Heart Rate Controller in Computed Tomography Coronary Angiography

Coronary computed tomography angiography (CCTA) is one of important non-invasive test for diagnosis of coronary artery disease. Cardiac motion artifact by heart rate (HR) has impact on CCTA interpretation. Current recommendation suggests HR reduction at less than 60 bpm with using of oral metoprolol. However, there are populations that are contraindicated for beta blockers. There were scantly data of calcium channel blocker and ivabradine. Moreover, there is no data comparing these 3 drug groups within single trial This double-blinded randomized controlled trial compares oral metoprolol immediate release, diltiazem immediate release and ivabradine with primary endpoint of patients' percentage to achieve target HR lower than 60 bpm prior to CCTA.

Coronary computed tomography angiography (CCTA) is one of important non-invasive test for diagnosis coronary artery disease. Information of CCTA can provide information such as coronary artery lumen, vessel wall, degree of stenosis and component of coronary arterial plaque. Most of studies in CCTA represent high negative predictive value (NPV) approximately 93-100 %.However, motion artifact has impact on CCTA interpretation, especially when heart rate (HR) at more than 70 beat-per-minute (bpm). Therefore, HR reduction maneuver is necessary for CCTA. Current recommendation suggests HR reduction at \< 60 bpm for best quality of CCTA imaging and to minimized duration of exposure to radiation using either beta blockers or non-dihydropyridine calcium channel blockers. According to North American Society for Cardiovascular Imaging (NASCI) recommendation in 2016, oral beta blocker prior to CCTA in patient with HR \> 60 bpm is the preferred intervention. The recommended oral beta blocker usually is metoprolol 50-100 mg 1 hour prior to CCTA. The dosage of metoprolol must not exceed 400 mg/day. However, there are populations that are contraindicated or need to avoid beta blockers, such as uncontrolled obstructive airway disease, patient with baseline SBP \< 100 mmHg, etc. Also, data in many clinical trials suggested that even high dose beta blockers can't controlled HR to target prior to CCTA in some patients. These pieces of information lead to alternative drugs to control HR prior to CCTA.

In previous clinical trials, the effective of non-dihydropyridine calcium channel blockers to control HR prior to CCTA compare to beta blockers had unclear results. In one study, Intravenous (IV) diltiazem is as effective in HR lowering to target to less than 60 bpm as IV metoprolol. Another study expressed inferior result of oral verapamil 1 hour before CCTA compared to oral metoprolol. However, there was heterogeneity in population of metoprolol and verapamil groups. According to FDA, immediate release (IR) diltiazem has onset of action faster than verapamil IR at 30 \& 60-120 min., respectively. Initial dose of diltiazem in patients with chronic stable coronary artery disease and supraventricular tachycardia is at 30 - 60 mg oral every 6 hour and not exceed 360 mg/day.

Another agent that started to gain more evidence in HR control is ivabradine. Ivabradine has high selective and inhibitive property to If current channel which related to sinus node pace maker activity. Thus, other ion current channel normally doesn't get involved and doesn't have direct other cardiovascular effect. From meta-analysis, patients received ivabradine significantly achieving target HR to at least 65 bpm more than beta blockers group prior to CCTA (OR 5.02; 95% CI 3.16- 7.98, p \< 0.00001, I 2 = 20%). In current recommendation, dosage of ivabradine shouldn't exceed 15 mg per day in patients with heart failure and chronic stable coronary artery disease. However, ivabradine has contraindication in patient with atrial fibrillation and/or sinus node disease, which require other agent to achieve target HR prior to CCTA. In current situation, there is no clinical trial to compare effect of beta blocker, non-dihydropyridine calcium channel blocker and Ivabradine in HR reduction to achieve target prior to CCTA.

The aim of this study is to compare percentage of patients achieving target HR \< 60 bpm medication prior to CCTA by using oral beta blockers, non-dihydropyridine calcium channel blocker and ivabradine for HR lowering. Our study is double-blinded randomized controlled trial using Metoprolol immediate release as representative of beta blockers for controlled group, Diltiazem immediate release as representative of non-dihydropyridine calcium channel blocker and ivabradine. We blinded both investigators and patients using encapsulated drugs distribute from Siriraj's dispensary and randomly assign to our patients. The secondary objective of this study is to compare side effects, time to achieve target HR \& CCTA image quality using 5 point grade scale and modified 15-segment American College of Cardiology and American Heart Association (AHA) between oral Metoprolol immediate, Diltiazem immediate release and ivabradine.

Eligibility Criteria:
Inclusion Criteria:

1. Age of at least 18 year-old
2. Received Coronary CT angiography at Siriraj Hospital to evaluate diagnosis of coronary artery disease or risk stratification of coronary artery disease
3. Normal sinus rhythm with baseline HR \> 60 bpm which cardiac imaging specialist suggest using HR lowering intervention

Exclusion Criteria:

1. Atrial fibrillation
2. Previous pacemaker implantation
3. II- and III-degree atrio-ventricular-block
4. NHYA class III - IV
5. Documented LVEF \< 40%
6. Contraindication for CCTA: Impaired renal function (serum creatinine \> 1.5 mg/dl), known allergy to iodinated contrast media, pregnancy, thyroid disease
7. Blood pressure \< 100/70 mmHg
8. Uncontrolled asthma and/or chronic obstructive pulmonary disease (defined as GOLD stage D) and/or uncontrolled reactive airway disease
9. Current medication which cause severe interaction with calcium channel blocker, beta blocker and/or Ivabradine
10. Known allergy to calcium channel blocker, beta blocker and/or Ivabradine