Pharmacotherapy For Cardiovascular Disorders Essay.

Pharmacotherapy For Cardiovascular Disorders Essay.

Abstract

Cardiovascular disease (CVD), including ischaemic heart disease (IHD) and heart failure (HF), and chronic obstructive pulmonary disease (COPD) are often concomitant because they share both risk factors (smoke) and pathological pathways (systemic inflammation). Cardiovascular disease and COPD association is increasing overtime. Several registries clearly showed a negative impact on the clinical outcome of the concomitant presence of CVD and COPD. Patients with CVD and COPD present an increased risk for myocardial infarction, HF, and hospital admission for acute exacerbation of COPD, with a negative impact on prognosis. To reduce the effect of this negative association, it is of paramount importance the pharmacological treatment with both cardiovascular and respiratory drugs, according to current guidelines. Nevertheless, several registries and studies showed that evidence-based drugs (both cardiovascular and respiratory) are often under administered in this subset of patients. In this overview, we summarize the available data regarding the use of cardiovascular drugs (antiplatelet agents, angiotensin converting enzyme inhibitors, β-blockers, and statins) in COPD patients, with or without concomitant IHD. Furthermore, we report advantages and disadvantages of respiratory drugs (β2 agonists, anti-cholinergics, and corticosteroids) administration in COPD patients with CVD.Pharmacotherapy For Cardiovascular Disorders Essay.

cardiovascular disease, ischaemic heart disease, heart failure, chronic obstructive pulmonary disease, β-blockers, ACE inhibitors, statins, acetylcholine antagonists

Issue Section:

Disease management

Introduction

Cardiovascular disease (CVD), including ischaemic heart disease (IHD) and heart failure (HF), is still the first cause of mortality and morbidity in western countries.¹ Chronic obstructive pulmonary disease (COPD) will soon become the third most common cause of death.² Since CVD and COPD share major risk factors (e.g. cigarette smoking and systemic inflammation), they are frequently associated.² The concomitant presence of CVD and COPD negatively impacts on long-term prognosis.³ Cardiovascular disease is the first cause of death in COPD patients² and, after acute exacerbation (AE) of COPD, we observed a significant increase in the risk of cardiac death and myocardial infarction (MI).⁴ Similarly, patients admitted to hospital for MI and/or receiving coronary revascularization (percutaneous or surgical) with concomitant COPD showed a decreased short- and long-term survival.^5–7

The aim of this overview is to summarize current data regarding cardiovascular drugs [antiplatelet, angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), β-blocker (BB), and statin] in COPD patients with or without CVD, and respiratory drugs (β2 agonist, anti-cholinergic, and corticosteroid) in CVD–COPD patients.

Cardiovascular drugs in chronic obstructive pulmonary disease patients with or without concomitant cardiovascular disease

Antiplatelet agents, ACE inhibitors or ARB, BB, and statins are the most commonly prescribed drugs in patients with CVD.¹

Antiplatelet agents and chronic obstructive pulmonary disease

During AE of COPD, the platelet count increased significantly.⁸ Thrombocytosis during AECOPD is associated with increased in-hospital and 1-year mortality (OR 2.37; 95% CI 1.29–4.34; and 1.53; 95% CI 1.03–2.29, respectively).⁹ We demonstrated that COPD patients treated with PCI have higher platelet reactivity (PR) when compared with patients without COPD.¹⁰ Nevertheless, the true clinical impact of antiplatelet agent administration in COPD patients is still controversial. No data from randomized clinical trials (RCTs) is available. All available findings are post hoc analyses from registries. In patients admitted to hospital for AECOPD (n = 1343), antiplatelet therapy was associated with a reduced 1-year mortality (OR 0.63; 95% CI 0.47–0.85).⁹ Similarly, Ekström et al. showed that antiplatelet agents were associated with a significant reduction in mortality (HR 0.86; 95% CI 0.75–0.99).¹¹ Similar finding is reported by Short et al. (HR 0.8; 95% CI 0.73–0.88), while other two studies reached to the opposite conclusion.^12–14 Data regarding new P2Y12 inhibitors (ticagrelor and prasugrel) in COPD patients are scanty. Recently, Alexopoulus et al. showed that ticagrelor administration was reduced in COPD patients admitted to hospital for ACS.¹⁵ The limited administration of ticagrelor may be partially explained by the fact that dyspnoea is one of the most commonly reported adverse events with ticagrelor.¹⁶ Dyspnoea may occur up to the 20% of patients receiving ticagrelor (data from RCT).¹⁶ Two RCTs evaluated the effect of ticagrelor on respiratory function including healthy subject and patients with asthma or COPD.¹⁷ Ticagrelor did not alter pulmonary function at rest and during exercise.¹⁷ Although these studies showed no interference by ticagrelor, physicians should be aware of this potential side effect that can affect up to one of five patients.Pharmacotherapy For Cardiovascular Disorders Essay.

