Covit, Andrew B
Recent advances in endovascular technology have radically changed the options available for the clinical management of the patient with renovascular disease. These treatment options have fueled an ongoing debate concerning the appropriateness of interventional endovascular therapy for the stenotic renal artery versus conservative medical management. This review examines a typical clinical case scenario and analyzes relevant published literature and the recent guidelines from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) highlighting the significant shortcomings of evidence-based data when it comes to the management of this complex patient population. Early diagnosis provides the best opportunity for appropriate utilization of therapeutic options and rational timing of deployment of interventional techniques. Recommendations for conservative medical management are made based on the review of the medical management arms of the published interventional series. In addition, suggestions are made for practical modifications to the JNC 7 hypertension management protocol to better address the challenging diagnostic and management issues raised by the renovascular patient.
In clinical practice, determining the appropriate treatment for any patient is often complicated by factors not addressed in clinical trials. The following case report is an example of this dilemma.
A 72-year-old man was referred for evaluation of renal insufficiency in the late 1980s. He had a prior history of tobacco use but had stopped 4 years before referral. The patient's serum creatinine was 1.8 mg/dl, and he had a 15-year history of moderate hypertension requiring gradually increasing dose, frequency, and numbers of antihypertensive medications. At the time of referral, his medications included atenolol 50 mg daily, hydrochlorothiazide 25 mg daily, and prazosin 5 mg three times daily. Physical examination revealed a thin man in no distress. Seated blood pressures were 176/66–180/60 mmHg without asymmetry or orthostasis. Bilateral radial Osler's signs were present. Other significant findings included retinal atherosclerosis, a barrel chest with diminished breath sounds bilaterally, and a grade I/VI systolic murmur at the second left intercostal space without radiation. Prominent bilateral (left greater than right) periumbilical systolic bruits were also evident, along with a left femoral bruit. Strong pedal pulses were present, however, and there was no livedo reticularis or petechial rash. Initial laboratory data were significant for serum creatinine of 1.7 mg/dl, blood urea nitrogen of 40 mg/dl, creatinine clearance (CrCl) of 54 ml/min, and urine protein of 320 mg/24 h, consistent with stage III chronic renal disease. Renal ultrasonography demonstrated mild renal asymmetry, vascular calcifications, and infrarenal aortic ectasia without aneurysm. The patient refused renovascular intervention, so a conservative medical approach was adopted.
The patient's blood pressure medications were adjusted over the next 6 weeks. Prazosin and hydrochlorothiazide were discontinued, and enalapril 10 mg, every morning, was instituted. Following this regimen, blood pressures improved to 152/64–160/72 mmHg, but the patient's serum creatinine rose to 2.4 mg/dl, blood urea nitrogen decreased to 38 mg/dl, and CrCl decreased to 50 ml/min.
For the next 5 years, the patient remained remarkably stable. His serum creatinine would intermittently increase with mild dehydration but responded to extra salt and volume. Over the following 6 years, his creatinine gradually rose to 4 mg/dl and his CrCl fell to 28 ml/min. His blood pressures remained stable, however, and he still refused intervention.
One year later at age 84, 12 years after initial presentation and 2 years after a 3-cm infrarenal abdominal aortic aneurysm was detected on routine ultrasonography, the patient developed sudden severe abdominal pain and unremitting shock. Despite pressors, he succumbed on the 10th hospital day. Postmortem examination, limited to the abdomen, revealed diffuse bowel ischemia and, as expected, atrophic kidneys.
Even though extremely common in clinical practice, older patients and patients with low diastolic blood pressure or long-standing hypertension, such as the patient discussed, are frequently excluded from clinical trials of renovascular disease [1,2]. Although these exclusion criteria may be understandable because of patient dropout, high mortality rates, and the confounding effects of comorbid conditions, the end result is that a great deal of the data are not relevant to clinical practice. Experience and knowledge are, therefore, crucial for making appropriate treatment decisions in the absence of compelling data from evidence-based medicine. Ideally, patients should be managed either directly by or in consultation with a subspecialist familiar with the pathophysiology of this disorder, so that they receive careful and repeated scrutiny of renal, vascular, and cardiovascular status to detect and appropriately respond to disease progression [3]. Lipid disorders must also be aggressively managed since this is a diffuse atherosclerotic disease, which just happens to be manifested in the kidneys [4].
