Metformin Continuation Safety in Diabetic Patients Undergoing Coronary Angiography
Phase: PHASE4
Conditions: Diabetes Mellitus, Coronary Artery Disease, Lactic Acidosis With Diabetes Mellitus, Contrast-induced Nephropathy, Metformin Associated Lactic Acidosis
Sponsor: Humanitas Hospital, Italy

 
 
METFORMIN CONTINUATION SAFETY IN DIABETIC 
PATIENTS UNDERGOING CORONARY ANGIOGRAPHY: 
THE NO-STOP STUDY 
 
 
 
 
 
PROTOCOL 
 
Milan, June 2019 
 
 

NO-STOP Protocol 
 
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INDEX 
INDEX ....................................................................................................................................................... 2 
1 
PROTOCOL SYNOPSIS ................................................................................................................... 3 
1.1. 
TIME SCHEDULE ................................................................................................................... 4 
2. 
BACKGROUND .............................................................................................................................. 5 
3. 
POTENTIAL RISKS AND BENEFITS ................................................................................................. 5 
4. 
STUDY OBJECTIVES ...................................................................................................................... 6 
5. 
STUDY DESIGN ...................................................................... Errore. Il segnalibro non è definito. 
7. 
ENDPOINTS .................................................................................................................................. 6 
7.1. 
Primary endpoint .......................................................... Errore. Il segnalibro non è definito. 
7.2     Secondary endpoints ............................................................................................................. 6 
8. 
STUDY POPULATION ............................................................. Errore. Il segnalibro non è definito. 
8.1. 
Sample size ....................................................................... Errore. Il segnalibro non è definito. 
9. 
STUDY PROCEDURE .............................................................. Errore. Il segnalibro non è definito. 
10. 
ADVERSE EVENTS AND RISK/BENEFIT ..................................................................................... 8 
10.1. 
Adverse events ......................................................... Errore. Il segnalibro non è definito. 
10.2. 
Cause of study withdrawal .............................................................................................. 8 
11. 
STATISTICAL ANALYSIS ....................................................... Errore. Il segnalibro non è definito. 
11.1. 
Methods ................................................................... Errore. Il segnalibro non è definito. 
12. 
ETHICAL IMPLICATIONS ........................................................................................................... 9 
12.1. 
General rules ................................................................................................................... 9 
12.2. 
Informed consent ............................................................................................................ 9 
13. 
DATA USE AND PUBLICATION .................................................................................................. 9 
14. 
REFERENCES .......................................................................................................................... 10 
 
 
 
 

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1 PROTOCOL SYNOPSIS 
 
Study title 
Metformin continuation safety in diabetic patients undergoing coronary 
angiography. 
Acronym 
NO-STOP 
IRCCS internal sites:  
Cardio Center, IRCCS Istituto Clinico Humanitas – Via Manzoni 56, Rozzano 
(MI) 
IRCCS external sites: 
None 
Population 
Diabetic patients treated with metformin undergoing coronary 
angiography. 
Objectives 
To assess the safety of metformin in diabetic patients undergoing 
coronary angiography in terms of risk of lactic acidosis. Individuate 
eventual clinical, echocardiographic predictors of lactic acidosis in this 
setting.  
Study design 
Prospective, no-profit, single arm trial, powered for non-inferiority with 
respect to historical cohort. 
Sample size 
The study require the enrollment of at least 110 patients. 
Primary endpoint 
Increase of 20% from preprocedural lactic acid values. 
Secondary endpoints 
Contrast-associated acute kidney injury after coronary angiography. 
Lactic acidosis development after coronary angiography. 
Correlation between clinical, laboratoristic, and echocardiographic 
variables and lactic acid values. 
Inclusion criteria 
Diabetic patients treated with metformin undergoing coronary 
angiography.  
Exclusion criteria 
Known coronary anatomy with planned complex percutaneous coronary 
intervention with high probability of large amount of contrast use (>150 
ml). 
Moderate to severe impairment of renal function (eGFR<45 ml/min).  
Moderate to severe impairment of liver function (Child-Pugh class B or C). 
Severely impaired left ventricular ejection fraction (LVEF <35%). 
Patients undergoing primary percutaneous coronary intervention (i.e., 
patients presenting with ST elevation myocardial infarction). 
Severe to very severe chronic obstructive pulmonary disease (GOLD class 3 
to 4). 
Patients scheduled for cardiac surgery in the following 5 days. 
Inability to provide informed consent. 
Prespecified 
subgroup analyses 
Patients taking other antiglycaemic drugs on top of metformin. 
Patients requiring percutaneous coronary angioplasty. 
Patients with mild and moderate renal function impairment (eGFR<90 and 
<60 ml/min). 
Patients undergoing urgent coronary angiography (<24 hours from the 
index event). 
Follow-up 
The days after coronary angiography, at discharge and after three days from 
coronary angiography. 

