Literature Review on Cardiovascular Disease in Diabetics

Diabetes mellitus is a chronic condition characterized by hyperglycemia as a result of a person being unable to control their blood glucose. There are three types, one which occurs during pregnancy known as gestational diabetes and then type one and type two diabetes (Ignatavicius & Workman, 2016). This paper will be focused around type one and type two. Both conditions result in the inability of a person to move glucose form their blood into their cells, resulting in hyperglycemia (Porth, 2015). Poor long term control of blood sugar as a result of diabetes has severe consequences on the vascular system including; retinopathy, nephropathy, peripheral vascular disease, stroke, and coronary artery disease (WHF, 2016).

Cardiovascular disease is the leading cause of mortality in people with diabetes (WHF, 2016) There are multiple risk factors for macrovascular disease found in people with diabetes including; obesity, hypertension, hyperglycemia, hyperinsulemia, hyperlipidemia, altered platelet function, endothelial dysfunction, systemic inflammation, and elevated fibrinogen levels (Porth, 2015). Typically, in people with type one the duration and onset occurs later in life while, people with type two diabetes show these manifestations around the time of their diagnosis (Porth, 2015). According to the American Heart Association (AHA, 2017) adults with diabetes are two to four times more likely to die from some type of heart disease than those who do not have it. In diabetic patients over the age of 65, 68% of diabetic patients die from coronary heart disease while 16% of them die from a stroke (WHF, 2016).

Platelets in both men and women diagnosed with diabetes are hypersensitive due to an increased in the release of thromboxane, a vasoconstrictor and platelet aggregant (Kirkman, 2010). Researchers have found an excess release of thromboxane in people with type two diabetes leading to enhanced platelet aggregation (Kirkman, 2010). This increased clotting puts these patients at a much higher risk for a cardiovascular event compared to people are not diabetic. Antiplatelet drugs have been used to help prevent and lower the chances of these cardiovascular events (Kirkman, 2010). When searching the use of antiplatelet drugs in diabetic patients it appeared that aspirin was the most widely studied. The action of aspirin has been shown to block the synthesis of thromboxane by acetylating platelet cyclooxygenase in both diabetic and non-diabetic patients (Kirkman, 2010).

It is important that healthcare professionals stay up to date in their field. This is where evidenced based practice comes into play. The purpose of evidenced based practice is to improve care processes and health outcomes in patients (Fain, 2013). This paper focuses on using aspirin as both primary and secondary prevention of cardiovascular disease in patients with diabetes. I will start by discussing the current recommendations from the American Diabetes Association and from there I will develop a question using the PICO format. I will then search different research articles and studies using different databases and keywords. A literature review will be conducted on the acquired materials to analyze whether the evidence supports or refutes current recommendations.

Current Recommendation

The effect of aspirin for the prevention of cardiovascular disease in adults who have diabetes is still unclear, but several trials suggest that aspirin can reduce the risk of cardiovascular events (Kirkman, 2010). The American Heart Association (AHA) and American Diabetes Association (ADA) jointly recommend that low dose aspirin (75 – 161 mg per day) should be used for adults who have diabetes, no previous history of vascular disease who but are at an increased risk of cardiovascular disease, and who are not at increased risk for bleeding. Risk reduction has been found to be as effective at lower doses when compared to higher doses (500 – 1,500 mg per day). (Kirkman 2010). Factors that put you at higher risk of cardiovascular events with diabetes are age (men over 50 and women over 60) and a history of the following; smoking, hypertension, dyslipidemia, family history of cardiovascular disease, and high levels of albumin in the urine (Kirkman, 2010). People who classified as at an increased risk of bleeding are those who have had previous gastrointestinal bleeding, peptic ulcer disease, or who currently use medications that increase bleeding risk (warfarin or NSAIDS) (Kirkman, 2010).

Clinical Question

Referencing the recommendation provided by the AHA and ADA the question that I would like to further look into is: In patients with diabetes, does taking aspirin daily reduce the risk of future cardiovascular disease compared to diabetic patients who do not take aspirin daily?

Integrated Literature Review

A literature review uses both identification and analysis of publications related to the research problem at hand (Fain, 2013). When doing a literature review the main purpose is to discover what is already known about the topic or problem that is being investigated (Fain, 2013). This literature review is going to look at six different research articles focused on the use of aspirin in diabetic patients. When searching for articles to review PubMed, Google Scholar, and The Walter Schroder Library (Summon) databases were used. Keywords used in the search criteria were; “aspirin”, “diabetes”, and “cardiovascular disease”. The following section is broken into inconclusive evidence and evidence refuting the recommendation. I could not locate any journals that were in support of the claim.