In conclusion, there is no evidence for using antiplatelet agents any differently among COPD patients than in non-COPD patients.

Angiotensin converting enzyme inhibitors or angiotensin receptor blocker and chronic obstructive pulmonary disease

Angiotensin II is a powerful vasoconstrictor, inflammatory modulator, and cellular growth factor.¹⁸ Angiotensin II contributes to the inflammatory response that characterizes COPD.¹⁸ Recently, Petersen et al. showed that ACE inhibitor administration was related to lower FEV₁ decline in smokers.¹⁹ These findings suggest a possible role for ACE inhibitors in modulating smoking effects on lung.¹⁹ Angiotensin converting enzyme inhibitor or ARB administration in COPD patients has been suggested to manage pulmonary hypertension (PH) and to reduce all-cause mortality (Table 1). Notably, studies evaluating their effect on PH are mainly small RCT, whereas those on hard clinical endpoints are post hoc analyses of observational and retrospective registries (Table 1). No RCT are available assessing if ACE inhibitor or ARB reduce mortality or AECOPD in COPD patients (Table 1).Pharmacotherapy For Cardiovascular Disorders Essay.

Table 1

Main studies evaluating the role of angiotensin converting enzyme inhibitors or angiotensin receptor blockers in chronic obstructive pulmonary disease patients

References	Patients (n)	COPD diagnosis	Study population characteristics	Design	Main findings
Studies on all-cause mortality
Mortensen et al.²⁰	11 212	Previous diagnosis of COPD (ICD 9)	Hospitalization for AECOPD and treated with LABA, ICS, ACh	Retrospective	Reduction 90 days mortality (OR 0.55, 95% CI 0.46–0.66)
Mancini et al.²¹	5853 cases 116 871 controls	Previous prescription of LABA, ICS, ACh.	Cohort high CV risk (previous MI and/or CR); cohort low CV risk (absence of previous factors)	Retrospective	ARBs reduce mortality: – low CV risk and receiving ICS (HR 0.63, 95% CI 0.44–0.89) – low CV risk and not receiving ICS (HR 0.62; 95% CI 0.44–0.87) – high CV risk and receiving ICS (HR 0.61; 95% CI 0.51–0.73) – high CV risk and not receiving ICS (HR 0.53; 95% CI 0.44–0.64) ACE is do not reduce mortality in high CV risk patients ACE is reduce mortality in low CV risk patients: – receiving ICS (HR 0.74; 95% CI 0.65–0.85) – not receiving ICS (HR 0.68; 95% CI 0.60–0.77)
Ekström et al.¹¹	2249	Physician diagnosed COPD	Patients starting long-term oxygen therapy for COPD	Prospective observational multicentre study	No reduction in mortality.
Zeng et al.²²	220	Spirometry	Hospitalization in geriatric department	Retrospective	ACE is reduce mortality (HR 0.15; 95% CI 0.03–0.68) ARBs reduce mortality (HR 0.38; 95% CI 0.18–0.82)
Studies on pulmonary hypertension
Zielinski et al.²³	15	Clinical COPD diagnosis	COPD patients hospitalized for right HF	RCT single blind	Captopril does not reduce pulmonary vascular resistance
Kanazawa et al.²⁴	36	Clinical COPD diagnosis	Genotyping of ACE gene	RCT double blind	Captopril reduces mPAP in ID/II carriers.
Morrell et al.²⁵	40	Clinical COPD diagnosis	Patients with both COPD and pulmonary artery hypertension	RCT double blind	Losartan does not influence trans-tricuspid pressure gradient.

