Dr. Shivam Patel has graduated from Lake Erie College of Osteopathic Medicine (LECOM) School of Pharmacy with a Doctor of Pharmacy degree. Completed PGY1 Pharmacy Residency at Martinsburg VA Medical Center. Currently Dr. Patel is continuing to serve veterans as a Clinical Pharmacist.

Shivam Patel, Pharm.D.

The use of beta blockers for rate control in patients with atrial fibrillation (AF) and heart failure (HF) has shown mortality benefits. A study performed by Fauchier et al. found that there was a reduction of 40% with the use of beta blockers in patients that have AF and HF.

Current recommendation of beta blockers in patient with HF include bisoprolol, carvediol, or metoprolol succinate. Metoprolol tartrate may provide better rate control with twice daily dosing.

Patients with AF that received carvedilol had an improvement in left ventricular end diastolic (p = <0.001), end-systolic dimensions (P = <0 .0001), and ejection fraction (P =<0 .0001) compared to patients who received metoprolol, which showed decreased end-systolic dimensions (P =0 .07), and increase in ejection fraction (P =0 .05). 

The Carvedilol or Metoprolol European Trial (COMET)

, a randomized double blind trial, looked into the comparison of metoprolol tartrate and carvedilol in patients with HF. Carvedilol was shown to have  beneficial effects on mortality (RR 0.836: CI 0.74—0.94; P=0.0042).

 A prognostic relevance analysis of AF was performed on patients that were a part of COMET. Patients with HF were randomized to receive carvedilol or metoprolol tartrate. AF was associated with increased mortality (RR 1.29: 95% CI 1.12—1.48; P=<0.0001), and higher all cause death or hospitalization (RR 1.25: CI 1.13–1.38; P= <0.0001).

 The authors concluded that carvedilol, compared to metoprolol, offers additional benefits among patients with AF.

A randomized trial performed by Fung J et al. compared the effectiveness of carvedilol and metoprolol tartratein patients with HF and AF.

 The study found that both treatment options had an equal improvement in left ventricular systolic function in HF with AF.

 These results were similar to those presented in other trials, such as the US Carvedilol Heart Failure Trials Program.

While there was no direct study regarding the use of metoprolol tartrate in a patient population involving HF and AF, many HF studies had a subgroup of patients who had concomitant AF that required assessment. One aspect of these studies to take into consideration would be the amount of patients that were assessed. A certain percentage of patients had HF and were in AF in many of the studies.

The overall conclusion is that the use of beta blocker therapy in patients with HF and AF has shown mortality benefit and would be recommended for use in management of patient’s care. Whether metoprolol tartrate would be preferred over carvedilol or other preferred beta blockers in patients with HF and AF, could not be determined.

Fauchier L, Grimard C, Pierre B et al. Comparison of Beta Blocker and Digoxin Alone and in Combination for Management of Patients With Atrial Fibrillation and Heart Failure. 

Meng F, Yoshikawa T, Baba A et al. B-Blockers Are Effective in Congestive Heart Failure Patients With Atrial Fibrillation

 Vol. 9 No. 5 2003. doi:10.1054/S1071-9164(03)00127-1

Poole- Wilson PA, Swedberg K, Cleland JG et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. 

Swedberg, K, Olsson L, Charlesworth A et al. Prognostic relevance of atrial fibrillation in patients with chronic heart failure on long-term treatment with beta-blockers: results from COMET. 

 Issue: Volume 26(13), July 2005, pp 1303-1308. DOI: 10.1093/eurheartj/ehi166

Fung J, Chan S, Yeung L, et al. Is beta-blockade useful in heart failure patients with atrial fibrillation? An analysis of data from two previously completed prospective trials

Articles

Metoprolol Tartrate Use in Patients with Congestive Heart Failure and Atrial Fibrillation

Both semaglutide and dulaglutide are in a glucagon-like peptide 1 (GLP-1) receptor agonist class of medications used in treatment of type 2 diabetes. GLP-1 receptor agonists reduce blood glucose by stimulating insulin secretion and reducing glucagon secretion, both occurring in a glucose dependent manner.

