Towards appropriate polypharmacy in older cardiovascular patients: How many medications do I have to take?

Abstract Background Polypharmacy in older adults leads to increased risks of side effects and drug‐drug interactions, affecting their health outcomes and quality of life. Deprescribing, the act of simplifying medication regimens, is challenging due to the lack of consensus guidelines. Hypothesis To offer some guidance on managing medication regimens for older cardiovascular patients. Methods We reviewed the most recent pertinent guidelines and literature. Results This review provides practical considerations for appropriate prescribing in the older population with cardiovascular disease in order to strike a balance between unnecessary or harmful medications and therapies with proven long‐term benefits. Conclusion On‐going dialogue between healthcare providers and patients allows close monitoring of medication effectiveness and prevention of side effects. Medication regimens require individualization, as patients' goals of care change with advancing age.

ability to manage complex medication regimens. 3,7,8 Finally, polypharmacy increases the risk of drug-drug Interactions (DDI). All of these factors can predispose older adults to drug accumulation and severe adverse effects. On the other hand, under-treatment, when therapy is withheld despite data clearly showing long term benefit, is also common in the older population. 3,9 Thus it is necessary to maintain a delicate balance between overtreatment leading to problematic polypharmacy secondary to medication use in the absence of strong indications, 5 and under-treatment when therapy is not prescribed despite a clear benefit. The goal is "appropriate polypharmacy," utilizing optimized medication regimens, according to best clinical practices shown to improve patient outcomes. It is imperative that clinicians regularly review the appropriateness of medications in both the clinic and acute care settings.
Furthermore, involvement of patients and families in the shareddecision making process will help to ensure their understanding of changes in medical management and improve patients' quality of life.
The American Geriatric Society (AGS) and the National Institute on Aging (NIA) developed tools to identify medications that are potentially inappropriate for older adults, delineate priorities and guiding principles for safe medication use, while promoting research on deprescribing practices in older populations. [10][11][12] The recently updated AGS Beers Criteria compiles a comprehensive list of medications potentially inappropriate in older patients. 10 Other tools are found in the literature: The STOPFrail criteria applies more specifically to the most vulnerable and frail patients; the STOPP/START criteria describes the use of software to aid in detecting inappropriate medications. 13,14 The Pharmacist's Letter also provides a number of tool kits and guides to deprescribing. 15 In this article we aim to provide some practical considerations on deprescribing, dose reduction, and drug selection in the older adult population.

| Primary prevention
Primary prevention for cardiovascular disease in older adults focuses on controlling major risk factors including hypertension, hyperlipidemia, and diabetes mellitus. 2 Chronic kidney disease becomes prevalent with advancing age, and often guides selection and dosing of pharmacotherapy.

| Blood pressure control
Current hypertension guidelines recommend mean blood pressure of less than 130/80 mmHg in patients over 79 years old. 16 However, resistant hypertension is common in the older population, in which 79% of men and 85% of women over 75 do not reach their blood pressure goals. 17 This commonly results in multiple agents being prescribed or titrated rapidly in an attempt to control hypertension, increasing the risks of drug interactions, orthostatic hypotension and falls when the medications achieve steady state. Generally, medication review or dose adjustment should be considered whenever patients experience dizziness, low systolic blood pressure (SBP < 85 mmHg) or bradycardia (Heart Rate <55 bpm). In the absence of compelling indications, hypertension agents should be started one at a time, at low doses and up-titrated over several weeks to the maximum tolerated dose before adding a different agent. This approach also has the advantage of decreasing pill burden. Monitoring parameters include vital signs, renal function and electrolytes as appropriate (see Table 1), noting that some medications (eg, amlodipine, lisinopril) reach their full effect after several weeks. It is best to avoid atenolol as it is a relatively less effective antihypertensive agent and may accumulate in older adults with renal dysfunction.

