As the field of cardio-oncology evolves, the focus of treatment has shifted from reactive to proactive care. Prevention of cancer therapy-related cardiac dysfunction through optimization of cardiac risk factors and periodic surveillance, as well as minimal interruption of cancer treatment, is the emphasis of modern treatment paradigms.¹ Cardio-protection frequently involves the initiation of cardiac medications, including certain beta-blockers, angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin-receptor blockers (ARBs), and statins. Similarly, patients with pre-existing cardiac diseases are often prescribed a number of medications, such as anticoagulants and antiarrhythmics, that have potential and real interactions with a variety of chemotherapies. Because the therapeutic window for most chemotherapies is narrow, special attention should be given to these drug-drug interactions that may increase or decrease chemotherapeutic efficacy or predispose patients to serious unintended side effects. These drug-drug interactions are quite prevalent in the cancer population; one study determined that 16% of patients receiving oral anticancer drugs had at least one major drug-drug interaction that could cause harmful adverse effects.² Health care providers should be aware of potential drug-drug interactions and mitigate risks as they manage cardiovascular health in the context of cancer treatment. In the following review of drug-drug interactions involving chemotherapeutic and common cardiac medications, areas of focus include typical pharmacokinetic (PK) and pharmacodynamic (PD) interactions, antithrombotics, and QT prolongation.

PK/PD Interactions

A drug interaction occurs as a result of PD and/or PK mechanisms. A PD interaction is due to the additive or synergistic effect of two agents with similar molecular targets, resulting in excessive clinical response or toxicity. A PK interaction involves one drug or substance altering the absorption, distribution, metabolism, or elimination of another drug or substance.^3,4 The most common PK interactions in oncology involve the cytochrome P450 (CYP450) enzymes and the efflux pump P-glycoprotein.⁴ The CYP enzymes are responsible for metabolism within the gastrointestinal (GI) tract. A drug-drug interaction occurs when an orally administered CYP3A substrate is given concomitantly with an inhibitor or inducer of intestinal CYP activity. For example, atorvastatin is metabolized through CYP3A4, and when co-administered with ceritinib (CYP3A4 inhibitor), elimination of atorvastatin decreases, resulting in increased plasma concentrations and pharmacologic effect. Dose reduction or alternative statin (with a different metabolic enzyme pathway) may be necessary. Several chemotherapeutic and cardiac agents are CYP450 inhibitors, as some are substrates. Certain agents, such as imatinib, are both substrates and inhibitors and can be involved in dual drug interactions.⁴

P-glycoprotein (P-gp), also known as ATP-binding cassette transporter family protein, is expressed in the intestinal epithelium and acts as an efflux pump, actively exporting drugs from the cell cytoplasm into the intestinal lumen for excretion. Co-administration of a drug that is a P-gp inhibitor will increase the bioavailability of a P-gp substrate drug, and an inducer will reduce the bioavailability of a substrate drug.^3,4 Frequently used chemotherapeutic agents known to be P-gp substrates include doxorubicin, paclitaxel, vinblastine, and vincristine.

Table 1 outlines common drug interactions of chemotherapeutic agents with cardiac medications, including the proposed mechanism (PK and/or PD) and the effect of the drug-drug interaction.^5,6 Clinical management recommendations for both cardiology and oncology providers are also provided. As cardiologists evaluate potential drug-drug interactions, they should be vigilant in their role as "chemo-facilitators," using alternative cardiac therapies when possible and/or increasing monitoring of patients if necessary. Accordingly, minimizing interruption of crucial cancer treatments should be of primary focus.

Table 1: Drug-Drug Interactions of Common Cardiac Drugs and Chemotherapeutic Agents*

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Antithrombotics

Patients with cancer (hypercoagulable state) and cardiovascular diseases (e.g., atrial fibrillation, mechanical prosthetic valve disease, and thromboembolism) are frequently prescribed chronic anticoagulation. Management of antithrombosis in these patients is a complex balance between the risks of bleeding and thrombosis. Several chemotherapeutic agents inherently increase risk of hemorrhage due to hematologic effects, such as thrombocytopenia, and antithrombotics may further complicate bleeding risk.

