Inactivation
Effect on thrombin High-affinity interaction; inhibits thrombin and factor Xa High-affinity interaction
Effect on factor Xa bound to platelets None Inactivation
Binding to endothelium and plasma proteins High; results in less heparin availability to activate antithrombin None
Risk of heparin-induced thrombocytopenia High None
Anticoagulant effects Highly variable Predictable
Laboratory monitoring Essential May be unnecessary with bivalirudin

Oral anticoagulants

Oral anticoagulants (OAC) are typically used for patients with conditions such as atrial fibrillation or prior venous thromboembolism (VTE). The concomitant use of OAC is a marker for high bleeding risk. Multiple contemporary randomized trials (WOEST, PIONEER-PCI, AUGUSTUS) have demonstrated that compared with triple therapy (warfarin + aspirin + clopidogrel), dual therapy with a P2Y12 inhibitor (usually clopidogrel) and an OAC reduces bleeding without increasing major adverse cardiovascular event (MACE) rates. These agents are best held before planned procedures because they increase the risk of bleeding from other anticoagulants for PCI.

Warfarin

Warfarin acts by inhibiting the gamma-carboxylation of glutamic acid residues in the clotting proteins II (prothrombin), VII, IX, and X. Despite the increasing use of direct OAC (DOACs), warfarin retains a role for patients with mechanical heart valves and active left ventricular or atrial thrombus.

Warfarin requires 4 to 7 days to produce a therapeutic level as measured by the international normalized ratio (INR). For femoral procedures, warfarin is held for several days to obtain a preprocedure INR of less than 1.8. Transradial procedures can often be safely performed regardless of the INR. The practice of “bridging” anticoagulation with LMWH or UFH before most surgical procedures is largely nonbeneficial and associated with higher bleeding rates. Bridging should be reserved for patients with mechanical heart valves or active VTE.

Oral anti-Xa inhibitors

The oral anti-Xa inhibitors (i.e., novel oral anticoagulants [NOAC] rivaroxaban, apixaban, and edoxaban) are replacing warfarin in many patients, but their role in PCI is uncertain currently. Rivaroxaban 2.5 mg twice daily has demonstrated a benefit in ACS patients after stabilization and revascularization (ATLAS ACS 2-TIMI 51 trial) and in the vascular disease patient in secondary prevention of MACE (COMPASS trial) but at the cost of increased bleeding.

The NOACs can generally be held 24 to 48 hours before planned procedures to minimize the risk of bleeding during PCI.

Antiplatelet agents

Antiplatelet agents are required for stenting and are very useful for primary and secondary prevention of thrombotic cerebrovascular or cardiovascular disease. Antiplatelet drugs decrease platelet aggregation and inhibit thrombus formation to prevent both acute and chronic stent thrombosis. These drugs are highly effective in the arterial circulation, where anticoagulants have reduced effect. Coupled with antithrombin drugs (e.g., heparin or bivalirudin), the antiplatelet drugs are the mainstay of PCI pharmacology.

There are multiple classes of antiplatelet drugs, each with different mechanisms of action. Several drugs are often given together for synergistic inhibition of platelet activity (weighing the risk of bleeding against benefit of preventing thrombosis). The classes of antiplatelet drugs are:

  • Cyclooxygenase inhibitors (aspirin)

  • Adenosine diphosphate (ADP) receptor inhibitors (clopidogrel [Plavix], prasugrel [Effient], ticlopidine [Ticlid], ticagrelor [Brilinta], cangrelor [Kengreal])

  • Phosphodiesterase inhibitors (cilostazol [Pletal])

  • GPIs (abciximab [ReoPro], eptifibatide [Integrilin], tirofiban [Aggrastat])

  • Adenosine reuptake inhibitors (dipyridamole [Persantine])

  • Thrombin receptor (PAR-1) antagonist (Vorapaxar)

Aspirin

Aspirin acetylate irreversibly binds and inactivates platelet cyclooxygenase, inhibiting production of thromboxane A2 (TXA2), which is a potent inducer of platelet aggregation and vasoconstriction via the production of cyclic adenosine monophosphate. Aspirin 81 mg is considered effective for most indications, but 162 to 325 mg is indicated for ACS. After oral ingestion, rapid absorption occurs with peak plasma levels in 20 minutes. Aspirin is rapidly cleared, but its effects last for the lifetime of the platelet (7–10 days). The whole-blood bleeding time can be used to gauge aspirin’s effect on platelet function, but this is rarely necessary. Aspirin should be used with caution in those with aspirin allergies (asthma), active peptic ulcer disease, or predisposition to bleeding. Platelet resistance to aspirin is rare.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here

Related Posts