| Hyperlipidemia
De novo hyperlipidemia management for primary prevention in older adults focuses on lifestyle modifications and thorough assessment of risk factors for AtheroSclerotic CardioVascular Disease (ASCVD) (diabetes, smoking history). 18,19 The ASCVD risk score is valid only until 79 years of age and data remain sparse for older patients. In-depth dialogue with patients and their family members regarding the risks and benefits of therapy as well as consideration of patient preference is necessary before initiating a statin. For patients already on a statin at the age of 75, the decision of continuing or stopping statin therapy depends on tolerability, risk for a cardiovascular event, and patient preference. For a more detailed discussion, refer to the chapter on Coronary Artery Disease (CAD) and secondary prevention.

| Diabetes mellitus
According to Center for Disease Control and Prevention data, 25% of older adults have a diagnosis of diabetes mellitus. 20 Current diabetes guidelines allow for less aggressive blood sugar control in older adults depending on co-morbidities. [21][22][23] For instance while healthy older adults may still aim for HgbA1c less than 7.5%, guidelines permit HgbA1c goals of 8% to 8.5% for patients with functional and cognitive decline. Patients' life expectancy, co-morbidities, health literacy and ability to manage complex medication regimens should be assessed and therapy should be simplified accordingly. Metformin is an appropriate first line agent; however, alternative therapies should be con-

| Vitamins and nutritional supplements
Vitamins and supplements are commonly believed to be safe with few side effects, leading to a false sense of security with their use; however, use of these agents in conjunction with prescription medications can lead to significant drug interactions and adverse effects. 29 Heart failure guidelines in particular, discourage the use of supplements in addition to guideline-directed medical therapy. 30 Despite questionable benefit, even possible harm, routine use of vitamins and supplements to prevent cardiovascular diseases remains a common occurrence. Clinicians should address the risks and benefits and recommend discontinuation of supplements without clear benefits.

| Secondary prevention and established CAD
The treatment of acute coronary syndrome (ACS) is well established and well defined by consensus guidelines. 3,9 Despite limited enrollment in clinical trials, older adults derive mortality benefits from guideline-recommended medications for secondary prevention after ACS; however, the benefits must be balanced with an increased risk of adverse side effects and DDIs.
Antiplatelet Therapy: Aspirin (ASA) and P2Y12 Antagonist (eg, clopidogrel, ticagrelor): Aspirin therapy has a class I recommendation as a life-long therapy after ACS as it decreases mortality and recurrence of cardiovascular events. 3,9 In the context of ACS, guidelines also rec- Statins: High-intensity statin therapy (goal LDL-C < 70 mg/dL) is recommended after ACS for pleiotropic effects, 3,9,18,19 but older adults have a greater risk of statin-associated muscle symptoms and moderate-intensity statin therapy may be preferred. 18,19 In order to reduce the incidence of adverse effects, the dose of simvastatin in particular should not exceed 40 mg daily. 33 In the very old (> 90 years old) with no recent ACS, statin therapy may be discontinued following a risk-benefit discussion with the patient, noting that statin-derived benefits are seen after 4 to 5 years of therapy. 18,19 Guidelines make provision for ezetimibe and PCSK9-inhibitors for patients unresponsive or intolerant to statin therapy. 3,9,18 Ezetimibe is very well tolerated, but discussion regarding expected benefits vs additional polypharmacy should be had prior to initiation.

PCSK9-inhibitors are powerful, parenteral, and costly anti-lipid agents
and have a limited use in older patients. 18 Fibrates should usually be avoided due to limited LDL Cholesterol inhibitors are a cornerstone of guideline-directed medical therapy post-ACS, especially if left ventricular dysfunction is present. 37 Older adults are at higher risk of acute kidney injury, and should be closely monitored for worsening renal dysfunction and hyperkalemia. Addition of an aldosterone antagonist to either an ACE-inhibitor or ARB should be done cautiously, while the combination of an ACE-inhibitor and an ARB should be avoided altogether. Consider reducing the dose or a temporary hold vs stopping therapy for worsening renal dysfunction or hyperkalemia (ie, serum creatinine>2.5 mg/dL in women, 3 mg/dL in men, K+ >5 mEq/L). 30 Avoid nephrotoxic medications like over-the-counter Non-Steroidal Anti-Inflammatory Drug (NSAIDs) or medications that can induce hyperkalemia, such as potassium-sparing agents, trimethoprim, or potassium-based salt substitutes. 3,9 Nitrates: Nitrates can relieve symptoms associated with cardiac ischemia but do not reduce mortality, in which case chronic use should be reserved for coronary vasospasm or incomplete revascularization. 3 Long-acting, once-a-day formulations cause less hypotension and are preferred. Sublingual nitroglycerin remains an important medication to have on hand for a relief of an ischemic attack.