COPD, chronic obstructive pulmonary disease; ACE I, angiotensin converting enzyme inhibitors; ARB, angiotensin receptor blocker; AECOPD, acute exacerbation of COPD; LABA, long-acting β2 agonists; ICS, inhaled corticosteroids; Ach, inhaled anti-cholinergics; Y, yes; OR, odds ratio; CI, confidence interval; CV, cardiovascular; MI, myocardial infarction; CR, coronary revascularization; HR, hazard risk; N, no; NS, not specified; PH, pulmonary hypertension; mPAP, mean pulmonary artery pressure; RCT, randomized clinical trial.

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In conclusion, available data are not sufficient to consider ACE inhibitor or ARB mandatory in COPD patients. They should be prescribed according concomitant disease (e.g. MI) and risk factors (e.g. arterial hypertension).

β-Blockers and chronic obstructive pulmonary disease

β-Blockers are considered selective or not according the ability to block only β1 adrenergic receptors or both β1 and β2 adrenergic receptors.²⁶ Despite the positive effect of BB in COPD patients with IHD is well established, data on their utilization in daily clinical practice are not encouraging. Quint et al. reported that <40% of eligible patients with MI and concomitant COPD received BB.²⁷ Comparably, in patients with HF, the presence of COPD represents the prevalent reason for BB avoidance.²⁸ Fisher et al. confirmed that, at the time of hospital discharge, COPD patients were less likely treated with evidence-based HF medications, including BB.²⁹ Cardioselective BB produced no change in FEV₁ or respiratory symptoms, as well as they did not affect the FEV₁ treatment response to long-acting β2 agonists (LABA).³⁰ The use of cardioselective BB in COPD patients has to be encouraged also considering data on mortality. A meta-analysis including studies until 2011 showed a pooled relative risk reduction in mortality for COPD patients receiving BB (RR 0.69, 95% CI 0.62–0.78).³¹ We reported in Table 2 all studies published subsequently. We did not have RCT evaluating the relationship between BB, COPD, and mortality.Pharmacotherapy For Cardiovascular Disorders Essay.

Table 2

Main studies evaluating the role of β-blockers in COPD patients

References	Patients (n)	COPD diagnosis	Study population characteristics	Design	Main findings
Rutten et al.³²	2230	Age ≥ 45 years and incident or prevalent diagnosis of COPD (ICD 9 and 10)	Hospitalization for AECOPD	Observational cohort study	Reduction of mortality (HR 0.68; 95% CI 0.5–0.8) Reduction of AECOPD (0.71; 95% CI 0.6–0.8) Reduction of mortality in BB and LABA users (HR 0.6; 95% CI 0.5–0.8)
Short et al.¹²	5977	GOLD criteria	Hospitalization for COPD (ICD 9 and 10)	Retrospective cohort study	Reduction in mortality (HR 0.2; 95% CI 0.2–0.4)
Zeng et al.²²	220	Spirometric data	Hospital admission in Geriatrics department	Retrospective cohort study	No relation with mortality
Quint et al.²⁷	1063	Previous diagnosis of COPD	COPD patients experiencing first MI	Population-based cohort study	Reduction of mortality for BB chronically users (HR 0.59, 95% CI 0.4–0.7) Reduction of mortality for new prescribed BB (HR 0.5, 95% CI 0.3–0.7)
Angeloni et al.³³	388	GOLD criteria	COPD patients undergoing CABG	Propensity-matched cohorts with prospective follow-up	Increased survival rate in BB users (91 ± 3% vs. 80 ± 4%) No variation in AECOPD
Lee et al.³⁴	1062	Previous diagnosis of COPD (ICD 9 and 10)	Outpatient or hospital diagnosis within 12 months	Population-based cohort study	No difference in all-cause mortality

COPD, chronic obstructive pulmonary disease; GOLD, global initiative for chronic obstructive lung disease; ICD, international classification of disease; HR, hazard risk; CI, confidence interval; AECOPD, acute exacerbation of chronic obstructive pulmonary disease; BB, β-blockers; LABA, long-acting β2 agonists; CABG, coronary artery bypass graft.

