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Optimizing the Prevention of Cardiovascular Events
Accepted Manuscript Optimising the Prevention of Cardiovascular Events David Fitchett, MD, GB John Mancini, MD, Anatoly Langer, MD PII:
S0828-282X(16)00189-6
DOI:
10.1016/j.cjca.2016.02.063
Reference:
CJCA 2050
To appear in:
Canadian Journal of Cardiology
Received Date: 19 February 2016 Revised Date:
21 February 2016
Accepted Date: 21 February 2016
Please cite this article as: Fitchett D, Mancini GJ, Langer A, Optimising the Prevention of Cardiovascular Events, Canadian Journal of Cardiology (2016), doi: 10.1016/j.cjca.2016.02.063. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
RI PT
Optimising the Prevention of Cardiovascular Events
M AN U
SC
David Fitchett MD 1, GB John Mancini MD 2, Anatoly Langer MD 1,3
1 St. Michael’s Hospital, and University of Toronto, Toronto, Ontario, Canada 2 Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
TE D
3 Canadian Heart Research Centre, Toronto, Ontario, Canada
EP
Short title: Optimising cardiac preventative strategies
AC C
Corresponding author David Fitchett MD Division of Cardiology St Michael’s Hospital 30 Bond St Toronto Ontario M4V 1W8
ACCEPTED MANUSCRIPT
Patients with cardiovascular disease are fortunate to have available a wide range of proven treatments that have greatly reduced the risk for cardiovascular complications1. Clinical trials involving large numbers of subjects have provided confident evidence of benefit. However the
RI PT
application of the findings published from clinical trials does not always reach the bedside. Despite guideline recommendations to use proven treatment, many patients either do not have the therapy prescribed or physicians fail to follow the strategy proven in the clinical trial2, 3.
SC
This supplement of the Canadian Journal of Cardiology provides therapeutic suggestions based upon clinical trial evidence for the management of two common cardiology scenarios.
M AN U
The first paper from the Canadian Heart Research Centre examines the management of the patient who has recently been hospitalized for an acute coronary event and provides evidence based step-by-step recommendations for long-term secondary prevention. The second paper
statin treatment.
TE D
discusses strategies in patients with statin related adverse effects or who are unable to tolerate
Hospitalisation with an acute coronary syndrome provides the opportunity to initiate optimal evidence based treatment. Treatment goals are to reduce both the risk of complications
EP
from the acute coronary event, and the chance of recurrent atherosclerotic cardiovascular
AC C
events. Vascular and cardiac protection are the principles of treatment for these high risk patients. For patients with an acute coronary syndrome it is often the start of long-term treatment of chronic atherosclerotic disease. Today, to provide optimal treatment to meet these goals during a short duration hospital admission is a challenge. An important role of the coronary care unit has been to provide patient education and review treatment goals. With improved technical care, especially early revascularization, the duration of hospitalization has shortened. Consequently, there is need for aids such as protocol driven discharge prescriptions
ACCEPTED MANUSCRIPT
to ensure that patients have the opportunity to be considered for all evidence-based treatment that may provide benefit. The application of clinical trial results to clinical practice should recognize the need to
RI PT
follow the protocol used in the study. Patient demographics, drugs and doses used, and duration of treatment should closely follow the proven strategy applied in the clinical trial. Guidelines recommend classes of drugs, yet relatively few individual drugs have been shown to
SC
have benefit in robust clinical trials. Consequently, a class effect cannot be assumed. Frequently doses of drugs used in the trials are not achieved. Treatments are often extended to groups of
M AN U
patients for which there is no proven benefit. If optimal benefit of the research findings from a clinical trial is to be achieved, then there is need for close respect of the trial protocol. However it is recognised that special patient groups may not be included in clinical trials. These groups include the elderly, and those with chronic kidney or liver disease. In these situations the
the treatment.
TE D
clinician is often left making a clinical judgment based upon the potential benefits and risks of
Clinical trials have introduced new treatments at widely different clinical epochs. For
EP
example, beta-blockers were studied before most of our current ACS treatments, including
AC C
coronary angioplasty, statins, and ACE inhibitors were available. When there are no recent studies, it remains a challenge to know whether treatment proven in a prior era remains beneficial when used with current treatment strategies. Often there are less stringent observational studies to provide clues of contemporary outcomes with the treatment. Several new medications with likely benefit in patients with a history of ACS and chronic cardiovascular disease, have recently become available. The PCSK9 inhibitors reduce LDL cholesterol 50% beyond that achieved with statin therapy. Preliminary data suggests the
ACCEPTED MANUSCRIPT
additional LDL lowering achieved with these agents in patients at high risk, is associated with a substantial reduction of CV adverse outcomes. The SGLT2 inhibitor empagliflozin was shown to reduce mortality and the incidence of heart failure in patients with diabetes and CVD
RI PT
(including patients with a history of myocardial infarction). For patients with heart failure, both neprilysin inhibition and Ik channel inhibition with ivabradine improve outcomes.