 This property provides a lower risk of hypoglycemia. These types of medications also delay gastric emptying in the early postprandial phase thus resulting lower blood glucose levels. A secondary outcome of delay gastric emptying may also result in reduction in body weight.

Semaglutide and Dulaglutide both have contraindication of a personal or familial history of medullary thyroid carcinoma (MTC) or patients with multiple endocrine neoplasia syndrome type 2 (MEN 2).

 Incidence of thyroid C-cell tumors occurred in animal studies, though currently it is unknown whether MTC have occurred in humans. European Union prescribing information for GLP-1 receptor agonists does not include contraindication of personal or family history of MTC or MEN 2.

When looking at warnings and precautions of semaglutide and dulaglutide, 1 difference is noted in labeling: dulaglutide does not include precaution of retinopathy. Incidence of diabetic retinopathy was reported in SUSTAIN 6 trial, which was a cardiovascular outcomes trial for semaglutide. Semaglutide was associated with increased risk of diabetic retinopathy vs placebo.

 The lack of diabetic retinopathy in labeling for dulaglutide may be due to studies not including the safety outcome or listed as exclusion in criteria.

Both semaglutide and dulaglutide are dosed once weekly for treatment of type 2 diabetes. The recommended dose of dulaglutide is 0.75mg weekly and may be increased up to 1.5mg weekly.

Semaglutide is dosed 0.25mg weekly for 4 weeks. The 0.25mg weekly dose is considered an initiation dose and not effective for appropriate glycemic control.

 Semaglutide should be increased to 0.5mg weekly after initiation is finished. If additional glucose control is warranted, semaglutide can be increased to 1mg weekly after 4 weeks of 0.5mg weekly.

Hemoglobin A1c (HbA1c) reduction for both medications were similar. Comparison trial SUSTAIN 7 investigated semaglutide vs dulaglutide. Semaglutide had a higher HbA1c reduction in comparison to dulaglutide (-1.4 vs -1.1 respectively, p=0.002) with comparing dulaglutide 0.75mg and semaglutide 0.5mg.

 A higher percentage of patients were able to achieve hba1c <7% at week 40 with semaglutide 0.5mg (65% vs 51%, p=<0.0001).

Semaglutide and dulaglutide have similar efficacy results. A difference is noted when considering precautions. The difference of diabetic retinopathy listed for semaglutide and not listed for dulaglutide may impact clinical decision making when prescribing medications. Though a patient history including retinopathy does not exclude a patient from using semaglutide. Patients with history of diabetic retinopathy should be monitored for progression of diabetic retinopathy with the use of semaglutide.

National Library of Medicine. Semaglutide. Drug Label Information. 

https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=adec4fd2-6858-4c99-91d4-531f5f2a2d79

 Updated January 16, 2020. Accessed February 6, 2020.

National Library of Medicine. Dulaglutide. Drug Label Information. 

https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=463050bd-2b1c-40f5-b3c3-0a04bb433309

 Updated September 26, 2019. Accessed February 6, 2020

Romera, I., Cebrián-Cuenca, A., Álvarez-Guisasola, F. et al. A Review of Practical Issues on the Use of Glucagon-Like Peptide-1 Receptor Agonists for the Management of Type 2 Diabetes. 

 10, 5—19 (2019) doi:10.1007/s13300-018-0535-9

Vilsboll T, Bain SC, Leiter LA et al. Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy. 

. 2018 Apr;20(4):889-897. doi: 10.1111/dom.13172

Novo Nordisk. Ozempic vs Trulicity SUSTAIN7. Ozempic website. 

https://www.ozempicpro.com/clinical-data/ozempic-vs-trulicity.html

 Reviewed January 2020. Accessed February 6, 2020

Both semaglutide and dulaglutide are dosed once weekly for treatment of type 2 diabetes.

Comparing Semaglutide Versus Dulaglutide

Medical professionals everywhere are fully supporting the benefits of exercise. The American College of Sports Medicine and American Diabetes Association state aerobic exercise and resistance training together can efficiently lower body weight, decrease cardiovascular risk factors, reduce disease progression, improve mood and so much more.