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In conclusion, BB administration in COPD patients is safe. Cardioselective BB, if indicated, should be administered in COPD patients, independently to pulmonary comorbidity. Although RCT are missing, all available studies suggest a mortality reduction in COPD patients assuming BB.Pharmacotherapy For Cardiovascular Disorders Essay.

Statins and chronic obstructive pulmonary disease

Statins are able to reduce both systemic and pulmonary cytokine-driven inflammation by inhibiting Rho guanosine triphosphatase proteins.^35,36 Simvastatin reverses pulmonary vascular effects of cigarette smoke, including PH and emphysema.³⁷ Accordingly, several authors evaluated the potential role of statin administration in COPD patients to reduce both all-cause mortality and AECOPD. The majority of data are derived from registries and retrospective studies (Table 3). Recently, a worthy RCT has been conducted.³⁸ The effect of simvastatin 40 mg on occurrence of AECOPD in patients with moderate-to-severe COPD has been evaluated in a prospective RCT.³⁸ The trial did not reached the primary endpoint, failing to demonstrate a change in the incidence of AECOPD in patients treated with simvastatin when compared with placebo.³⁸ No effect on hard cardiac endpoints was reported.³⁸

Table 3

Main studies evaluating the role of statins in chronic obstructive pulmonary disease patients

References	Patients (n)	COPD diagnosis	Study population characteristics	Design	Main findings
Mancini et al.²¹	5853 cases 116 871 controls	Previous prescription of LABA, ICS, ACh	Cohort high CV risk (previous MI and/or CR); cohort low CV risk (absence of previous factors)	Retrospective	Significant reduction in mortality: – high CV risk receiving ICS (HR 0.5; 95% CI 0.4–0.62) – high CV risk not receiving ICS (HR 0.53; 95% CI 0.45–0.65) – low CV risk receiving ICS (HR 0.53; 95% CI 0.44–0.64) – low CV risk not receiving ICS (HR 0.49; 95% CI 0.41–0.58)
Soyseth et al.¹³	854	Previous diagnosis of COPD (ICD 9 and 10)	Hospitalization for AECOPD	Retrospective cohort study	Reduction in mortality (HR 0.57; 95% CI 0.38–0.87)
Mortensen et al.²⁰	11212	Previous diagnosis of COPD (ICD 9)	Hospitalization for AECOPD	Retrospective	Reduction in 90 days mortality (OR 0.51, 95% CI 0.4–0.64)
Sheng et al.¹⁴	1717	Previous diagnosis of COPD (ICD 9 and 10)	Outpatients	Retrospective cohort study	Primary prevention: – all-cause mortality reduction (HR 0.6; 95% CI 0.43–0.85) Secondary prevention: – all-cause mortality reduction (HR 0.58; 95% CI 0.35–0.97) – CV mortality reduction (HR 0.32, 95% I 0.13–0.7)
Lawes et al.³⁹	1687	Diagnosis of COPD (ICD 10)	Outpatients	Cohort study	All-cause mortality reduction (HR 0.69; 95% CI 0.58–0.84)
Ekström et al.¹¹	2249	Physician diagnosed COPD	Patients starting long-term oxygen therapy for COPD	Prospective multicentre study	No significant reduction in mortality
Lahousse et al.⁴⁰	363 cases vs. 2345 controls	Spirometric data	Outpatients	Nested case–control analysis from a population-based cohort study	Reduction in mortality (RR 39; 95% CI 0.38–0.99) Patients with CRP > 3 mg/L: RR 78% (95% CI 0.06–0.74)

COPD, chronic obstructive pulmonary disease; LABA, long-acting β2 agonists; ICS, inhaled corticosteroids; ACh, inhaled anti-cholinergic; AECOPD, acute exacerbation of COPD; HR, hazard ratio; CI, confidence interval; CV, cardiovascular; GOLD, global initiative for chronic obstructive lung disease; ICD, international classification of disease; CRP, C-reactive protein; RR, relative risk.Pharmacotherapy For Cardiovascular Disorders Essay.

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In conclusion, the potential benefit of statins in COPD patients has not been demonstrated. If indicated, statins must be administered to COPD patients, but there is no particular reason to start statins in COPD patients who do not otherwise have an indication.Pharmacotherapy For Cardiovascular Disorders Essay.