 
 
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1.1.  TIME SCHEDULE 
Event 
Screening 
Post-procedure 
At discharge 
At three days 
Type of contact with the patient 
Visit 
 
Visit 
Visit/phone call 
Inclusion/exclusion criteria 
X 
 
 
 
Informed consent 
X 
 
 
 
Medical hystory 
X 
 
 
 
Physical examination 
X 
X 
X 
 
Hemocrome, kidney and liver function, lactic acid 
 
X 
X 
X 
X 
CK-MB, hs-troponin I, BNP 
X 
X 
X 
 
Transthoracic echocardiography 
X 
 
 
 
12-leads electrocardiogram 
X 
X 
X 
 
Lactic acidosis, death, kidney failure, liver failure 
 
X 
X 
X 
 

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2. BACKGROUND 
Metformin is an antiglycemic drug member of biguanide class, firstly introduced in 1957 for the treatment of 
non-insulin dependent diabetes mellitus. It is the most widely prescribed drug for glycemic control in diabetic 
patients and it is often used in combination with other antiglycemic drug and insulin.1,2 Its mechanism of action 
depends on decreased hepatic gluconeogenesis and glycogenolysis,3 and increased skeletal muscle glucose 
uptake.4 Moreover, metformin is also associated with a reduction in cardiovascular morbidity and mortality, when 
compared to insulin or sulfonylureas.5 Diabetes mellitus is extremely common among patients with coronary 
artery disease, with prevalence reaching 40% in some reports of patients undergoing percutaneous coronary 
intervention.6 Therefore, metformin is one of the most common drug prescribed to patients with indication for 
coronary angiography. Notwithstanding, the biguanide agent that preceded metformin, phenformin, was 
withdrawn from clinical practice in 1978, due to an unacceptable risk of lactic acidosis, ranging from 40 to 64 
cases per 
100,000 patient-years.7 However, metformin 
present different 
pharmacokinetics 
and 
pharmacodynamics properties, with an estimated risk of lactic acidosis ten to twenty times less than that of 
phenformin. Considering the high risk of lactic acidosis with its predecessor phenformin and the high mortality 
of this condition, the vast majority of physician used to suspend metformin before contrast use.8  
The incidence of lactic acidosis after metformin has recently come into question, while it has been recognized 
that the routinely discontinuation of metformin could carry the converse risk of deleterious effects on glycemic 
control, increased cardiovascular and acute kidney injury risk.9 Metformin itself is not directly nephrotoxic,10 but 
in patients predisposed to acute deterioration in renal function after contrast administration, i.e., contrast-
induced nephropathy (CIN), it has been postulated that there is the potential for metformin to accumulate, 
leading to lactic acidosis. However, evidence for this is totally lacking.8,11 Firstly, although CIN occurs in 2% to 25% 
of patients undergoing coronary intervention,12 not every patient on metformin that develops CIN develops lactic 
acidosis.13 Secondly, most of the reported cases of lactic acidosis in patients taking metformin have been in 
patients with severe underlying conditions, including renal dysfunction, septicemia, hepatic failure and acute left 
ventricular failure, any of which could in themselves contribute to the lactic acidosis.14–16  
 