It is a cornerstone of patient self-treatment for many acute and chronic disease processes across the spectrum. However, a new and up-and-coming theorem is that exercise can decrease addiction, substance abuse, and therefore prevent imminent bad outcomes. A study published in 

 looked at the effects of acute exercise on drug cravings, mood, and self-esteem, and presented preliminary findings. The study concluded that football, circuit training, and walking are feasible therapeutic activities for inpatients with poly-substance dependence.

One big limitation of this study was that it was performed in a select group of patients, and further randomized controlled studies would have to be performed to determine long-term effects.

In addition to risk reduction, aerobic exercises such as running and weight lifting have shown to improve psychological imbalances.

Increased intensity aerobic exercises decrease down-regulation of activity in the prefrontal cortex. This area is often up-regulated in anxiety and depression. Many nicotine users state they use tobacco products to curb the effects of their anxiety. Exercise has been shown to decreased nicotine withdrawal and cravings with increased levels of exercise. When comparing steady-state running and anaerobic sprint training, the latter has been found to increase levels of dopamine and brain-derived neurotropic factor (BDNF).

Findings from preclinical studies have hypothesized that BDNF is increased by exercise and serves as a substitute reward for drug intake by increasing dopaminergic activity.

Evidence shows aerobic exercise can change the mesolimbic pathway, altering seeking and addiction behaviors in substance users.

This alteration is theorized to be mediated by decreased binding of the dopamine type 1-like and dopamine type 2-like receptors.

The evidence regarding use of forms of exercise and impact on drug cravings and substance use disorders is limited. Given the limited evidence available, further exploration in this theory may impact the lives of many in a multifactorial way. Exercise improves psychological, behavioral, neurobiological, and overall health of patients. The overall safety profile of this treatment does more benefits than harm in most cases.

This provides pharmacist and other health care professionals another opportunity to provide counseling regarding this possibility as this approach may have a multifactorial impact.

Ellingsen MM, Johannesen SL, Martinsen EW et al. Effects of acute exercise on drug craving, self-esteem, mood and affect in adults with poly‐substance dependence: Feasibility and preliminary findings. 

. Volume 37, Issue 6. 04 June 2018. doi.org/10.1111/dar.12818

Colledge F, Gerber M, Ludyga S et al. Anaerobic Exercise Training in the Therapy of Substance Use Disorders: A Systematic Review. 

. 04 December 2018. doi.org/10.3389/fpsyt.2018.00644

Robison LS, Swenson S, Hamilton J et al. Exercise Reduces Dopamine D1R and Increases D2R in Rats: Implications for Addiction. 

Medicine and Science in Sports and Exercise

Linke SE, Ussher M. Exercise-based treatments for substance use disorders: evidence, theory, and practicality. 

The American Journal of Drug and Alcohol Abuse

Exercise improves psychological, behavioral, neurobiological, and overall health of patients.

Exercise: Another Potential Option for Substance Abuse Disorder

Atherosclerotic cardiovascular disease (ASCVD) is one of the leading causes of death in the United States today. According to the American College of Cardiology (ACC) and American Heart Association (AHA) Task Force, managing elevated cholesterol is one of the the key elements to decreasing negative outcomes in this multifactorial disease state.

The ASCVD Risk algorithm is used to calculate a 10-year risk of heart disease or stroke and for recommendations of statin therapy. This algorithm calculates this risk by evaluating the following factors: history of ASCVD, low-density lipoprotein (LDL) cholesterol levels, age, current diagnosis of diabetes, sex, race, total cholesterol, high-density lipoprotein (HDL) cholesterol levels, medication controlled hypertension, and smoking history. Any history of the following conditions is considered a known history of ASCVD: acute coronary syndrome, myocardial infarction, stable angina, coronary revascularization, stroke, transient ischemic attack, peripheral arterial disease, or patients with very high LDL levels (>190).

Risk factors for ASCVD include smoking, dyslipidemia, diabetes, and hypertension. The cornerstone to preventing bad outcomes is focusing on a heart healthy lifestyle. According to the CDC, a heart healthy lifestyle revolves around maintaining a healthy weight, eating a well-rounded diet, exercising 3 to 5 times per week for 30-minute increments, avoiding tobacco products, and limiting alcohol use. 