Inconclusive Evidence

Study 1. In 2008, The Japanese Primary Prevention with Aspirin for Diabetes (JPAD) trial was performed to examine the efficacy of low dose aspirin (81 – 100 mg) therapy for primary prevention of cardiovascular disease in patients with type two diabetes (Ogawa et al., 2008). This trial was a prospective, randomized, open label, controlled trial with blinded end point assessment. The trial began in 2002 and completed in 2005 and then follow up with the patients was in 2008 in 163 institutions across Japan (Ogawa et al., 2008). To be included in the study you had to be diagnosed with type two diabetes, be within the ages of 30 – 85 years old, and be able to provide informed consent for participation (Ogawa et al., 2008). Exclusion criteria included many cardiac abnormalities; ischemic ST-segment depression, ST-segment elevation, or pathological Q waves, history of coronary heart disease, history of cerebrovascular disease, cerebral hemorrhage, subarachnoid hemorrhage, transient ischemic attack, history of atherosclerotic disease, atrial fibrillation, pregnancy, use of antiplatelet or antithrombotic therapy, history of severe gastric or duodenal ulcer, severe liver dysfunction, severe renal deficiency, or an allergy to aspirin (Ogawa et al., 2008). It was estimated that the trial would need 2450 patients, so they screened 2567 patients with type two diabetes and after exclusions and drop outs they ended up with 2539 patients for the study (Ogawa et al., 2008).

Random assignment was used to assign patients to a group; 1262 patients were put in the group to receive daily aspirin and 1277 patients were put into the non-aspirin group, with the median follow up period being 4.37 years (Ogawa et al., 2008). Patients who were placed in the aspirin group were given 81 – 100 mg of aspirin per day across the trial (Ogawa et al., 2008).

Primary endpoint for this study was any atherosclerotic events occurring in a patient while a secondary end point was death from any other causes. End points were estimated by using the Kaplan Merrier method and differences between groups were assessed with the log rank test (Ogawa et al., 2008). The Cox proportional hazards model estimated hazard ratios of aspirin use along with a 95% confidence interval and P values of less than 0.5 were considered significant (See Appendix A). 154 atherosclerotic events occurred in the study with 68 coming from the aspirin group and 86 from the non-aspirin group. At the conclusion of the study it was found that aspirin did not demonstrate a significant effect on reducing atherosclerotic events in patients with diabetes and more studies should be done before suggesting that aspirin for primary prevention is beneficial in diabetic patients (Ogawa et al., 2008).

One major limitation of this study comes from the design itself. The Japanese Pharmaceutical Affairs Law limits the use of placebo in physician studies because it is not considered approved for medical use (Ogawa et al., 2008). So, it did not possess the advantages of having a double blind randomized trial.

My analysis: This study was conducted well and contained a large number of participants. It studied only people who have diabetes rather than comparing non diabetics to diabetics, so we could actually see if taking aspirin was significant for reducing cardiovascular events. In this study though the follow up time (4.37 years) seemed short for a follow up on cardiovascular disease and should have been longer to see the full effect. This study also said that both groups could take additional antiplatelet therapy if needed, but didn’t go on to explain what was done with that data (Ogawa et al.)

Study 2. A meta-analysis conducted by Mamas and Ludwig in 2010 was set out to determine the benefits and the harm of low dose aspirin in patients diagnosed with diabetes. This study pulled information from Medline and Cochrane central register for controlled trials (Mamas & Ludwig, 2010). Inclusion criteria for this meta-analysis was; randomized, prospective, controlled, open, or blinded trials of patients who have diabetes and were given aspirin or a placebo. 157 studies were found relevant to the guidelines they were looking for, but after the exclusion process only six trials were included into the meta analysis (Mamas & Ludwig, 2010). This gave the meta-analysis 10117 total patients to be included (Mamas & Ludwig, 2010). End-points in this study included myocardial infarction, stroke, death from cardiovascular disease and all-cause mortality and they were pooled using the random effect model. (Mamas & Ludwig, 2010).

A meta-analysis was conducted on the six studies included using a 95% confidence interval (See appendix A) (Mamas & Ludwig, 2010). The results of this study showed that there was a significant interaction for men in reduction of myocardial infarction, but overall there was no significant effect in the use of aspirin as primary prevention in preventing cardiovascular disease in people with diabetes (Mamas & Ludwig, 2010).