Low molecular weight heparins (LMWHs) are the preferred method of anticoagulation for the treatment of cancer-associated thrombosis and may mitigate drug-drug interactions associated with vitamin K antagonists.^7,8 Often, warfarin (a vitamin K antagonist) is alternatively used due to cost or patient preference. Most drug-drug interactions involving chemotherapeutic agents and warfarin are a result of reduction in warfarin metabolism, leading to increased risk of bleeding (Table 2).^5,6 Warfarin dose adjustment and close international normalized ratio (INR) monitoring are most often appropriate; a LMWH may be necessary when a moderate/major drug-drug interaction is present or in the complicated patient with labile INRs or chemotherapy-induced GI intolerance. Although direct oral anticoagulants (DOACs) can be used in place of vitamin K antagonists or LMWH in many clinical settings, their role in the oncologic patient has not yet been established. Data on the use of DOACs in cancer are emerging, with evidence demonstrating similar efficacy to LMWHs; however, an increased risk of bleeding, primarily in GI malignancies, has been observed.^9-11 Although fewer than warfarin, significant drug-drug interactions are present with DOACs and chemotherapeutic agents. Table 3 outlines the most common of these interactions involving rivaroxaban and edoxaban, the two DOACs predominantly studied in cancer-associated thrombosis.^9-12

Table 2: Drug-Drug Interactions of Common Chemotherapeutic Agents and Warfarin

Click Here For Table 2

Table 3: Drug-Drug Interactions of Common Chemotherapeutic Agents and Antithrombotic Agents*†

Click Here For Table 3

Antiplatelet therapy, primarily P2Y12 inhibitors, is the mainstay of treatment of acute coronary syndromes, peripheral vascular disease, and cerebrovascular disease. In addition to augmented bleeding risk, drug-drug interactions with chemotherapeutic agents may conversely decrease antiplatelet effect. These types of drug-drug interactions may have catastrophic implications in patients who have recently undergone stent implantation. As such, cardiology providers must be aware of potential drug-drug interactions in prescribing antiplatelet therapy in the setting of oncologic treatments (Table 3).^9-11 In most cases, an alternative P2Y12 inhibitor can be used to avoid PK interactions with specific chemotherapeutic agents. Anticoagulation in the oncologic setting can be managed effectively through individualized patient evaluation, considering all clinical risk factors and potential drug-drug interactions and tailoring drug therapy and monitoring plans as needed.

QT Prolongation

Several chemotherapeutic agents are known to prolong the QT interval, which can increase the risk of torsades de pointes (TdP), a life-threatening arrhythmia (Table 4).^5,6,13 The most common are those of the tyrosine kinase inhibitor drug class, with vandetanib carrying the highest risk.^13,15 Moreover, many chemotherapy regimens comprise of a number of supportive agents, such as antiemetics, antidepressants, antihistamines, or antibiotics that may prolong the QT interval. Predisposing risk factors to QT prolongation are prevalent in oncologic patients, including hypomagnesemia and hypokalemia due to poor oral intake or GI losses, elderly age, and impaired renal function.¹⁴ Those with pre-existing cardiac disease are also more susceptible and may be on concomitant cardiac medications that potentiate QT prolongation and increase risk of TdP. For example, arsenic trioxide is associated with a high incidence of TdP (2.4%), and co-administration with other QT-prolonging agents, such as certain antiarrhythmics, should be avoided.^5,13 Alternatively, select cardiac medications may increase plasma concentration levels of chemotherapeutic agents through PK interaction, thereby increasing risk of QT prolongation. Hence, cardiologists should consider alternative agents or frequent ECG monitoring when high-risk patients are on multiple QT-prolonging therapies that are essential for cancer care. Few QT-prolonging chemotherapeutic agents include ECG monitoring recommendations in the prescribing information, but specific parameters are not often offered. The European Society of Cardiology suggests obtaining an ECG at baseline, 7-15 days after initiation or changes in dose, monthly for the first 3 months, and then periodically during treatment depending on the chemotherapy drug and patient status.¹³ These recommendations can used as a guide; however, monitoring should be individualized depending on patient-specific risk factors and combination of drugs. In any case, if significant QT prolongation occurs (QTc > 500 msec or 60 msec above baseline), all efforts should be made to treat electrolyte abnormalities and control other cardiac risk factors for QT prolongation. Treatment should be only temporarily interrupted and resumed at a reduced dose once the QTc normalizes.^13,15 In most malignancies, the benefit of chemotherapy outweighs the risk of TdP, and all efforts should be made to decrease risk through correction of predisposing factors and surveillance ECG monitoring when no alternatives exist.

Table 4: Common QT-Prolonging Chemotherapeutic Agents

High Risk of QT Prolongation	Moderate Risk of QT Prolongation
Arsenic trioxide*†	Bendamustine	Lenvatinib†
Nilotinib†	Bortezomib	Midostaurin
Toremifene	Bosutinib	Necitumumab
Vandetanib*†	Capecitabine (PO)/ 5-Fluorouracil (IV)	Osimertinib
	Ceritinib†	Oxaliplatin
	Crizotinib†	Panobinostat
	Dabrafenib	Pazopanib*
	Dasatinib	Ribociclib†
	Doxorubicin	Sorafenib
	Encorafenib	Sunitinib*
	Eribulin	Vemurafenib†
	Lapatinib	Vorinostat
* Known incidence of TdP. † Package insert includes ECG monitoring parameters.

