# Presentation: 301221

- Please note:
- Due to technical difficulties the medical contrast images will not be in motion, the image will appear as a still picture.
- For medical images please refer to the transcript, Part 1 beginning on page 64, for the description of the images that were provided by the presenter.

## Clinical Experience and Safety Considerations

- Professor R. Senior
- Consultant Cardiologist and Director of Cardiac Research
- Northwick Park Hospital, Harrow, UK

## Contrast Echocardiography with SonoVue

- Clinical Utility: Assessment of LV structure and function (global and regional) and assessment of microcirculation (cardiac and extra-cardiac)
- Side-effect Profile
- Risk-Benefit

## Annualized Incidence of Death by LVEF

- Solomon SD.  Circulation 2005; 112: 3738-3744

##  55-Year-Old Male, previous DDD pacemaker, presented with shortness of breath who underwent Echo for the assessment of LV  function

## Contrast Echo with SonoVue

## Subgroup Differences in LV Volumes and EF Between MRI and Echocardiography

|  | Poor Baseline Image Quality |  | Good Baseline Image Quality |  |
| --- | --- | --- | --- | --- |
| Subgroup | Baseline Echo | Contrast Echo | Baseline Echo | Contrast 
Echo |
| EDV (ml)
ESV (ml)
EF (%) | -56.4±47.8
-16.2±31.8
-6.0±13.9 | -24.4±23.8
-6.5±15.6
-1.9±6.5 | -56.3 ±41.8
-21.8 ±47.2
-3.8 ±12.9 | -25.7 ±24.4
-9.0 ±20.2
-1.4 ±5.9 |

- Malm S, et al JACC 2004; 44: 1030-5

## Global Function: Lower Inter-observer Variability

-    * Echo  vs. CINE:	 	p = 0.02
-    ** CINE vs. MRI: 		p = 0.15
-  *** MRI vs. Contrastecho: 		p = 0.002

**Notes:**
In a multicenter study comparing echocardiography without contrast, cineventriculography, MRT and contrast echocardiography the interobserver variabilty between thre readers in the assessment of global left ventricular function using contrast echocardiography was significantly decreased using contrast echo and reached the level of MRT.

## Case Study: History

- 29-year-old obese Asian female
- Right shoulder pain and short of breath two months post delivery when pushing pram
- Diabetic for 2 years
- Normal resting ECG
- Non-diagnostic Exercise ECG
- Advised to have Stress Echo

## Non-Contrast Echo

## Rest

**Stress**

## Coronary Arteriography

## Stress Echo After Angioplasty

**Stress Echo After Angioplasty**

## Northwick Park Study: Risk Stratification by Exercise ECG and Stress Echocardiography

**21**

**33**

**22**

**77**

**69**

**39**

**69**

**3**

**10**

**29**

**8**

**20**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

**Pre Test**

**Post Test**

**PreTest**

**Post Test**

**ExECG**

**SE**

**Number of Patients (%)**

**Low**

**Intermediate**

**High**

**Jeetley and Senior *****Eur Heart J. *****2007;28:116-223**

## Outcome of Stress Echo vs Exercise ECG

**Jeetley P et al. *****Eur Heart J. *****2007;28:116-223.**

## Diagnostic Accuracy of Each Imaging Method to Detect the Presence of Regional Wall Motion Abnormalities Defined by a Panel Decision

**Hoffmann R  et al. *****J Am Coll Cardiol*****. 2006;47:121-128.**

|  | EchoUnenhanced | Echo Contrast-Enhanced | Cineventriculography | cMRI |
| --- | --- | --- | --- | --- |
| All patients
  Sensitivity
  Specificity
  Accuracy
Only cMRI patients
  Sensitivity
  Specificity
  Accuracy | 100
85.7%
77.3%
82.9%
56
83.3%
73.0%
79.5% | 100
90.2%
81.3%
87.2%
56
90.7%
83.8%
88.2% | 199
86.5%
75.0%
82.8%
56
84.1%
69.4%
78.7% | 56
90.8%
74.4%
84.9%
56
90.8%
74.4%
84.9% |

**Mean From All 3 Readers**

## International Stress Echo Complication Registry85,997 patients

| Complication  | Dobutamine 
35103 | Dipyridamole 
24599 | Exercise 
26295 |
| --- | --- | --- | --- |
| Death | 5 (1/7020) | 1  | 0 |
| Acute MI | 11 (1/3191) | 5 (1/4919) | 1 |
| Sustained VT | 27(1/1200) | 1  | 2 |
| Ventricular fibrillation | 11(1/3191)  | 2  | 0 |
| Cardiac rupture | 5  | 0  | 1 |
| Asystole | 2  | 4  | 0 |
| TIA/Stroke | 3  | 3  | 0 |
| Hypotension  | 2  | 4  | 0 |
| 3rd Degree AV block  | 2  | 0  | 0 |

**Safety of Stress Echocardiography (from the International Stress Echo Complication Registry)**(2006) *American Journal of Cardiology*, 98 (4), pp. 541-543.