Prior data from the Canadian Heart Research Centre4 has demonstrated that secondary
SC
prevention was less than optimal as a result of underestimation of cardiovascular risk (knowledge gap) as well as a number of additional practical factors (practice gap or treatment
M AN U
inertia). Thus, by providing clear and agent specific suggestions (informed by evidence from clinical trials) the first paper from the Canadian Heart Research Centre attempts to provide a comprehensive platform for clinical decision making in support of the management of patients with cardiovascular disease.
TE D
The paper from The Canadian Consensus Working Group examines statin adverse effects and intolerance. Symptoms attributed to statin therapy are the most important limitation of statin treatment today. As there are now effective non-statin cholesterol lowering
EP
agents available, it is timely to examine the problem of statin adverse effects and intolerance.
AC C
The paper provides a pragmatic definition of statin intolerance and strategies for management. Statins are one of the most widely used medications today. In the USA approximately
25% of individuals over the age of 40 take a statin5. Clinical trials involving more than 100,000 subjects have shown the efficacy and safety of statin treatment. A review of 35 clinical trials with 6 statin drugs (excluding cerivastatin), including more than 70,000 individuals, concluded statin therapy is associated with a small excess risk of transaminase elevations, but not of myalgias, creatine kinase elevations, rhabdomyolysis, or withdrawal of therapy compared with
ACCEPTED MANUSCRIPT
placebo6. Yet the incidence of attributed adverse effects in clinical practice (largely musculoskeletal symptoms) is 20-30%. However the majority of patients with statin perceived symptoms can be successfully re-challenged with a statin7. Furthermore a recent study of
RI PT
patients with statin intolerance receiving either a statin or ezetimibe in a double blind strategy, showed that most patients could tolerate the statin and muscle related symptoms were as frequent with ezetimibe as with a statin8. It is apparent that a substantial number of patients
SC
with statin attributed symptoms do not have true statin intolerance. The identification and management of the patients with true statin intolerance remains an important challenge.
M AN U
The current Canadian Working Group Consensus Update provides a new practical definition termed goal-inhibiting statin intolerance (GISI). GISI is the failure to achieve cholesterol goals due to symptoms or biochemical abnormalities that prevent the long- term adherence to statins. The definition emphasizes the importance of re-challenging the patient
TE D
with other statins and the need to exclude potentially reversible causes of intolerance such as drug-drug interactions. It is in this setting that the consensus update discusses the application of the non-statin cholesterol lowering medications. This has important clinical implications
EP
given the cost of the biological agents currently available for PCSK9 inhibition.
AC C
In everyday clinical practice, statins have many attributed adverse effects such as cognitive dysfunction, and intra-cerebral haemorrhage that have not been observed in clinical trials. For the most part, population studies and meta-analyses of clinical trial data do not provide support of any significant risk. Although the development of new-onset diabetes may be increased by statin treatment, the risk is not conclusively proven, is small, and if real occurs infrequently (one patient in 130 treated for 4 years) in a population at high cardiometabolic
ACCEPTED MANUSCRIPT
risk. Furthermore the benefit of statins in this population greatly exceeds the cardiac risk of developing diabetes. Optimisation of treatment in patients at high risk of cardiovascular adverse outcomes
RI PT
has been shown to reduce long-term event rates in the years after an acute coronary event9. We should strive to provide evidence-based treatment that when possible closely follows the strategies proven in clinical trials. For patients who appear to not tolerate statin treatment
SC
a structured strategy may allow a high proportion of patients to use effective doses of statins. For those who are truly intolerant of statins alternative evidence proven therapy is now Accordingly, these two overviews provide valuable clinical information and
M AN U
available.
approaches that should help the practitioner optimally translate the proven benefits of
AC C
EP
TE D
effective therapies into practice.
ACCEPTED MANUSCRIPT
References
5. 6.
7.
8.
9.
RI PT
SC
M AN U
4.
TE D
3.
EP
2.