| Heart failure
Heart failure prevalence is as high as 13% in patients over the age of 80. 30 30 Furosemide has highly variable oral bioavailability, and switching to a more potent agent, for example, torsemide or bumetanide, may overcome diuretic resistance and reduces pill burden. 39 Maintenance diuretic therapy should be adjusted to maintain euvolemia with the use of intermittent metolazone as indicated (see Table 1). Thiazide agents may not be effective in the setting of low eGFR (less than 40 mL/min), and should be assessed for discontinuation.

| Arrhythmias, atrial fibrillation
Atrial fibrillation (AF) is a common cardiac arrhythmia seen in older adults with prevalence increasing with age. 43 The primary goals of AF management include prevention of thromboembolic events, primarily ischemic stroke, and reduction of symptoms and hospitalizations. 43 Anticoagulation: Systemic anticoagulation should be considered in all patients with atrial fibrillation; however, concern over falls and subsequent bleeding may lead to under-prescribing. Implementation of the HAS-BLED and CHA 2 DS 2 -VASc scores may help guide pharmacotherapy decision-making. 44,45 Newer agents such as the direct oral anticoagulants (DOACs) are now considered the preferred option demonstrating similar efficacy in preventing stroke and systemic embolism, with a lower risk of major bleeding compared to warfarin. 46 Warfarin also seems to be associated with increased risk of osteoporotic fractures compared to the DOACs. 47 All DOACs require dose adjustments for renal function. Apixaban is often considered the preferred agent for older adults, as it has lower renal excretion than dabigatran and rivaroxaban. For those with end stage renal disease, either apixaban or warfarin is reasonable.
Rate vs rhythm control: Symptomatic management of AF consists of either rhythm control or rate control. Rhythm control was shown to be inferior to rate control with respect to mortality in older adults and is associated with more adverse drug events and hospitalizations. 48 Moreover, antiarrhythmic agents use is limited in this population due to co-morbidities including structural heart disease, heart failure, and renal dysfunction. Amiodarone may often be the only appropriate option, although its use is associated with many long term side effects. Once AF becomes permanent and the decision to pursue rate control is made, all antiarrhythmic agents should be discontinued.
Rate control is usually achieved with beta-blockers, or a nondihydropyridine calcium channel blocker (CCB) such as diltiazem. 49 Atenolol should be avoided in this population due to its renal excretion. Digoxin may also be used for rate control when hypotension limits beta-blocker or CCB use, but it requires strict monitoring to ensure therapeutic drug levels. Chronic digoxin use appears to be associated with increased mortality. 50 Therefore, initiation of digoxin therapy in older adults with atrial fibrillation alone should generally be avoided when possible.

| CONCLUSION
The impact of polypharmacy in older adults can range from reduced quality of life (pill burden, drug cost) to serious adverse drug events (side effects, toxicity due to decreased metabolism, drug-drug interactions). Most would agree that striking a balance between over-and under-treatment is important, yet doing it effectively is challenging due to the lack of clear guidance and insufficient clinical experience.
When assessing whether or not to deprescribe, decisions should be individualized with an emphasis on shared decision-making with the patient and family, if at all possible. Each time a provider comes in contact with an older adult is an opportunity to review current medications and assess the risk and benefit of each therapy.