The primary goal of a cardio-oncology program is to deploy all life-saving or disease-modifying chemotherapies while attenuating acute and long-term cardiovascular effects. One component of meeting this goal for patients with cancer and heart disease is to mitigate, minimize, or modify significant drug-drug interactions. Understanding potential and real drug-drug interactions should build awareness to help practitioners prevent excessive toxicities. We advocate for a formal medication review by a clinical pharmacist of the oncologic treatment plan for patients who are receiving cardiac medications. Risks should be mitigated through increased awareness of drug-drug interaction potentials, using alternative agents when possible, and close monitoring of adverse events. When evaluating drug-drug interactions, the primary focus of the cardio-oncologist should be to reduce interruption of life-saving cancer therapies while managing cardiac therapies as necessary. The tables provided in this article can be used as guides; however, an individualized approach must be taken with the assessment of clinical risk-benefit of both cardiac and chemotherapeutic treatments with each patient. In some cases, concomitant use of interacting drugs is unavoidable, and appropriate monitoring and precautions must be practiced. With the rapid emergence of novel chemotherapy classes and agents, the concepts in this review can be applied as new drug-drug interactions in the cardio-oncology field are encountered.

References

1. Lancellotti P, Suter TM, López-Fernández T, et al. Cardio-Oncology Services: rationale, organization, and implementation: A report from the ESC Cardio-Oncology council. Eur Heart J 2018;Aug 6:[Epub ahead of print].
2. van Leeuwen RW, Brundel DH, Neef C, et al. Prevalence of potential drug-drug interactions in cancer patients treated with oral anticancer drugs. Br J Cancer 2013;108:1071-8.
3. Kennedy C, Brewer L, Williams D. Drug interactions. Medicine 2016;44:422-6.
4. Sasu-Tenkoramaa J, Fudin J. Drug Interactions in Cancer Patients Requiring Concomitant Chemotherapy and Analgesics. Prac Pain Manag 2013;13:50-64.
5. Micromedex® (IBM Corporation website). 2018. Available at: https://www.micromedexsolutions.com/. Accessed September 4, 2018.
6. Lexicomp® Online™ (Lexicomp website). 2013. Available at: https://online.lexi.com/lco/help/lco-ug.pdf. Accessed September 5, 2018.
7. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016;149:315-52.
8. Samuelson Bannow BT, Lee A, Khorana AA, et al. Management of cancer-associated thrombosis in patients with thrombocytopenia: guidance from the SSC of the ISTH. J Thromb Haemost 2018;16:1246-9.
9. Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism. N Engl J Med 2018;378:615-24.
10. Young A, Marshall A, Thirlwall J, et al. Anticoagulation Therapy in Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism: Results of the Select-D™ Pilot Trial. Blood 2017;130:625.
11. Li A, Garcia DA, Lyman GH, Carrier M. Direct oral anticoagulant (DOAC) versus low-molecular-weight heparin (LMWH) for treatment of cancer associated thrombosis (CAT): A systematic review and meta-analysis. Thromb Res 2018;Mar 2:[Epub ahead of print].
12. Steffel J, Verhamme P, Potpara TS, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018;39:1330-93.
13. Zamorano JL, Lancellotti P, Rodriguez Muñoz D, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines:  The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016;37:2768-801.
14. Vandael E, Vandenberk B, Vandenberghe J, Spriet I, Willems R, Foulon V. Development of a risk score for QTc-prolongation: the RISQ-PATH study. Int J Clin Pharm 2017;39:424-32.
15. Lenihan DJ, Kowey PR. Overview and management of cardiac adverse events associated with tyrosine kinase inhibitors. Oncologist 2013;18:900-8.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Arrhythmias and Clinical EP, Cardio-Oncology, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Atherosclerotic Disease (CAD/PAD), Anticoagulation Management and ACS, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and ACS, Interventions and Vascular Medicine

Keywords: Cardiotoxins, Cardiotoxicity, International Normalized Ratio, Fibrinolytic Agents, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Atrial Fibrillation, Risk Factors, Biological Availability, Acute Coronary Syndrome, Pyridines, Pyrimidines, Angiotensin Receptor Antagonists, Patient Preference, Angiotensin-Converting Enzyme Inhibitors, Paclitaxel, Thiazoles, Drug Interactions, Thrombosis, ATP Binding Cassette Transporter 1, Thrombocytopenia, Thromboembolism, Doxorubicin, Peripheral Vascular Diseases, Gastrointestinal Tract, Vincristine, Antineoplastic Agents, Cerebrovascular Disorders, Intestinal Mucosa, Vitamin K, Vinblastine, Heparin, Low-Molecular-Weight, Anticoagulants, Stents, Warfarin, Sulfones

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