## Safety of SonoVue Enhanced Stress Echocardiography

- No deaths, No AMI, No life threatening allergic reactions
- 2 life threatening events (Ventricular tachycardia/Ventricular fibrillation)(0.04%)
- Patients with EF<0.40 (N=1153, 22.0%) showed higher frequency of cardiac arrhythmias of any kind (9.5%) versus patients with EF>0.40 (5.4%, p<0.001).
- 5 vasovagal reactions (0.1%)
- 3 elevation of troponin I (0.04%)
- Dry mouth most frequent symptom (19.8%)

- 5250 patients undergoing dobutamine stress test*

- *Aggeli et al.  Heart 2008

## Simultaneous Assessment of Wall Motion & Microcirculation

## Acute Coronary Syndrome:   Relationship between Function and Perfusion and Outcome

- Janardhanan and Senior AJC 2004:93;1207-11

## Kaplan Meier Survival Curves for MCE Defect Size for the Prediction of Cardiac Death in 95 Patients Following AMI

- Dwivedi and Senior J Am Coll.Cardiol2007;50:327-34

- Good Perfusion

- Reduced Perfusion

## ?

**?**

**Focal Liver Lesions Characterization**

**Benign or Malignant?**

## Liver: Characterization of Hepato Cellular Carcinoma

**Liver: Characterization of Hepato Cellular Carcinoma**

## Liver: Characterization of Focal Liver Lesions

| N = 310 in 4 studies | CE-CT | SonoVue US |
| --- | --- | --- |
| Sensitivity | 88% - 93% | 91%-100% |
| Specificity | 89% |     90% |
| Accuracy | 78%-88% | 86%-91% |

- SonoVue US demonstrated a higher sensitivity, specificity and accuracy than unenhanced US and lower inter-observer variability.

- SonoVue**®** US is comparable to contrast enhanced CT.

| N = 3872 in 9 studies | Unenhanced US | SonoVue US |
| --- | --- | --- |
| Sensitivity | 28.1%-88% | 81%-100% |
| Specificity |    22.1%-91.9% |     78.4%-96.5% |
| Accuracy | 30.6%-88% | 85%-92.7% |

## Impact of SonoVue Enhanced Ultrasound in Clinical Practice

- ESFUMB guidelines*:
- Focal liver lesions of incidental detection
- Follow-up of cirrhotic patients
- Staging-Follow-up of patients with malignancies
- Percutaneous image-guided tumor ablation
- Monitoring of tumor response to chemotheraphy (TACE-neo angiogenesis drugs)
- American Association for Study of Liver Diseases (AASLD)**
- has indicated CE-US as a key imaging modality for diagnosis of HCC

- *Update 2008 Ultraschall in Med 2008; 29: 28–44
- **Management of Hepatocellular Carcinoma hepatology HEPATOLOGY, 2005: 42, No. 5,

## Stroke Treatment – Role of SonoVue

## Safety in Worldwide Bracco Clinical Trials

- Completed clinical trials: 	57
- Patients enrolled:            	4730
- Cardiac studies:		1840
- Microvascular studies:		2133
- Macrovascular studies:		  555

- Low incidence of adverse events:
- All: 11.9%, of which 6.1% drug related
- The most frequent were headache (1.2%) and nausea (0.7%)
-       Serious: 0.5% of which 0.02% drug related.

- 7 special population studies did not demonstrate any significant
- clinical signs after SonoVue administration

## SonoVue: PMS Analysis over 6 years

**SonoVue: PMS Analysis over 6 years**

## Comments on 6 year PMS Data

- Overall, incidence of events very low
- 5 deaths (1:145,000)
- 1 unrelated: 9 hours after SonoVue injection and few minutes after morphine administration
- 1 case was classfied as possible and was a consequence of anaphylactic shock
- 3 deaths in cardiac patients with severe three coronary vessel disease** **

## Event Cascade in Majority (76%) of Serious SonoVue ADRs

- Classified as allergic-like reactions
- Independent of dose
- Onset:                	within 1-2 minutes from					injection
- First symptom: 	Hypotension, vasovagal 					syncope.
- Resolve after administration of Adrenaline and/or Cortisone

## Events Classified as Cardiac Disorder

**Events Classified as Cardiac Disorder**

**Overall 40 cardiac manifestations (by MedDRA terms) **
**in 30 (1: 25,000) patients**

## Risk/Benefit Ratio

| Risk Category | Incidence | Substance Class |
| --- | --- | --- |
| Low | 0.005% - 0.015% | Analgesics 
Antibiotics
MRI-Contrast Media |
| Medium | 0.03% - 0.1% | Penicillin IV
Blood Dextrane 
Pentoxyphylline
Iodine-Contrast Media |
| High | > 0.1% | Plasma
Streptokinase |

- Incidence of Severe Anaphylaxis by Substance Class as Defined by
-  the International Collaborative Study of Severe Anaphylaxis*

**SonoVue****®**** **
**RR 0****.01%**

***The International Collaborative Study of Severe Anaphylaxis. Risk of anaphylaxis in a hospital population**
** ****in relation to the use of various drugs: an international study. Pharmacoepidemiol Drug Saf 2003; 12:195–202****.**

## Mortality in Cardiac Procedures

_**Procedures**_**	****	****	****	**_**Mortality**_
**Contrast Echo****	****	****	****1:145,000(SonoVue)**
**Myocardial Scintigraphy****	****1:10,000**
**Exercise ECG****	****	****	****1:2,500 (or AMI)**
**Coronary Arteriography****	****1:1,000**

- Modified from Main et al; J Am Coll Cardiol 2007; 50: 2434-7

## Conclusions

- Contrast Enhanced Ultrasound provides incremental diagnostic and prognostic information over standard clinical criteria and may be superior to competing techniques
- SonoVue safety analysis of Bracco-sponsored clinical trials and 6 years of PMS suggests SonoVue falls in the low-risk category
-  SonoVue has excellent risk benefit profile