 
3. POTENTIAL RISKS AND BENEFITS  
The present study aims to evaluate the strict application of the 2018 European Society of Cardiology on 
myocardial revascularization, that recommends to check renal function if patients have taken metformin 
immediately before angiography and withhold metformin if renal function deteriorates.11  
A recent meta-analysis, using pooled data from 347 prospective comparative trials and observational cohort 
studies, found no cases of fatal or non-fatal lactic acidosis in 70,490 patient-years of metformin use nor in 
55,451 patient-years in the non-metformin group.17 Using Poisson statistics with 95% confidence interval the 
authors reported that the upper limit for the incidence of lactic acidosis in patients taking metformin was 4.3 
cases per 100,000 patient-years, and in the non-metformin group the upper limit for the incidence of lactic 
acidosis was 5.4 cases per 100,000 patient-years. The risk for acute kidney injury in patients undergoing 
angiographic procedure with those preventive measures constantly applied in our center is considered to be 
the same of those patients not undergoing procedure without iodinated contrast medium. Moreover, we will 

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exclude from the study all those patients considered at augmented risk of CIN.10,12 Therefore, we assume that 
the risk for lactic acidosis in our expected population is the same that patients have with their everyday 
metformin assumption.  
Moreover, considering the documented augmented risk of hyperglycemia in patients suspending metformin for 
angiographic procedure,8 and the augmented risk of serious adverse events in patients with hyperglycemia,18 
there could be the advantage of maintaining the usual antiglicemic therapy including metforminthat should be 
probably more appropriate than an empiric insulin regimen started at hospital admission.   
 
 
4. STUDY OBJECTIVES 
Assess the safety of metformin in diabetic patients undergoing coronary angiography in terms of risk of lactic 
acidosis. Individuate eventual clinical, echocardiographic predictors of augmented lactic acid after coronary 
angiography.  
 
  
5. STUDY DESIGN 
The study is designed as a prospective, observational, single arm study.  
Enrollment timing: enrollment rate will determine the duration of the study. We estimate that one year will be 
sufficient to achieve this objective.  
Enrollment center: the study will be conducted at the Cardiac Center of the Humanitas Research Hospital, via 
Manzoni 56, Rozzano (MI).  
 
7. 
ENDPOINTS 
7.1. 
Primary endpoint 
An increase of lactic acid of 20% from preprocedural values in patients undergoing coronary angiography 
without discontinuing metformin. 
 
7.2     Secondary endpoints 
Contrast-associated acute kidney injury after coronary angiography. 
Lactic acidosis development after coronary angiography. 
Correlation between clinical, laboratoristic, and echocardiographic variables and lactic acid values. 
 
 
8. 
STUDY POPULATION 
8.1. 
Sample size 
In our historical cohort of diabetic patients taking metformin, we observed a mean value of lactic acid of 1.2+0.7 
mmol/l. 
A total of 106 patients in an estimated time of one years are planned to be enrolled in order to detect with 90% 
power a prespecified increase of lactic acid of 20% from preprocedural values with a probability of alpha error of 

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0.05.  
 
8.2. 
Patients’ features 
All diabetic patients undergoing coronary angiography will be screened for the enrollment in the present study.   
Inclusion criteria: 
We will include diabetic patients treated with metformin undergoing coronary angiography.  
 
Exclusion criteria: 
All patients presenting the following features will be excluded from the study:  
 
1. 
Known coronary anatomy with planned complex percutaneous coronary intervention with high probability 
of large amount of contrast use (>150 ml). 
2. 
Moderate to severe impairment of renal function (eGFR<45 ml/min).  
3. 
Moderate to severe impairment of liver function (Child-Pugh class B or C). 
4. 
Severely impaired left ventricular ejection fraction (LVEF <35%). 
5. 
Patients undergoing primary percutaneous coronary intervention (i.e., patients presenting with ST elevation 
myocardial infarction). 
6. 
Severe to very severe chronic obstructive pulmonary disease (GOLD class 3 to 4). 
7. 
Patients scheduled for cardiac surgery in the following 5 days. 
8. 
Inability to provide informed consent. 
 
9. 
STUDY PROCEDURE 
The aim of the study is to evaluate if metformin continuation in diabetic patients undergoing coronary 
angiography could lead to an increase in lactic acid values. Clinical, laboratoristic, and echocardiographic data 
will be collected in order to evaluate the presence and the eventual impact on the risk of increased lactic acid 
values. All these data will be collected in an anonymous form at the Cardio Center of the Humanitas Research 
Hospital, via Manzoni 56, Rozzano (MI). We will add lactic acid to all the routinely laboratoristic parameter 
collected before and after coronary angiography in our center. 
 
