Author + information
- ↵*Reprint requests and correspondence:
Dr. William J. French, Harbor–UCLA Medical Center, 1000 West Carson Street, Torrance, California 90509, USA.
Clinical studies have greatly expanded efforts to recognize the importance of gender, and more recently the role of diabetes and obesity, as significant co-morbidities for coronary artery disease (CAD) (1,2). However, renal disease, which appears endemic in the U.S., has not received the same attention (3). In fact, studies testing new therapies for acute coronary syndromes may exclude patients with renal insufficiency. The increasing prevalence of hypertension, diabetes, and obesity among an aging population places more patients at risk for renal failure and dialysis.
Only recently have studies suggested that patients with renal failure have poorer outcomes in the setting of unstable angina and myocardial infarction (MI). The seminal work by Herzog et al. (4)was the initial observation that unveiled the horrible prognosis faced by patients with end-stage renal disease suffering acute MI (AMI) (4). These observations were confirmed and extended by Chertow et al. (5). More recently, data from the Mayo Clinic and the Veterans Affairs Hospital at the University of San Francisco have revealed the significant morbidity and mortality risks faced by those with even minor renal insufficiency suffering non–ST-elevation myocardial infarction (STEMI) and STEMI events (6,7).
In this issue of the Journal,Gibson et al. (8)continue to reveal new insights about the increased risk associated with renal insufficiency for patients suffering AMI. What little data existed prior to the Gibson report have suggested a potential modest benefit from reperfusion therapy for this population (6). Gibson et al. (8)have extended previous observations of the pervasive adverse influence of renal disease to patients with STEMI who received reperfusion therapy with fibrinolytic agents. Pooled patient data in 16,710 patients from four studies (TIMI [Thrombolysis In Myocardial Infarction] -10A, -10B, and -14, and the InTIME-2 trial) who were followed for two years were analyzed. Unlike many trials that evaluated the treatment of patients with STEMI, patients in these four studies received some form of reperfusion therapy, including all patients with renal insufficiency. In addition, these patients received appropriate adjunctive therapies for their MI. But despite more appropriate treatment, mortality was still higher in patients with renal insufficiency independent of age and TIMI Risk Score. Previous reports (4–6), as well as data from the National Registry of Myocardial Infarction (NRMI) (personal communication, August 2003), have demonstrated less frequent use of thrombolytic agents (<4%), primary percutaneous coronary intervention (<3%), aspirin, beta-blockers, angiography, and angioplasty in patients with STEMI and renal insufficiency and higher mortality.
Although mean blood pressures on admission were normal, there was an increased history of hypertension, as well as diabetes, in patients with severe renal disease. Nonwhite patients were more likely to have severe renal impairment, although Herzog has demonstrated that African ethnicity is protective in end-stage renal disease and AMI.
The incidence of renal insufficiency was surprisingly high in this analysis. Gibson demonstrated that over 26% of patients had a creatinine value of >1.2 mg/dl, but some 63% had an abnormal creatinine clearance (CrCl) ≤90 ml/min, with nearly 23% having moderate or severe renal insufficiency with a CrCl ≤60 ml/min. Data from the Mayo Clinic suggested that over 50% of all patients admitted for AMI had some degree of renal impairment, whereas a Veterans Affairs study revealed that 63% of patients on admission had a serum creatinine <1.5 mg/dl, but only 33% of all patients had “normal renal function” defined as a CrCl >55 ml/min. Previous work has demonstrated that a CrCl of 60 to 85 cc/min may be associated with some increased mortality risk at the time of AMI (Fig. 1) (6).
Taken together, these observations suggest that clinical cardiologists must no longer solely rely upon serum creatinine as a means of estimating renal function in their patient populations. Instead, we recommend that clinicians estimate CrCl using the modified Cockcroft-Gault formula (9)that relies on age, weight, gender, and serum creatinine:
Creatinine clearance 
In the study by Gibson et al. (8), mortality from heart failure increased with more severe renal insufficiency. The incidence of intracranial hemorrhage also was increased in patients with more severely elevated creatinine levels, but there was only a trend noted among patients with an increased creatinine clearance. This observation complements and concurs with previous work and further highlights the risks faced by patients with renal impairment (4–7).