Oral anti-coagulants and chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease emerged as significant predictor of atrial fibrillation/atrial flutter (23 vs. 11%, P < 0.01) after adjustment for all confounding factors.⁴¹ Warfarin is the most commonly prescribed oral anti-coagulant in general population. Retrospective studies reported that anti-coagulation treatment is inadequate in patients with atrial fibrillation and COPD.^41,42 This may be explained by the higher occurrence of coexisting morbidities and by the higher risk of bleeding complications in COPD patients.^5,43,44 Nowadays, dabigatran, rivaroxaban, and apixan are available in the market.⁴⁵ They significantly reduced bleeding complications.⁴⁵ Nevertheless, no studies evaluated if this reduction is confirmed or different in COPD patients. Interestingly, in a substudy of the ROCKET-AF trial, COPD emerged as independent predictor of major bleeding risk.⁴⁶

In conclusion, although COPD patients are at higher risk of bleeding complications, oral anti-coagulants should not be denied if clinically indicated.

Respiratory drugs in patients with concomitant chronic obstructive pulmonary disease and ischaemic heart disease

Treatment of COPD is based on long-acting inhaled bronchodilators (anti-cholinergics or LABA), inhaled corticosteroids (ICS) or a combination of these agents.Pharmacotherapy For Cardiovascular Disorders Essay.

Acetylcholine antagonists

Ipratropium, oxitropium, and tiotropium are the most common anti-cholinergic drugs.² Patients treated with tiotropium are at higher risk of tachy-arrhythmias (RR 3.70, 95% CI 0.79–17.4) and atrial tachycardias (RR 7.39, 95% CI 0.92–59.1).⁴⁷ The cardiovascular effects of inhaled anti-cholinergics have been evaluated in several studies (both RCT and registries). Some registries and post hoc analyses suggested a higher risk of cardiac adverse events in COPD patients receiving anti-cholinergics. In view of these concerns, systematic reviews and meta-analyses have been performed and we reported their results in Table 4. Two main RCT investigated this topic. In the UPLIFT trial, tiotropium administration was associated with reduced 4-years cardiac mortality (HR 0.86, 95% CI 0.75–0.99).⁴⁸ To explain the differences, a relationship between formulation (dry-powder vs. aqueous solution), dose (18 vs. 5 μg), and the outcome has been suggested. Accordingly, the TIOSPIR trial has been planned. This was a large-scale (n = 17183 patients), randomized, prospective evaluation of the safety and efficacy of tiotropium Respimat, when compared with tiotropium HandiHaler.⁴⁹ No difference in mortality, exacerbations, causes of death and major cardiovascular adverse events has been observed.⁴⁹

Table 4

Inhaled respiratory drugs and mortality/cardiac adverse events in chronic obstructive pulmonary disease patients (data from meta-analyses)

References	Patients (no.)	Studies type	Studies included	Drug	Main findings
Salpeter et al.⁵⁰	6855	RCT	20	LABA vs. placebo	Increased risk of CV adverse event (RR 2.5; 95% CI 1.6–4) No difference in MACE
Sin et al.⁵¹	5085	RCT	7	ICS vs. placebo	ICS reduced all-cause mortality by ∼25% Mortality reduction in woman (HR 0.6, 95% 0.39–0.91) Mortality reduction in former smokers (HR 0.6, 95% CI 0.36–0.93)
Salpeter et al.⁵²	15276	RCT	22	B2A vs. anti-cholinergic vs. placebo	Anti-cholinergic reduces severe AECOPD (RR 0.7, 95% CI 0.5–0.9) Anti-cholinergic reduces respiratory death (RR 0.3, 95% CI 0.1–0.8) B2A did not affect severe AECOPD B2A increases respiratory death (RR 3, 95% CI 1.7–5.5)
Gartlehner et al.⁵³	4300	Double-blinded RCT	13	ICS vs. placebo	No difference in overall mortality
Drummond et al.⁵⁴	14 426	Double-blinded RCT	11	ICS vs. placebo	No difference in 1-year mortality
Rodrigo et al.⁵⁵	18 111	RCT	19	Inhaled tiotropium vs. placebo	No difference in CV adverse events No increase in CV mortality No increase in nonfatal MI No increase in nonfatal stroke
Loke et al.⁵⁶	23 396	RCT and controlled observational studies	–	ICS vs. placebo	In RCT, no effect on MI In RCT, no effect on CV death In RCT, no effect on mortality In COS, reduction of CV death (RR 0.79, 95%CI 0.72–0.86) In COS, no effect on mortality
Singh et al.⁵⁷	6522	Parallel group RCT	5	Tiotropium inhaler vs. placebo	Increased all-cause mortality (RR 1.52, 95% CI 1.06–2.16) Increased CV mortality (RR 2.05, 95% CI 1.06–3.99)
Dong et al.⁵⁸	52 516	RCT	42	Tiotroprium vs. LABA vs. ICS	Soft mist inhaler vs. placebo on death (OR 1.5, 95% CI 1.1–2.2) Soft mist inhaler vs. dry-powder on death (OR 1.7, 95% CI 1.1–2.4) Soft mist inhaler vs. LABA on death (OR 1.6; 95%CI 1.1–2.5) Soft mist inhaler vs. LABA-ICS on death (OR 1.9; 95% CI 1.3–2.8) LABA-ICS was associated with the lowest risk of death No excess risk was noted for tiotropium dry powder or LABA