Assessment of ASCVD risk is crucial for primary prevention of cardiovascular disease. For those aged 20 to 39 years, traditional risk factors such as tobacco use, hypertension, or others, can be measured to identify whether lifestyle optimization or treatment is needed.

 For adults aged 20 to 39 years and 40 to 59 years, who are not at an elevated (

 7.5%) 10-year risk, an estimation of a lifetime or 30-year risk for ASCVD can be made.

Estimating ASCVD 10-year risk can be performed using an online risk calculator provided by ACC. The 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease guidelines suggest the race and sex specific Pooled Cohort Equation to estimate 10- year ASCVD risk of asymptomatic adults ages 40 to 79 years. 

 Adults are categorized into low (<5%), borderline (5% to 7.5%), intermediate (

With the 2019 ACC/AHA guidelines for primary prevention of cardiovascular disease, statin treatment recommendations vary from previous guidelines. Patients’ aged 20 to 75 years and LDL 

 190 mg/dl use high-intensity statin without risk assessment. 

 Moderate-intensity statin can be used in patients aged 40 to 75 years and with type 2 diabetes mellitus. High intensity statin in this patient population may be considered based on risk estimation. For patients aged 40 to 75 years and with LDL 

70 mg/dl and <190 mg/dl without diabetes, use risk estimator to identify intensity of statin.

Patients on statin therapy should be assessed for compliance, therapy effectiveness, and adverse effects. Fasting lipid levels should be checked to assess effectiveness. These should be compared to values prior to statin initiation. Adverse effects are usually experiences in the first 4 to 12 weeks of starting treatment. Common adverse effects include myalgia. Certain drug-drug interactions can increase risk of patients experiencing myalgia with statins. Patients should also be screened for type 2 diabetes mellitus.

Statins and a heart healthy lifestyle are able to manage the risks of ASCVD effectively; however, there are times when additional treatments are needed. Specifically, other agents should be considered in patients with a heavy history of ASCVD events or with multiple high-risk factors. Ezetimibe is often the second-line agent added to maximized statin therapy. Additional therapy can be considered if ezetimibe and statin combination therapy do not lower the LDL-C level below 70 mg/dL. The next agent considered is a proprotein convertase subtilisin/kexin type 9 inhibitor. 

Updated 2019 guidelines by ACC/AHA for primary prevention of cardiovascular disease shows different categories of patients and respective statin intensity treatment compared with previous guidelines. Identifying appropriate risk factors and category will help with selecting the appropriate intensity statin. 

Grundy SM, Stone NJ, Bailey AL et al. 2018 Guideline on the Management of Blood Cholesterol. 

. Nov 2018. DOI: 10.1016/j.jacc.2018.11.003.

Preventing Heart Disease: Healthy Living Habits. Center for Disease Control and Prevention. 

https://www.cdc.gov/heartdisease/healthy_living.htm

 Reviewed August 10, 2015. Accessed October 17, 2019.

2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. 

Managing elevated cholesterol is one of the the key elements to decreasing negative outcomes in atherosclerotic cardiovascular disease.

A Review of the 2019 ACC/AHA Updated Lipid Guidelines

In the United States, fluoroquinolones are the third most commonly prescribed outpatient class of antibiotic with an estimated 115 prescriptions per 1000 persons annually.

 In 2014, 31.5 million fluoroquinolones prescriptions were dispensed for visits related to skin, respiratory, genitourinary, and gastrointestinal conditions.

t is estimated that 25% of fluoroquinolones prescriptions were for medical conditions where antibiotics are not recommended or specifically fluoroquinolones are not recommended first-line therapy.

 These conditions include acute bronchitis, acute sinusitis, and uncomplicated urinary tract infections. Inappropriate antibiotic use, specifically fluoroquinolone use, can put patients at increased risk of adverse reactions and unnecessary antibiotic resistance.

The FDA first added a boxed warning to fluoroquinolones in July 2008 regarding increase risk of tendon rupture and tendinitis.

 Fast forward few years and in February 2011, another boxed warning regarding risk of worsening symptoms for those with myasthenia gravis was added. In August 2013, updates to the label required description of potential for irreversible peripheral neuropathy.