Before choosing medical therapy, the potential consequences of this choice must be carefully considered. It is well accepted that renal artery stenosis is a progressive disorder. Over the course of 1 year, five out of 25 patients (20%) managed exclusively with medical therapy developed a >= 20% increase in the degree of stenosis [1]. In that series, four out of 43 patients (9%) initially assigned to medical therapy developed occlusion of the renal artery [1]. In the Scottish series, one out of eight patients (13%) randomized to medical therapy had progression of their renal artery stenosis over a 1-year period in another evaluation [2]. A potential consequence of conservative medical therapy is thus disease progression, potentially leading to occlusion of the renal artery. This could significantly limit treatment options, since it can be extremely difficult and often impossible to cross an occluded vessel with a catheter, precluding less invasive catheter-based interventions. Any subsequent intervention is going to be much more problematic or is going to necessitate an open surgical procedure. The significant risk of progression to occlusion would favor interventional therapy over medical therapy. However, determining this risk is problematic, since currently available data come from relatively short-term studies in small numbers of highly selected patients.
Another potential consequence of medical therapy is worsening renal function leading to end-stage renal disease. Interestingly, in a retrospective cohort evaluation, patients with incidental renal artery stenosis (>= 50%) detected on angiography were compared with age-matched and gender-matched controls [5]. Although the patients with renal artery stenosis had a significantly lower CrCl at baseline (58 vs. 65 ml/min; P < 0.05) [5], serum creatinine levels remained stable in both groups (Table 1), and no patient required renal replacement during a 10-year follow-up period [5]. These data suggest that serum creatinine levels and renal function may remain stable over long periods of time in many patients with significant degrees of stenosis. The logical conclusion to be drawn is that interventional therapy to preserve renal function may not be required in all patients. However, as in most of these studies, there is a ‘morbidity drain’ such that, within the 6–8 years of observation, 75–80% of the patients in this study had dropped out. While these data are suggestive, it is hard to base real clinical management decisions on observations made in only 25–30 patients.
Despite the potential risk for progression of stenosis and the development of end-stage renal disease, medical management has indeed proven to be safe and effective in select patients. In the Scottish and Newcastle collaborative study, 12 patients (9%) were excluded from randomization at the outset because their blood pressures were already well controlled with minimal medical therapy [2]. In the actual study population, a fixed antihypertensive regimen decreased mean blood pressures from 193/103 to 179/97 mmHg at the conclusion of a 4-week run-in period [2]. Moreover, this blood pressure reduction was maintained throughout the study in patients randomized to medical therapy; at last follow-up, these patients had a mean blood pressure of 166/90 mmHg [2]. In fact, for the patients who were randomized to medical therapy, the mean number of blood pressure medications increased from 2.4 at baseline to 2.7 at final follow-up [2]. Monotherapy is probably a thing of the past, at least until newer and better agents are developed. In this study, the risk-factor-adjusted time to first major event was similar for medical versus interventional therapy [2].
Similar results were seen with medical therapy in the Dutch Renal Artery Stenosis Intervention Cooperative (DRASTIC) trial. Mean blood pressure fell from 180/103 mmHg at randomization to 163/96 mmHg at the end of the trial [1]. As in the Scottish and Newcastle study, this reduction was the result of aggressive medical management, with the mean number of blood pressure medications increasing from 2.0 at randomization to 2.4 at the trial end [1]. These studies demonstrate that pharmacologic control of hypertension can be achieved in a significant number of patients with renal artery stenosis.
If hypertension can be pharmacologically controlled, are there other parameters that justify intervention? Table 2 summarizes mortality data by treatment indication, blood pressure, and renal function for patients following percutaneous renal angioplasty and stenting [6]. In this evaluation, heart failure and renal insufficiency significantly increased the risk of death following intervention, and similar results were obtained when these data were analyzed for all cardiovascular events [6]. These data suggest that it may be better to intervene before heart failure or significant renal insufficiency develops, but there are little actual data on this kind of anticipatory intervention.