COPD, chronic obstructive pulmonary disease; RCT, randomized clinical trials; LABA, long-acting β2 agonists; CV, cardiovascular; MI, myocardial infarction; MTC, mixed treatment comparison; n, number; RR, relative risk; OR, odds ratio; HR, hazard risk; CI, confidence interval; AECOPD, acute exacerbation of chronic obstructive pulmonary disease; ICS, inhaled corticosteroids; MACE, major adverse cardiac event (ventricular arrhythmias, myocardial infarction, and sudden death); COS, controlled observational studies.

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In conclusion, the administration of inhaled anti-cholinergics is safe and effective in COPD patients, also with concomitant CVD.

Long-acting β2 agonists

The study of the relationship between LABA and cardiac adverse events in patients with concomitant COPD and CVD showed conflicting results. All data derived from registries. No RCT are available. Meta-analyses trying to assess the relationship between LABA and cardiac adverse events are reported in Table 4. A post hoc analysis of the TORCH study merits a special consideration.⁵⁹ In this analysis, it was reported the relationship between salmeterol, fluticasone (in combination or alone) vs. placebo, and the incidence of CV adverse events. The analysis found that salmeterol alone or in combination with fluticasone did not increase the risk of events (HR 0.89, 95% CI 0.72–1.10).⁵⁹

In conclusion, LABA administration is safe. It showed only minor cardiac side effects and did not influence long-term mortality.Pharmacotherapy For Cardiovascular Disorders Essay.

Inhaled corticosteroids

Inhaled corticosteroids are frequently prescribed to control progression and symptoms of COPD.² Even ICS cause a slight increase in gastrointestinal bleedings (HR 1.26, 95% CI 1.02–1.56).⁶⁰ Of note, the adequate use of spacer device reduced significantly these complications (0.26, 95% CI 0.2–0.34).⁶⁰ To evaluate the safety and effectiveness of ICS in COPD patients, several RCT have been performed. Some studies have yielded conflicting results regarding survival and risk of MI. Meta-analysis clarifying this issue are reported in Table 4.Pharmacotherapy For Cardiovascular Disorders Essay.

In conclusion, no evidences support a negative relationship between ICS and mortality or cardiac adverse events in COPD patients with or without concomitant CVD.Pharmacotherapy For Cardiovascular Disorders Essay.

Conclusions and future perspectives

Available studies strongly suggest that evidence-based treatment should not be modified in patients with concomitant presence of COPD and CVD. In daily clinical practice, it is mandatory to obtain the optimal titration of both cardiovascular and respiratory drugs. Available data strongly suggested that patients with concomitant COPD and CVD are at higher risk of death and adverse events. This is confirmed in several registries and trials. The early identification of the comorbidity and a prompt treatment of each singular disease may significantly improve the quality of life and the prognosis of these patients. Obviously, we did not have RCT on these topics and the majority of evidences are extrapolated from registries, observational studies or post hoc analysis from trials. Nevertheless, all findings are consistent and, awaiting further data from specific RCT, any effort should be considered to identify these patients and to optimize their pharmacological treatment.Pharmacotherapy For Cardiovascular Disorders Essay.