Given the potential for irreversible impairment with use of fluoroquinolones, an FDA advisory committee concluded in November 2015 to restrict use of fluoroquinolones for treatment of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, or uncomplicated urinary tract infection for patients who have no alternative treatment option.

A labeling change in July 2018 regarding class of fluoroquinolones, requires mental health adverse effects to be listed separately from other central nervous system side effects. In addition, blood glucose disturbances subsection for all systemic fluoroquinolones will be required to reflect risk of hypoglycemic coma.

A safety announcement by the FDA regarding fluoroquinolones was released in December 2018 to warn about increased risk of ruptures or tears in the aortic artery. It noted that fluoroquinolones use should be limited in patients who have an aortic aneurysm or at risk for developing an aortic aneurysm related to vessel blockages, hypertension, genetic conditions such as Marfan syndrome and Ehlers-Danlos syndrome, and elderly patients.

Fluoroquinolones are concentration dependent and offer bactericidal activity by inhibiting DNA gyrase and topoisomerases, key enzymes for bacterial DNA replication.

 This class of antibiotic provides broad spectrum of activity with great efficacy covering many common pathogens including but not limited to 

, streptococci species, legionella species, etc. 

Older considered fluoroquinolones include ciprofloxacin, norfloxacin and ofloxacin with delafloxacin, Gemifloxacin, levofloxacin, and moxifloxacin considered newer.

 Many antibiotic classes are experiencing resistance with increased use, including fluoroquinolones.

It is important to realize the risk vs benefit of using all antibiotics for conditions. Antibiotic resistance is reality and changes in prescribing practices may need to occur to help limit building resistance.

Resistance to ciprofloxacin has been increasing with 

 For conditions such as, but not limited to, acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, or uncomplicated urinary tract infection, risk versus benefit of using a fluoroquinolone should be considered. In doing so, the patient may benefit from reduced amounts of antibiotic resistance due to unnecessary antibiotic exposure.

As fluoroquinolone antibiotic class has an extensive safety profile, other antibiotic classes present their own safety restrictions. Appropriate antibiotic use will help limit antibiotic resistance and provide patients with optimal evidence based medicine care.

Sarah Kabbani, Adam L Hersh, Daniel J Shapiro, Katherine E Fleming-Dutra, Andrew T Pavia, Lauri A Hicks, Opportunities to Improve Fluoroquinolone Prescribing in the United States for Adult Ambulatory Care Visits, 

, Volume 67, Issue 1, 1 July 2018, Pages 134—136, 

FDA News Release. FDA updates warnings for fluoroquinolone antibiotics. U.S. Food and Drug Administration. 26 July 2016. Available at 

https://www.fda.gov/news-events/press-announcements/fda-updates-warnings-fluoroquinolone-antibiotics

FDA updates warnings for fluoroquinolone antibiotics on risks of mental health and low blood sugar adverse reactions [news release]. Silver Spring, MD; July 10, 2018: FDA website. 

https://www.fda.gov/news-events/press-announcements/fda-updates-warnings-fluoroquinolone-antibiotics-risks-mental-health-and-low-blood-sugar-adverse

FDA In Brief: FDA warns that fluoroquinolone antibiotics can cause aortic aneurysm in certain patients [news release]. Silver Spring, MD; December 20, 2018: FDA website.  

https://www.fda.gov/news-events/fda-brief/fda-brief-fda-warns-fluoroquinolone-antibiotics-can-cause-aortic-aneurysm-certain-patients

Werth BJ. Fluoroquinolones. Merck Manual. https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-drugs/fluoroquinolones Reviewed July 2018. Accessed July 2019.

Fluoroquinolones are a commonly used antibiotic given its broad spectrum of activity. This class of antibiotics has an extensive safety profile that needs to be considered prior to initiating therapy.

Consider Risk Vs. Benefit of Fluoroquinolones 

It is estimated 103 million United States adults have hypertension, according to American Heart Association, and the death rate from hypertension increased by 11% in the US between 2005 and 2015.

On a worldwide scale, hypertension affects nearly a third of the adult population and is a common cause of cardiovascular related deaths.