Ford ES, Ajani UA, Croft JB, Critchley JA, Labarthe DR, Kottke TE, Giles WH, Capewell S. Explaining the decrease in u.S. Deaths from coronary disease, 1980-2000. The New England journal of medicine. 2007;356:2388-2398 Arnold SV, Spertus JA, Masoudi FA, Daugherty SL, Maddox TM, Li Y, Dodson JA, Chan PS. Beyond medication prescription as performance measures: Optimal secondary prevention medication dosing after acute myocardial infarction. Journal of the American College of Cardiology. 2013;62:1791-1801 Rosenson RS, Kent ST, Brown TM, Farkouh ME, Levitan EB, Yun H, Sharma P, Safford MM, Kilgore M, Muntner P, Bittner V. Underutilization of high-intensity statin therapy after hospitalization for coronary heart disease. Journal of the American College of Cardiology. 2015;65:270-277 Tsang JL, Mendelsohn A, Tan MK, Hackam DG, Leiter LA, Fitchett D, Lin PJ, Grima E, Langer A, Goodman SG, Vascular Protection R, Guidelines Oriented Approach to Lipid Lowering Registry I. Discordance between physicians' estimation of patient cardiovascular risk and use of evidence-based medical therapy. The American journal of cardiology. 2008;102:1142-1145 Gu Q, Paulose-Ram R, Burt VL, Kit BK. Prescription cholesterol-lowering medication use in adults aged 40 and over: United states, 2003-2012. NCHS data brief. 2014:1-8 Kashani A, Phillips CO, Foody JM, Wang Y, Mangalmurti S, Ko DT, Krumholz HM. Risks associated with statin therapy: A systematic overview of randomized clinical trials. Circulation. 2006;114:2788-2797 Mampuya WM, Frid D, Rocco M, Huang J, Brennan DM, Hazen SL, Cho L. Treatment strategies in patients with statin intolerance: The cleveland clinic experience. American heart journal. 2013;166:597-603 Moriarty PM, Thompson PD, Cannon CP, Guyton JR, Bergeron J, Zieve FJ, Bruckert E, Jacobson TA, Kopecky SL, Baccara-Dinet MT, Du Y, Pordy R, Gipe DA, Investigators OA. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The odyssey alternative randomized trial. Journal of clinical lipidology. 2015;9:758-769 Shah BR, O'Brien EC, Roe MT, Chen AY, Peterson ED. The association of in-hospital guideline adherence and longitudinal postdischarge mortality in older patients with non-st-segment elevation myocardial infarction. American heart journal. 2015;170:273280 e271
AC C
1.
S0828-282X(16)00189-6
DOI:
10.1016/j.cjca.2016.02.063
Reference:
CJCA 2050
To appear in:
Canadian Journal of Cardiology
Received Date: 19 February 2016 Revised Date:
21 February 2016
Accepted Date: 21 February 2016
Please cite this article as: Fitchett D, Mancini GJ, Langer A, Optimising the Prevention of Cardiovascular Events, Canadian Journal of Cardiology (2016), doi: 10.1016/j.cjca.2016.02.063. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
RI PT
Optimising the Prevention of Cardiovascular Events
M AN U
SC
David Fitchett MD 1, GB John Mancini MD 2, Anatoly Langer MD 1,3
1 St. Michael’s Hospital, and University of Toronto, Toronto, Ontario, Canada 2 Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
TE D
3 Canadian Heart Research Centre, Toronto, Ontario, Canada
EP
Short title: Optimising cardiac preventative strategies
AC C
Corresponding author David Fitchett MD Division of Cardiology St Michael’s Hospital 30 Bond St Toronto Ontario M4V 1W8
ACCEPTED MANUSCRIPT
Patients with cardiovascular disease are fortunate to have available a wide range of proven treatments that have greatly reduced the risk for cardiovascular complications1. Clinical trials involving large numbers of subjects have provided confident evidence of benefit. However the
RI PT
application of the findings published from clinical trials does not always reach the bedside. Despite guideline recommendations to use proven treatment, many patients either do not have the therapy prescribed or physicians fail to follow the strategy proven in the clinical trial2, 3.
SC
This supplement of the Canadian Journal of Cardiology provides therapeutic suggestions based upon clinical trial evidence for the management of two common cardiology scenarios.
M AN U
The first paper from the Canadian Heart Research Centre examines the management of the patient who has recently been hospitalized for an acute coronary event and provides evidence based step-by-step recommendations for long-term secondary prevention. The second paper
statin treatment.