When looking back at the study there were a few limitations noted by the authors. First of all, the studies that were examined had different dosages of aspirin used when used for primary prevention (Mamas and Ludwig). Different lengths of study were used as well, but were not specified in the study (Mamas & Ludwig, 2010). Lastly, the authors didn’t specify any test used to evaluate heterogeneity across the studies, but rather they only explained what heterogeneity was (Mamas & Ludwig, 2010).

My analysis: This study like the others showed that there was not a significant impact on using aspirin for primary prevention of cardiovascular disease in diabetic patients. This study was the highest level of evidence and had strict exclusion criteria to only include the population of patients that I wanted to focus on. Over 10000 patients were included in the meta-analysis so the results of the study could be confirmed with degree certainty and be applied to the population as a whole (Fain, 2013). The average length of study was not given in this meta-analysis though, which could serve as another limitation as to why there was no significant difference between the two groups in the study.

Study 3. In 2014 a meta-analysis by Xie et al., was conducted to evaluate the benefits and harms of aspirin for the primary prevention of cardiovascular disease and to determine whether the effect varied by gender or type of diabetes (one vs. two). Data sources for the meta-analysis came from randomized control trials that compared the effectiveness of aspirin with a placebo or control in people who did not possess a preexisting cardiovascular condition (Xie et al., 2014). Databases used for searching for these trials included Medline, Embase, and Central, with the keywords “diabetes” and “primary prevention” being used (Xie et al., 2014). When selecting studies, to be included they had to possess the following; prospective, randomized, controlled, open, or blinded trials; participants had to be randomly assigned to the aspirin or placebo group; trials carried out with a background of anticoagulation had to be available; and follow up had to exceed 90 days (Xie et al., 2014).

The Cochrane Q test and the I2 test were used to assess heterogeneity. A P-value of less than 0.10 indicated significant heterogeneity while the I2 metric was as follows; 25% – low, 50% – moderate, 75% -high (Xie et al., 2014). The relative risks and 95% confidence interval was estimated using a Mantel-Haenszel fixed-effect model when heterogeneity was negligible or moderate, but a DerSimonian and Laird random effects model when it was significant (Xie et al., 2014). A funnel plot, The Begg’s and Egger’s test were all used to help assess for publication bias (Xie et al., 2014). 373 potentially relevant articles were obtained at the beginning of the study, but after the screening and exclusion process only 14 were to be included (Xie et al., 2014). A meta-analysis was done on those 14 studies (See appendix A).

At the conclusion of the study they determined that aspirin had an insignificant effect on the outcome of cardiovascular events in the overall diabetic population (Xie et al., 2014) They saw that there was more harm done as a result of the increasing hemorrhagic stroke and bleeding events. The study concluded with that there may be an inadequate power in the study due to the fact that the diabetic population had a wider confidence interval and more studies involving them should be done (Xie et al., 2014).

Two limitations were found at the end of this study. The first was that there was moderate heterogeneity among trials for the outcome being focused on due to the fact that there was no access to patient level data and the author response rate was relatively low, leading to a reduced statistical power (Xie et al., 2014). A second limitation, one which doesn’t affect the PICO questions at hand, is that the data was insufficient to report separate outcomes for type one and type two diabetes (Xie et al., 2014). This didn’t have any effect on the information I was looking for because I am focused on diabetes as a whole.

Study 4. A meta-analysis conducted by Simpson et al was conducted to explore the relationship between aspirin and the prevention of cardiovascular events in diabetic patients. Databases used to find studies to include in the meta-analysis were Medline, Embase, Cochrane Library, Web of Science, Science Citation Index, International Pharmaceutical Abstracts, and Scopus (Simpson et al., 2011). To be included in the study the trials had to meet the following criteria; compared aspirin to a placebo, reported all-cause mortality, heart attack, or stroke as an outcome, specified aspirin dose being used in each study, and included the proportion of diabetic patients in it (Simpson et al., 2011). 198 studies were considered eligible, but after the exclusion process only 21 (17522 participants) of the studies were used, 17 of which were random control trials and the other four were cohort studies (Simpson et al., 2011).

Review manager was used to analyze all of the data and the I2 was used to examine heterogeneity amongst the studies (Simpson et al., 2011). Risk ratios and a 95% confidence interval was calculated using the random effects model and studies were grouped according to the daily aspirin dose (Simpson et al., 2011). Diabetics made up the entire study in four of the 21 studies, but the median percentage of diabetics was only 8.8% (Simpson et al., 2011).