 Recent ACC/AHA High Blood Pressure Guidelines have changed the recommendation for stage 1 hypertension to systolic between 130-139 or diastolic between 80-89, previously set at 140/90 mmHg.

 Specific blood pressure goals do exist for select patient populations based on their comorbidities and age.

Treatment of hypertension has many approaches and factors that play a role. Nonpharmacological interventions are just as important as pharmacological interventions.

In some patients, sodium restrictions, increase in exercise, or weight reduction may reduce blood pressure thus not requiring pharmacological treatment. Treatment with blood pressure lowering medications is recommended in patients with stage 2 hypertension and patients with stage 1 hypertension and have clinical ASCVD or estimated 10 year CVD risk of 

Primarily agents used to treat hypertension include thiazide diuretics, ACE inhibitors, ARBs, and CCBs. Secondary agents include loop diuretics, potassium sparing diuretics, aldosterone antagonists, beta blockers, direct renin inhibitor, alpha-1 blocker, central alpha-2 agonist, and direct vasodilators. 

In a select patient population, a combination of primary and secondary treatment options may not control high blood pressure. These patients may have a diagnosis of resistant hypertension.

Diagnosis of resistant hypertension is made when patients take 3 antihypertensive medications with collaborating mechanism of actions (diuretic included in therapy) with no achieved control of blood pressure (office systolic/diastolic 

 130/90 mm Hg) or when blood pressure control is achieved with more than 4 medications.

 It is beneficial to obtain home blood pressure readings to limit white coat effect. Health care providers should also review patient medication compliance to ensure patient is taking medications as prescribed.

Management of resistant hypertension may include identifying any reversible causes such as obesity, inactivity, excessive alcohol consumption, and/or diet high in sodium.

 Discontinue interacting substances such as Non-Steroidal Anti-inflammatory Drugs, amphetamines, stimulants, oral contraceptives, ephedra, licorice, monoamine oxidase inhibitors etc.

Most patients with resistant hypertension may have a secondary cause of hypertension. Obstructive sleep apnea, chronic kidney disease, and primary hyperaldosteronism are most frequent comorbidities.

There is limited randomized trial data to guide choice of drug treatment with resistant hypertension. Optimizing dosing regimens, switching diuretics such as hydrochlorothiazide to chlorthalidone, or adding spironolactone, may be potential options. It is recommended to maximize diuretic therapy, add mineralocorticoid receptor antagonist, and/or utilize secondary agents in overall therapy.

 Vasodilating beta blockers, such as carvedilol and labetalol, may be considered as fifth-line drug therapy.

 Secondary agents include prazosin, clonidine, methyldopa, minoxidil, and hydralazine. Many patients with secondary causes of hypertension, associated organ damage, requirement of >4 medications for control, and/or proteinuria >1g/day may require referral to a specialist.

High blood pressure has become a worldwide clinical problem. Nonpharmacological and pharmacological treatment interventions have shown to be beneficial at reducing and controlling blood pressure. In a select patient population, resistant hypertension may occur. Optimizing therapy and utilizing primary and secondary agents along with nonpharmacological interventions remains the current management efforts of this problem.

American Heart Association News. More than 100 million Americans have high blood pressure, AHA says. AHA website. 

https://www.heart.org/en/news/2018/05/01/more-than-100-million-americans-have-high-blood-pressure-aha-says

. Published January 31, 2018. Accessed April 2019.

American College of Cardiology. New ACC/AHA High Blood Pressure Guidelines Lower Definition of Hypertension. ACC website. 

https://www.acc.org/latest-in-cardiology/articles/2017/11/08/11/47/mon-5pm-bp-guideline-aha-2017

.  Published November 13 2017. Accessed April 2019.

Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. 

Journal of American College of Cardiology

. Volume 71, Issue 19, May 2018.  DOI: 10.1016/j.jacc.2017.11.006

Yaxley JP, Thambar SV. Resistant hypertension: an approach to management in primary care. 

. 2015;4(2):193—199. doi:10.4103/2249-4863.154630

After use of nonpharmacological and multiple blood pressure lowering medications, uncontrolled blood pressure still may be present. Thus, potential for patient to be diagnosed with resistant hypertension.