To institute anticipatory intervention, patients whose renovascular disease was going to get worse would have to be identified with reasonable certainty. As discussed by Dr Textor in his article in this supplement, progression of renal artery stenosis is directly related to the degree of stenosis already present. In a prospective evaluation, univariate analysis demonstrated that high-grade (>= 60%) stenosis, systolic blood pressure >= 160 mmHg, diabetes mellitus, age, and ankle-arm index < 0.7 were all associated with an increased risk of disease progression [7]. When these parameters were entered into a multivariate model, high-grade stenosis in either the ipsilateral (relative risk: 1.9; 95% confidence interval: 1.2-3.0) or contralateral (relative risk: 1.7; 95% confidence interval: 1.0-2.8) renal artery, systolic blood pressure (relative risk: 2.1; 95% confidence interval: 1.2-3.5), and diabetes (relative risk: 2.0; 95% confidence interval: 1.2-3.3) continued to be significant and independent predictors of disease progression [7]. Furthermore, renal artery occlusion occurred in approximately 3% of affected kidneys, all of which had >= 60% stenosis at baseline [7]. These data demonstrate that progression is likely in patients with high-grade stenosis and/or multiple comorbidities. Patients without these findings can probably be managed conservatively.
While numerous investigators have reported limitations and issues with medical therapy [8–14], it is beyond the scope of this analysis to review all of these reports. However, two of the reports highlight an important clinical scenario that does merit further discussion. In 1988, Pickering et al. [13] reported that successful revascularization improved blood pressure control and renal function, and virtually eliminated pulmonary edema, in 11 patients with renovascular hypertension and recurrent episodes of pulmonary edema. These findings were confirmed in a more recent report by Gray et al. [9]. These findings are important because primary care physicians frequently refer patients with recurrent pulmonary edema to cardiologists, without considering that these episodes may actually be related to renovascular disease. Since pulmonary edema secondary to renovascular disease responds well to interventional therapy, a crucial therapeutic opportunity can be realized from a thorough evaluation of renovascular status in patients with recurrent pulmonary edema.
It is also important to consider the economic cost of medical therapy. Previously published data demonstrate that the cost of antihypertensive therapy is neither trivial nor limited to the initial cost of drug acquisition, and must include laboratory monitoring, required secondary medications such as potassium supplementation, clinical follow-up, and treatment of side effects [15]. In a 1994 analysis, the cost of antihypertensive therapy, adjusted to 1992 price levels, was $895 for [beta]-blockers, $1043 for diuretics, $1165 for centrally acting [alpha]2-agonists, $1243 for angiotensin-converting enzyme inhibitors, $1228 for [alpha]1-blockers, and $1425 for calcium channel blockers [15]. As previously discussed, medical therapy for renal artery stenosis frequently requires two or more drugs to achieve adequate blood pressure control. Thus, the cost of this therapy can easily exceed $2000–3000 per year.
For comparison, the cost of interventional therapy should be analyzed in a similar fashion. This analysis must consider not only the cost of the catheters and stents, but also the cost of hospitalization, follow-up assessments, and subsequent medication requirements. There is probably no cost benefit if, as in the DRASTIC study, the mean number of drugs used only drops from 2.0 to 1.9 following intervention [1]. The problem is that most analyses of both medical and interventional management do not take into account this more global view of the cost of therapy.
Physicians agree that opening stenotic or occluded coronary arteries is beneficial [16] and that peripheral revascularization to improve blood flow to the lower extremity helps ischemic ulcers heal better [17]. It would seem that the same would be true for the stenotic renal artery. Unfortunately, preconceived ideas such as this permeate renovascular clinical trials, despite claims that the trial parameters are unbiased.