A meta-analysis was done on the 21 studies (See appendix A). The results of this came back to show that there was a non-significant difference in the pooled risk ratios (Simpson et l., 2011). It did suggest a lower mortality with aspirin use, but there was a lot of heterogeneity between the studies that it was viewed as insignificant. Thus the authors said they could neither confirm nor refute the use of aspirin to prevent cardiovascular events in patients with diabetes (Simpson et al., 2011).

A few limitations were noted by the authors of this study. The first limitation being that they were only able to find one study that randomly distributed the different aspirin doses to patients across all studies and were also unable to find a significant amount of information on doses that were greater than 100 mg (Simpson et al., 2011). Another limitation noted was the fact that 8 of the studies had a short follow up time (< 2 years), so there may not have been enough time to see an effect of the different doses of aspirin used between groups.

My analysis: This study not only took into account how aspirin affected patients with diabetes, but which dose would be more effective for them. The results in the end were insignificant, but I believe it opened doors for similar studies to be conducted on aspirin doses. The study admittedly included studies with very short follow up and had a lack of data for 100+ mg doses. So, it would be beneficial for someone to conduct an RCT comparing different dosages of aspirin in diabetics for primary prevention with a longer (10+ years) follow up period.

Study 5. Since the use of aspirin in patients with diabetes in controversial Kokoska et al., created a meta-analysis with the objective of evaluating the safety and efficacy of aspirin when used as primary prevention of cardiovascular disease. PubMed and Cochrane databases were used in the search with the keywords cardiovascular disease, aspirin, and diabetes mellitus (Kokoska et al., 2016). Inclusion in this study required the articles to be available in full text, published in English, and look at aspirin use as primary prevention in patients diagnosed with diabetes mellitus (Kokoska et al., 2016). The end points being observed in the study were; all-cause mortality, heart attack, stroke, TIA, PAD, angina, bleeding, GI bleed, and intracranial hemorrhage (Kokoska et al., 2016).

Depending on the heterogeneity of the studies the Mantel-Haenszel fixed effects model or the DerSimonian and Laird random effects model were used to created odds ratios and the 95% confidence interval (Kokoska et al, 2016). When searching for literature they found 516 articles that could potentially be in the meta-analysis, but after the exclusion process only six studies were included in it (Kokoska et al., 2016). The number of people of diabetes included in the study was 10117, 5064 of which received aspirin and 5053 which received a placebo (Kokoska et al., 2016). Dose of aspirin ranged from 100 mg to 650 mg and follow up for the people included ranged from 3.6 – 10.1 years (Kokoska et al., 2016).

A meta-analysis was done with the six studies (See appendix A). The results of the meta-analysis showed that there was no difference in the following endpoints; all-cause mortality, atherosclerotic events, and bleeding rates in patients who took aspirin or the placebo (Kokoska et al., 2016). They concluded by saying that there was no significant difference in the rate of atherosclerotic events and mortality for people with diabetes who took aspirin as primary prevention compared to those who received a placebo and more research should be done before we encourage supplementing it for people who have diabetes (Kokoska et al., 2016).

My analysis: This study like most other studies that I read concluded with the statement that there wasn’t any proof that aspirin for primary prevention was beneficial for people who are diagnosed with diabetes. The sample size included in the study was also large and look strictly at patients who have diabetes, so this study could be applied to the diabetic population. This study could aid in helping in organizations and federations restructuring their recommendations on aspirin use for diabetic patients.

Evidence Refuting Recommendation

Study one. A meta-analysis conducted by Calvin et al. in 2009 sought out to determine two different topics; estimation of the effect of aspirin therapy in patients with diabetes and to estimate the difference in which the effect of aspirin differs from a patient with diabetes and without. Databases included in this study were MEDLINE, EMBASE, Cochrane Library, Web of Science, and Scopus (Calvin et al., 2009). Studies that were considered eligible were random control trials that included patients with diabetes without prior history of stroke, and assessed the efficacy of aspirin doses (Calvin et al., 2009). Articles were excluded if they were not original, irrelevant, outcomes weren’t reported, excluded diabetic patients, excluded patients with a prior cardiovascular event, and they were not randomized or placebo controlled. A total of 652 studies were identified by the search, but after exclusion only eight of the journal articles were chosen to be part of the meta-analysis (Calvin et al., 2009).