9.1. 
Patients instructions 
All patients potentially enrolled will be informed regarding the study and will have to sign an informed consent 
before the inclusion in the study. A time schedule of study procedure is resumed in Table 1.1 
 
9.2. 
Pre-enrollment and pre-procedure evaluation (baseline) 
Before the inclusion, all patients will undergo to: 
1. 
Medical history and physical examination; 
2. 
Hemocrome, kidney and liver function, lactic acid evaluation at venous sample; 
3. 
CK-MB, hs-troponin I, BNP evaluation at venous sample; 
4. 
Transthoracic echocardiography; 
5. 
12-leads electrocardiogram. 
 
 
9.3. 
Post-procedure evaluation (the same day after coronary angiography and before hospital discharge) 

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During postprocedure monitoring (after coronary angiography and before discharge) the following clinical, 
laboratoristic, and echocardiographic data will be collected:  
1. 
Hemocrome, kidney and liver function, lactic acid evaluation at venous blood sample; 
2. 
CK-MB, hs-troponin I, BNP evaluation at venous blood sample; 
3. 
Transthoracic echocardiography; 
4. 
12-leads electrocardiogram. 
5. 
Lactic acidosis, death, kidney failure, liver failure 
 
9.4. 
Follow up 
All patients will undergo a venous blood sample and will be contacted by phone call (if already discharged) to 
collect the following data: 
1. 
Hemocrome, kidney and liver function, lactic acid evaluation at venous blood sample; 
2. 
Lactic acidosis, death, kidney failure, liver failure 
 
Visit schedule and data that will be collected are resumed in Table 1.1.  
 
 
10. ADVERSE EVENT RISK/BENEFIT NOTIFICATION  
10.1. 
Adverse event 
According to the 2018 ESC guidelines on myocardial revascularization and literature data, there should not be 
an augmented risk for lactic acidosis in those patients that will satisfy our inclusion and exclusion criteria.  
10.2. 
Cause of study withdrawal 
All patients that will develop CIN will suspend metformin, as recommended by the 2018 ESC guidelines on 
myocardial revascularization.  
 
11. STATISTICAL ANALYSES 
11.1. 
Methods  
Continuous variables will be reported as mean ± standard deviation and compared with Student's t test or 
Mann–Whitney or Wilcoxon tests on the basis of normality of data verified by Kolmogorov–Smirnov goodness-
of-fit test. In case of non-normal distribution, variables will be reported as median and interquartile range (IQR). 
For the primary endpoints of postprocedure lactic acid values, also 95% confidence intervals will be reported. 
Categorical variables are reported as N (%) and will be compared with χ2 test without Yates correction for conti-
nuity or the Fisher exact test as appropriate. Subgroup analyses will be performed to assess eventual differ-
ences in the following subgroups: 
- 
Patients taking other antiglycaemic drugs on top of metformin. 
- 
Patients requiring percutaneous coronary angioplasty. 
- 
Patients with mild and moderate renal function impairment (eGFR<90 and <60 ml/min). 

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- 
Patients undergoing urgent coronary angiography (<24 hours from the index event). 
Furthermore, linear regression will be performed to assess the correlation between clinical, laboratoristic, 
and echocardiographic variables with postprocedural lactic acid values. 
 
 
11.2. 
Level of significance 
Statistical test will be used to: 
- to refuse the null hypothesis of lack of association between metformin continuation and postprocedural 
increase of lactic acid of 20% from baseline values (primary endpoint) and our secondary endpoints (Ho = 
metformin continuation not associated with the endpoint) 
Association between variables or events will be set at probabilistic level of 5% (p value< 0.05)  
 
 
12. ETHICAL IMPLICATIONS 
12.1. 
General rules 
This study will be conducted based on Good Clinical Practices (GCP) and following all Helsinki Declaration 
principles 
 
12.2. 
Informed consent 
Every enrolled patient will sign and write the data on the approved format of informed consent after explanation 
of all study related procedures. 
  
13. DATA USE AND PUBLICATION 
At the end of data collection and statistical analysis, obtained data will be used for potential publication on 
internationl scientific journals.  
 

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14. REFERENCES 
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