In the DRASTIC study, 22 of the 50 patients randomized to medical therapy were actually revascularized after only 3 months of follow-up [1]. The reasons given for this cross included persistent hypertension, progressive renovascular disease as indicated by a 0.2-mg/dl increase in serum creatinine, or worsening of the time–activity curve on renal scintigraphy. After only 3 months of medical therapy, what constitutes persistent hypertension? The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) now says that two, three, or even more medications should be used to lower blood pressure to optimal levels [18]. Furthermore, variations of 0.2 mg/dl in serum creatinine levels are routinely seen in clinical practice; it is the overall trend in creatinine level increase that is important. The high intervention rate in patients supposedly randomized to medical therapy in the DRASTIC study probably reflects a preconceived idea by the investigators that revascularization is superior to medical therapy.
Similarly, preconceived ideas regarding the benefits of revascularization may have influenced two of the major exclusion criteria in the DRASTIC study. This study excluded patients with significant renal insufficiency (defined as serum creatinine <= 2.3 mg/dl) [1]. In clinical practice, patients with normal renal function or only mild insufficiency are typically managed conservatively. It is the more severely affected patients, those who already have moderate to severe renal dysfunction, whose appropriate management is more of an issue, and these patients were not included in this study. Similarly, the DRASTIC study excluded patients on antihypertensive therapy with diastolic blood pressures >= 95 mmHg [1]. As the earlier case report demonstrated, renovascular disease may present as isolated systolic hypertension. JNC 7 states that isolated systolic hypertension is a more important cardiovascular risk factor than diastolic hypertension [18]. Excluding these patients leaves a significant proportion of high-risk patients unevaluated. Such an exclusion would be unacceptable in any modern evaluation of pharmacotherapy for hypertension. Thus, these are not the patients who are typically seen in clinical practice, and again, preconceived ideas and risk stratifications taint the data.
Several other problems also exist with the currently available clinical trial data. First, a 1-year follow-up, while adequate for publishing reports, means absolutely nothing in the management of these patients. Long-term outcomes are what really need to be identified. Second, small patient numbers are a major problem with most of the clinical trials. In the DRASTIC study, only 50 patients were randomized to medical therapy, and only 27 were still receiving this therapy after 1 year [1]. Third, there is no consistent definition for renovascular disease. Logically, management of an isolated discrete stenosis should be completely different from management of diffuse renal artery involvement. Thus, study results may depend on the degree and extent of vascular disease. Finally, these trials usually have very broad exclusion criteria, including not only renal dysfunction and blood pressure, but also age and the presence of other atherosclerotic disorders such as severe aortic or aortoiliac disease [1,2]. Elderly patients with comorbidities are often excluded, even though they represent the very population that needs to be evaluated. Although pharmacotherapy can always be instituted, it is important to determine the safety and efficacy of intervention in these patients.
In electing medical therapy over intervention, it is important to understand the expected results. In the DRASTIC study, medical therapy produced a significant overall improvement in blood pressure (P <= 0.002); at 12 months, blood pressure control was improved in 18 out of 48 (38%) patients randomized to medical therapy with complete follow-up [1]. This blood pressure response is not unrealistic for medical therapy. In fact, some drugs are Food and Drug Administration approved based on this level of response. However, blood pressure control worsened in 16 (33%) of the patients randomized to medical therapy [1], confounding the issue. The percentages of patients who improve, stay the same, or worsen are approximately the same. This suggests that there are a significant number of patients who can be managed medically, as long as they are followed carefully.
When evaluating medical therapy, it is important to consider the potential role of a placebo effect. In the recent Veterans Affairs cooperative study of antihypertensive monotherapy, blood pressure control was achieved in nearly one-third of patients randomized to placebo (Fig. 2) [19]. Since monotherapy with active drugs was approximately 60–70% efficacious, this placebo effect accounted for nearly one-half of the efficacy seen in this trial.
The success rate of medical therapy can be further improved with combination therapy, but compliance may then become an issue. Similar to multiple doses of the same drug, multiple medications can adversely affect compliance. Often patients run out of one of their medications and continue to take the other(s); they want to know why they do not feel quite as well [3].