Gibson et al. (8)are to be commended for defining the independent risk of renal insufficiency and the importance of even “mild” forms of renal disease on outcomes in patients with STEMI. In addition, the clear design, concise analysis, and superb writing of the study add a clear perspective to the subject for the reader. The cohort analyzed in their report contained only those who received reperfusion therapy. There was no indication of diminished efficacy of reperfusion therapy in those with renal insufficiency, but the investigators did report that patients with severe renal insufficiency were more likely to suffer intracranial hemorrhage.
What to do with patients with renal disease and STEMI? Evidence-based data with newer pharmaceuticals and/or an invasive strategy are lacking. Data from the Gibson et al. (8) study suggest that even with appropriate therapy given in a timely manner, this may not be sufficient to ameliorate many adverse consequences on outcomes from underlying renal insufficiency. However, if less than appropriate treatment is provided in the community settings, as suggested by NRMI data, even poorer outcomes may be expected than demonstrated in these randomized trials.
Future clinical trials testing new or established therapies for ischemic heart disease need to be more inclusive of patients with renal insufficiency, especially with the high incidence of mild, moderate, and severe renal impairment described in the study by Gibson et al. (8). Exclusion of patients with renal insufficiency not only precludes many patients who potentially might benefit from newer treatments, but also may limit the study population to lower-risk patients who might not mirror those treated in clinical practice. In the past, women and even diabetics were excluded from trials for a variety of reasons. But we have learned that inclusion of these groups in clinical trials has had a salutary effect on their outcomes. Perhaps the same will be said one day about patients with renal insufficiency.
The inclusion of patients with varying degrees of renal insufficiency in AMI research should become a compelling national priority as the impact of renal insufficiency on outcome in AMI is now well established. The incidence of renal insufficiency will rise well into the 21st century given its association with diabetes and hypertension, both of which are seeing dramatic increases in incidence rates. The time has come to move beyond the attitude of “therapeutic nihilism” toward patients with renal failure and develop targeted strategies from well-designed research, which will ultimately reduce the burden of risk in this population.
A word of caution is warranted as we embark upon more research in patients with renal insufficiency. Greater utilization of current therapies to treat serious clinical conditions such as STEMI in patients with renal insufficiency may not be enough, however, even if applied appropriately, to reduce significantly expected adverse outcomes. Clinical efficacy of many commonly used therapies, such as low molecular weight heparin, IIb/IIIa platelet inhibitors, thrombolytics, and angioplasty may be less in these patients (6,7). Newer agents or procedures need to be developed to achieve improved outcomes. Patients with renal insufficiency may experience higher rates of serious adverse events as clinical research progresses, and we may have to accept higher adverse event rates as the offset costs of bringing newer therapies to this population.
We may also learn that more aggressive treatment of AMI in patients with renal insufficiency may not be the most effective way to reduce overall morbidity and mortality. It may be that more aggressive primary and secondary prevention specifically targeted at this population is the only effective means by which the overall disease burden is reduced. Such a hypothesis has been initially advanced by Wright et al. (6)and should be tested. At a minimum, we need more education to highlight risk factors that lead to renal disease, with a major emphasis on prevention through earlier recognition and treatment of hypertension, diabetes, and obesity.
Whatever the ultimate outcome, the study by Gibson et al. (8)highlights the compelling need to recognize the increased risks faced by those with renal insufficiency suffering AMI and highlights the challenge we face in educating the medical community on the need to better recognize renal insufficiency in those with even mild creatinine elevations as a marker of worsened prognosis.
The challenge is daunting—reduce the incidence of renal disease through education and treatment, provide adjunctive therapies recommended for STEMI that are not affected by the presence of renal insufficiency to appropriate patients, and develop newer therapies that reduce mortality in this group of patients. Gibson et al. (8)have described the problem; the solution is up to us.
↵* Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
- American College of Cardiology Foundation
- Kuller L.H.
- ↵Gibson CM, Pinto DS, Murphy SA, et al. Association of creatinine and creatinine clearance on presentation in acute myocardial infarction with subsequent mortality. J Am Coll Cardiol 2003;42:1535–43