TE D
discusses strategies in patients with statin related adverse effects or who are unable to tolerate
Hospitalisation with an acute coronary syndrome provides the opportunity to initiate optimal evidence based treatment. Treatment goals are to reduce both the risk of complications
EP
from the acute coronary event, and the chance of recurrent atherosclerotic cardiovascular
AC C
events. Vascular and cardiac protection are the principles of treatment for these high risk patients. For patients with an acute coronary syndrome it is often the start of long-term treatment of chronic atherosclerotic disease. Today, to provide optimal treatment to meet these goals during a short duration hospital admission is a challenge. An important role of the coronary care unit has been to provide patient education and review treatment goals. With improved technical care, especially early revascularization, the duration of hospitalization has shortened. Consequently, there is need for aids such as protocol driven discharge prescriptions
ACCEPTED MANUSCRIPT
to ensure that patients have the opportunity to be considered for all evidence-based treatment that may provide benefit. The application of clinical trial results to clinical practice should recognize the need to
RI PT
follow the protocol used in the study. Patient demographics, drugs and doses used, and duration of treatment should closely follow the proven strategy applied in the clinical trial. Guidelines recommend classes of drugs, yet relatively few individual drugs have been shown to
SC
have benefit in robust clinical trials. Consequently, a class effect cannot be assumed. Frequently doses of drugs used in the trials are not achieved. Treatments are often extended to groups of
M AN U
patients for which there is no proven benefit. If optimal benefit of the research findings from a clinical trial is to be achieved, then there is need for close respect of the trial protocol. However it is recognised that special patient groups may not be included in clinical trials. These groups include the elderly, and those with chronic kidney or liver disease. In these situations the
the treatment.
TE D
clinician is often left making a clinical judgment based upon the potential benefits and risks of
Clinical trials have introduced new treatments at widely different clinical epochs. For
EP
example, beta-blockers were studied before most of our current ACS treatments, including
AC C
coronary angioplasty, statins, and ACE inhibitors were available. When there are no recent studies, it remains a challenge to know whether treatment proven in a prior era remains beneficial when used with current treatment strategies. Often there are less stringent observational studies to provide clues of contemporary outcomes with the treatment. Several new medications with likely benefit in patients with a history of ACS and chronic cardiovascular disease, have recently become available. The PCSK9 inhibitors reduce LDL cholesterol 50% beyond that achieved with statin therapy. Preliminary data suggests the
ACCEPTED MANUSCRIPT
additional LDL lowering achieved with these agents in patients at high risk, is associated with a substantial reduction of CV adverse outcomes. The SGLT2 inhibitor empagliflozin was shown to reduce mortality and the incidence of heart failure in patients with diabetes and CVD
RI PT
(including patients with a history of myocardial infarction). For patients with heart failure, both neprilysin inhibition and Ik channel inhibition with ivabradine improve outcomes.
Prior data from the Canadian Heart Research Centre4 has demonstrated that secondary
SC
prevention was less than optimal as a result of underestimation of cardiovascular risk (knowledge gap) as well as a number of additional practical factors (practice gap or treatment
M AN U
inertia). Thus, by providing clear and agent specific suggestions (informed by evidence from clinical trials) the first paper from the Canadian Heart Research Centre attempts to provide a comprehensive platform for clinical decision making in support of the management of patients with cardiovascular disease.
TE D
The paper from The Canadian Consensus Working Group examines statin adverse effects and intolerance. Symptoms attributed to statin therapy are the most important limitation of statin treatment today. As there are now effective non-statin cholesterol lowering
EP
agents available, it is timely to examine the problem of statin adverse effects and intolerance.
AC C
The paper provides a pragmatic definition of statin intolerance and strategies for management. Statins are one of the most widely used medications today. In the USA approximately
25% of individuals over the age of 40 take a statin5. Clinical trials involving more than 100,000 subjects have shown the efficacy and safety of statin treatment. A review of 35 clinical trials with 6 statin drugs (excluding cerivastatin), including more than 70,000 individuals, concluded statin therapy is associated with a small excess risk of transaminase elevations, but not of myalgias, creatine kinase elevations, rhabdomyolysis, or withdrawal of therapy compared with
ACCEPTED MANUSCRIPT
placebo6. Yet the incidence of attributed adverse effects in clinical practice (largely musculoskeletal symptoms) is 20-30%. However the majority of patients with statin perceived symptoms can be successfully re-challenged with a statin7. Furthermore a recent study of
RI PT
patients with statin intolerance receiving either a statin or ezetimibe in a double blind strategy, showed that most patients could tolerate the statin and muscle related symptoms were as frequent with ezetimibe as with a statin8. It is apparent that a substantial number of patients
SC
with statin attributed symptoms do not have true statin intolerance. The identification and management of the patients with true statin intolerance remains an important challenge.