The diagnosis and management of renovascular disease is problematic because it is a silent epidemic. Several studies demonstrate that the prevalence of renovascular disease in high-risk categories exceeds 15–20% [20,21]. Despite this, renovascular disease is mentioned only once in the express report of JNC 7, which states only that it is an identifiable cause of hypertension; it does not address diagnosis or management [18].
In the published treatment scheme, lifestyle modification followed by pharmacotherapy is essentially the same for all patients (Fig. 3) [18]. Even the proposed drug classes (diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, [beta]-blockers, and calcium channel blockers) do not differ much from one patient group to the next. Moreover, there is no feedback loop to deal with patients who do not respond adequately to this approach. JNC 7 states that referral to a hypertension specialist should be considered for resistant hypertension, defined as a failure to achieve the target blood pressure on an appropriate three-drug regimen, but it suggests no time course for dose titrations, initiation of new drugs, or referral [18]. As a result, 5 years, 10 years, or more could elapse before patients with renovascular hypertension are referred and correctly diagnosed; this delay may adversely alter their prognosis and treatment options. These patients will be older and have a higher comorbidity burden than the patients with renovascular hypertension currently described in the literature. It must be remembered that the compelling indications listed in JNC 7 – heart failure, ischemic heart disease, cerebrovascular disease, diabetes, and chronic kidney disease – are all potential markers of renovascular hypertension. Anyone with hypertension and one or more of these compelling indications should be immediately referred to a hypertension specialist (Fig. 3), who can look at the global clinical picture, evaluate the patient's response to therapy, and determine when and which additional diagnostic evaluations should be performed. Similarly, any patient who fails to respond to medical therapy within a short time (6–12 months) should be evaluated for secondary causes of hypertension including endocrine and renovascular disorders (Fig. 3).
In most patients with renovascular hypertension, the role of medical versus interventional therapy is an unresolved issue, and resolution will be problematic. The DRASTIC study initially screened 1205 subjects and ultimately ended up with subsets of only 20–25 subjects [1]. To ensure sufficient patient numbers for meaningful analyses, approximately 10 times this number of subjects will have to be screened. This will require multiple centers with clearly defined standards for the diagnosis and classification of renovascular disorders.
Evaluating patients who are typically excluded from clinical trials – the elderly and patients with normal to low diastolic blood pressure, moderate to severe renal insufficiency, significant atherosclerotic disease outside of their renal vasculature, and other comorbidities – will help resolve this issue. While these confounding factors will significantly increase the complexity of the evaluation and make interpreting the results more difficult, the potential outcome, better treatment for patients with more complex disease, will certainly be worthwhile [22].
Enrollment and subsequent randomization must be unbiased so that the medical and interventional groups are truly equal and reflective of the population as a whole. Furthermore, without compelling indications to the contrary, treatment assignments need to be maintained throughout the study. For the analysis to be meaningful, patients randomized to medical therapy cannot cross over to the intervention group in large numbers.
Finally, the primary endpoint must be overall outcome, not just blood pressure or renal function. The ultimate question is which treatment regimen reduces morbidity and mortality.
Medical therapy is effective and appropriate in some patients. Although there may be a price for interventional procrastination, these complications typically occur in specific patient subsets and can probably be minimized with careful and consistent follow-up. Since medical therapy is effective, the presence of a renal artery stenosis is not an indication, in and of itself, to offer interventional therapy.
Successful management of renovascular hypertension should be judged by the same standards used for essential hypertension. Currently we do not know which factors influence this management. However, we do know that disease progression does correlate with disease severity. Patients with evidence of disease progression, treatment-resistant hypertension, chronic renal insufficiency, or diabetes ought to be considered for interventional therapy.
Finally, it is important to remember
that it is still not clear whether interventional therapy is better than medical
therapy for most patients typically seen in clinical practice. Improvements in
pharmacologic agents and interventional technology constantly shift the balance
between the two treatment modalities. Better drugs favor more conservative
medical therapy, while better devices and delivery systems favor more
interventional therapy. Improvements in both are necessary. Although selected
patients can be managed medically, the ability to provide a relatively safe
intervention, should it become necessary, is an essential component of the
therapeutic armamentarium.
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