Treatment effects of aspirin in preventing cardiovascular events and death in patients with and without diabetes was estimated with a Random-effects meta-analysis, While heterogeneity was measured by the I2 statistic (Calvin et al., 2009). There were three methods used to determine whether a difference exists in the effect of aspirin for patients with and without diabetes. First, the method of Altman and Bland was used to estimate the risk ratio (RR) and the 95% confidence interval (CI) and then it is compared across sub groups of patients with and without diabetes across trials (Calvin et al., 2009). Second, the ratio of RRs was estimated by comparing the aspirin effect in both patients with and without diabetes (Calvin et al., 2009). In the first two steps any estimate that excluded a ratio of one were considered evidence of an aspirin-diabetes interaction. Lastly a Bayesian random-effects logistics regression was used with aspirin and diabetes as the main effectors. The effects of aspirin are different in patients with and without diabetes was indicated by a 95% credible interval of the coefficient of the interaction term that excludes 0 (Calvin et al., 2009).

A meta-analysis was conducted using the eight articles accepted into the study (Refer to appendix A). Similar to previous studies there was no significant benefit from people with diabetes supplementing aspirin to preventing a cardiovascular event (Calvin et al., 2009). So, it cannot be said confidently that aspirin aids in the primary prevention of cardiovascular disease. Further random control trials should be conducted before we support the claim that it does (Calvin t al., 2009).

Within this study a few limitations are present. First of all, publication bias could not be assessed and corrected due to the low number of random control trials that were involved in the study (Calvin et al., 2009). The strict literature search lowered the risk of bias, but resulted in a low author response rate which led to a lack of data to include within the met-analysis (Calvin et al., 2009). The statistical power of this study was also reduced by the limited number of studies, therefor reducing the precision of the estimates in the main analysis between aspirin and diabetes (Calvin et al., 2009).

My analysis: After reading this study I felt that it was a little misleading. It had started by saying that there was no difference between the effect of aspirin on cardiovascular events in people with and without diabetes, but didn’t further explain if it benefitted both, but not one more than the other or if it did not benefit either equally. Also, only five of the random control trials included people with just diabetes rather than a meta-analysis on only diabetic patients. Of the eight RCT’s used one of them actually only had six participants, so that hurt credibility a little bit. Lastly, as mentioned before the length of the study ranged between two to five years, which seems extremely short for a study on cardiovascular disease.

Summary & Risks

After review of the six articles they all concluded to be inconclusive or refute the claim for aspirin use in diabetics to prevent cardiovascular events. During my search for evidence I tried as hard as I could to find a study that had conclusive evidence from a credible study that was in support of aspirin use, but I could find none. Among my six articles, five of them were meta-analyses, the highest level of research, comparing the use of aspirin to a placebo or no treatment. Four of those five articles stated that there was inconclusive evidence or not significant enough data to say that it was beneficial to supplement aspirin and that more studies should be done. The article by Calvin et al refuted the recommendation completely. The JPAD study was a randomized control trial, the second highest level of evidence, that concluded by saying there was inconclusive evidence in support for using aspirin as primary prevention of cardiovascular disease.

When looking at the risks vs. the benefits it is difficult to say what the benefit of aspirin use is in diabetic patients. In the meta-analysis by Mamas & Ludwig it showed there was a decrease in the rate of myocardial infarction in men, but that was the only exception. The rest of studies stated there was no significant difference between aspirin and no aspirin. That insignificant finding coupled with the risk of bleeding associated with aspirin use calls for a reevaluation of the current guidelines and recommendation.

Answering the PICO Question

My question regarding whether the risk of cardiovascular disease is reduced in diabetic patients who take aspirin compared to those who don’t can be answered confidently at this point by saying no it is not. None of the literature that I was able to gather was in support of the use of aspirin as primary prevention. Although some of the literature showed a slight decrease in the rate of cardiovascular disease when supplementing aspirin, it was insignificant when compared to the placebo or no treatment groups. More studies need to be done before we can confidently say as healthcare professionals that this is a good therapy for diabetic patients because we could just put them at a higher risk of bleeding with no benefit at all on cardiovascular disease prevention. Until research can confirm that this is beneficial, other proven methods of cardiovascular protection should be encouraged.

Recommendations

When looking back at the limitations in the studies there were a few that I believed affected the studies more than others. First, in the JPAD randomized control trial they were not allowed to use placebos in the non-aspirin group, so it didn’t have the same advantages as a double blind study. In that case I would like to have seen a different type of antiplatelet therapy used and then compare the two therapies against each other in a double blinded study to see which was more effective. A second limitation was the short follow up that was present in all of the studies. Some follow up was as short as 90 days which doesn’t give clear picture of the effectiveness of the aspirin therapy. To combat this, I would like to see a longitudinal study done on a cohort of patients who are taking aspirin therapy compared to a cohort of a patients who are taking a placebo. Lastly, although none of the studies said it was a limitation, some of the studies included in the meta-analyses contained a scant number of patients (one was as low as six). When deciding on exclusion criteria they should make the number of patients included one of the criterion.