M AN U
The current Canadian Working Group Consensus Update provides a new practical definition termed goal-inhibiting statin intolerance (GISI). GISI is the failure to achieve cholesterol goals due to symptoms or biochemical abnormalities that prevent the long- term adherence to statins. The definition emphasizes the importance of re-challenging the patient
TE D
with other statins and the need to exclude potentially reversible causes of intolerance such as drug-drug interactions. It is in this setting that the consensus update discusses the application of the non-statin cholesterol lowering medications. This has important clinical implications
EP
given the cost of the biological agents currently available for PCSK9 inhibition.
AC C
In everyday clinical practice, statins have many attributed adverse effects such as cognitive dysfunction, and intra-cerebral haemorrhage that have not been observed in clinical trials. For the most part, population studies and meta-analyses of clinical trial data do not provide support of any significant risk. Although the development of new-onset diabetes may be increased by statin treatment, the risk is not conclusively proven, is small, and if real occurs infrequently (one patient in 130 treated for 4 years) in a population at high cardiometabolic
ACCEPTED MANUSCRIPT
risk. Furthermore the benefit of statins in this population greatly exceeds the cardiac risk of developing diabetes. Optimisation of treatment in patients at high risk of cardiovascular adverse outcomes
RI PT
has been shown to reduce long-term event rates in the years after an acute coronary event9. We should strive to provide evidence-based treatment that when possible closely follows the strategies proven in clinical trials. For patients who appear to not tolerate statin treatment
SC
a structured strategy may allow a high proportion of patients to use effective doses of statins. For those who are truly intolerant of statins alternative evidence proven therapy is now Accordingly, these two overviews provide valuable clinical information and
M AN U
available.
approaches that should help the practitioner optimally translate the proven benefits of
AC C
EP
TE D
effective therapies into practice.
ACCEPTED MANUSCRIPT
References
5. 6.
7.
8.
9.
RI PT
SC
M AN U
4.
TE D
3.
EP
2.
Ford ES, Ajani UA, Croft JB, Critchley JA, Labarthe DR, Kottke TE, Giles WH, Capewell S. Explaining the decrease in u.S. Deaths from coronary disease, 1980-2000. The New England journal of medicine. 2007;356:2388-2398 Arnold SV, Spertus JA, Masoudi FA, Daugherty SL, Maddox TM, Li Y, Dodson JA, Chan PS. Beyond medication prescription as performance measures: Optimal secondary prevention medication dosing after acute myocardial infarction. Journal of the American College of Cardiology. 2013;62:1791-1801 Rosenson RS, Kent ST, Brown TM, Farkouh ME, Levitan EB, Yun H, Sharma P, Safford MM, Kilgore M, Muntner P, Bittner V. Underutilization of high-intensity statin therapy after hospitalization for coronary heart disease. Journal of the American College of Cardiology. 2015;65:270-277 Tsang JL, Mendelsohn A, Tan MK, Hackam DG, Leiter LA, Fitchett D, Lin PJ, Grima E, Langer A, Goodman SG, Vascular Protection R, Guidelines Oriented Approach to Lipid Lowering Registry I. Discordance between physicians' estimation of patient cardiovascular risk and use of evidence-based medical therapy. The American journal of cardiology. 2008;102:1142-1145 Gu Q, Paulose-Ram R, Burt VL, Kit BK. Prescription cholesterol-lowering medication use in adults aged 40 and over: United states, 2003-2012. NCHS data brief. 2014:1-8 Kashani A, Phillips CO, Foody JM, Wang Y, Mangalmurti S, Ko DT, Krumholz HM. Risks associated with statin therapy: A systematic overview of randomized clinical trials. Circulation. 2006;114:2788-2797 Mampuya WM, Frid D, Rocco M, Huang J, Brennan DM, Hazen SL, Cho L. Treatment strategies in patients with statin intolerance: The cleveland clinic experience. American heart journal. 2013;166:597-603 Moriarty PM, Thompson PD, Cannon CP, Guyton JR, Bergeron J, Zieve FJ, Bruckert E, Jacobson TA, Kopecky SL, Baccara-Dinet MT, Du Y, Pordy R, Gipe DA, Investigators OA. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: The odyssey alternative randomized trial. Journal of clinical lipidology. 2015;9:758-769 Shah BR, O'Brien EC, Roe MT, Chen AY, Peterson ED. The association of in-hospital guideline adherence and longitudinal postdischarge mortality in older patients with non-st-segment elevation myocardial infarction. American heart journal. 2015;170:273280 e271
AC C
1.