A personal recommendation for study that I would like to see is a randomized control trial examining three different groups. Those groups would be; low dose aspirin, exercise, and a combination of exercise and low dose aspirin therapy. I would be curious to see the results of that because then we may be able to recommend aspirin as an adjunct therapy to exercising in an aim to prevent a cardiovascular event.

Conclusion

When doing this literature view the goal was to prove that taking aspirin as a diabetic patient will help prevent a cardiovascular event compared to diabetic patients who do not. None of the six articles that I reviewed had evidence in support of the claim made by the ADA and AHA. Five of the studies concluded that there was inconclusive evidence and the other study refuted it entirely. Although there were certain subgroups within each study that showed benefit, they were not significant enough to recommend it to the group of patients. Aspirin was also associated with a higher risk of bleeding in patients who use it as antiplatelet therapy. More studies need to be done before we recommend this therapy to our clients. Until then the guidelines showed be removed or restructured so the general population does not see them and think that it is helping them prevent a cardiovascular event.

References

American Heart Association (AHA) (2017). Cardiovascular Disease and Diabetes. Retrieved on
April 10th , 2017 from
http://www.heart.org/HEARTORG/Conditions/More/Diabetes/WhyDiabetesMatters/Cardiovascular-Disease-Diabetes_UCM_313865_Article.jsp/#.WRm11Y-cE2y

Calvin, A.D., Aggarwal, N.R., Murad, M.H., Shi, Q., Elamin, M.B., Geske, J.B., Fernandez-Balsells, M.M., Albuquerque, F.N., Lampropulos, J.F., Erwin, P.J., Smith, S.A., Montori, V.M. (2009). Aspirin for the Primary Prevention of Cardiovascular Events. Mayo School of Graduate Medical Education. Rochester, Minnesota. DOI: 10.2337/dc09-1297

Fain, J.A. (2013). Reading, Understanding, and Applying Nursing Research, 4th Ed. Philadelphia, Pennsylvania: F.A. Davis Coompany.

Kirkman, S.M. (2010). Aspirin for Primary Prevention of Cardiovascular Events in People with Diabetes. American Diabetes Association. 33(6): 1395-1402.

Kokoska, L.A., Wilhelm, S.M., Garwood, C.L., Berlie, H.D. (2016). Aspirin for Primary
Prevention of Cardiovascular Disease in Patients with Diabetes: A Meta-Analysis.
International Diabetes Federation. St. Louis, MO; Elsevier

Mamas, A.M. & Ludwig, N. (2010). Meta-Analysis: aspirin for patients with diabetes. ProQuest. BMJ Publishing Group. Volume 18.

Ogawa, H., Nakayama, M., Morimoto, T., Uemura, S., Kanauchi, M., Doi, N., Jinnouchi, H., Sugiyama, S., Saito, Y. (2012). Low Dose Aspirin for the Primary Prevention of Atherosclerotic Events in Patients with Type Two Diabetes. JAMA-EXPRESS. 300(18).

Porth, C. M. (2015). Essentials of pathophysiology. (4th ed.). Philadelphia: Wolters Kluwer, Lippincott Williams & Wilkins.

Simpson, S.H., Gamble, J.M., Mereu, L., Chambers, T. (2011). Effect of Aspirin Dose on Mortality and Cardiovascular Events in People with Diabetes: A Meta-Analysis. JGMI. Society of General Internal Medicine. DOI 10.1007/s11606-011-y.

World Heart Federation (WHF) (2016). Diabetes as a Cardiovascular Disease Risk Factor. Retrieved on April 10th, 2017 from http://www.world-heart-federation.org/cardiovascular-health/cardiovascular-disease-risk-factors/diabetes/

Xie, M., Shan, Z., Zhang, Y., Chen, S., Yang, W., Bao, W., Rong, Y., Yu, X., Hu, F.B., Liu, L. (2014). Aspirin for Primary Prevention of Cardiovascular Events: Meta-Analysis of Randomized Controlled Trials and Sub Group Analysis by Sex and Diabetes Status.
PLOS ONE. 9(10).

Appendices

Appendix A: Evidence Table