Hypertension, together with proteinuria, is probably one of the major factors contributing to progression of chronic kidney disease (CKD), and it is also a significant determinant of morbidity and mortality among hemodialysis patients. It is well known that cardiovascular disease accounts for more than 50% of the deaths of hemodialysis patients and, as Silverberg et al pointed out some years ago1, patients afflicted by end-stage renal disease (ESRD) have already reached, or are going to reach, "near-terminal cardiac failure." Indeed, the prevalence of echocardiographic and clinical manifestations of cardiovascular disease is already high at the beginning of renal replacement therapy. Data from a Canadian echocardiographic evaluation of 432 patients starting dialysis showed that only 16% had a normal echocardiogram2. This suggests that the mechanisms leading to cardiovascular impairment have been operating early in the pre-dialysis phase of CKD. Levin et al found that left ventricular hypertrophy prevalence is already high in patients with mild chronic renal failure (CRF; about 30% in patients with creatinine clearance of 50 to 75 mL/min) and significantly increases with declining of renal function3. Considering these striking numbers, CKD has been defined as "a vasculopathic state"4. Indeed, a number of large-scale trials identified an increase in serum creatinine as an important cardiovascular risk factor5,6,7.
Thus, care must be taken to treat the cardiovascular risk factors optimally in CKD patients. For this reason, in addition to the correction of anemia and hyperphosphoremia, effective antihypertensive therapy is the single most important treatment in these patients, not only in order to delay CKD progression, but also to reduce the burden of cardiovascular disease.
However, over recent years it has become clear that not all antihypertensive agents are equally effective in slowing CKD progression, and that some may have an additional renoprotective effect that is at least partially independent of blood pressure reduction.
Similarly, not all antihypertensive drugs display the same properties in preventing cardiovascular disease or in reducing mortality. ACE inhibitors (ACEIs) reduce mortality by 19 to 25% in patients with acute myocardial infarction and left ventricular dysfunction with a potential of 12 to 42 lives saved per 1000 patients treated per year8. In addition, they reduce complications of acute myocardial infarction such as congestive heart failure and may prevent its recurrence8. More recently, the Heart Outcomes Prevention Evaluation (HOPE) study showed that these agents also significantly reduce the rates of death, myocardial infarction, and stroke in a broad range of patients at high risk for cardiovascular events in the absence of left ventricular dysfunction or heart failure9. Angiotensin II receptor antagonists (ATIIRAs) probably display similar properties. Results of the Losartan Intervention for Enpoint reduction in hypertension (LIFE) study indicated that losartan prevented more cardiovascular morbidity and death than atenolol for a similar reduction in blood pressure in 9123 patients with essential hypertension10.
As shown by a quantitative overview of actively controlled trials in hypertension, compared to older drugs and ACEIs, calcium channel blockers (CCBs) probably provide more reduction in the risk of stroke but less reduction in risk of myocardial infarction11. CCB use also has been associated with a lower risk of total and cardiovascular mortality among ESRD patients12.
Furthermore, increasing evidence supports the notion that the combination of some of these agents may have additive or even synergistic effects in delaying CKD progression and to prevent, or at least reduce, the burden of cardiovascular disease. This is of particular interest because it is not possible to control blood pressure with one agent alone in the majority of patients with renal disease.
For this reason, it is important, not only to identify the antihypertensive agent of first choice, but also to clarify whether the combination of various agents can offer a further renoprotective advantage beside the achievement of target blood pressure.
BLOOD PRESSURE AND PROTEINURIA INTERACTION
Although the mechanisms leading to proteinuria in CKD are complex and not yet fully elucidated, there is certainly a clear relationship between urinary protein excretion and blood pressure levels. Essential hypertensive patients often have increased urinary protein excretion even in the absence of established renal damage, and it correlates with blood pressure levels. This increase in proteinuria has been attributed to the transmission of high systemic pressure to the glomeruli and, according to this hypothesis, any antihypertensive therapy is capable of decreasing proteinuria when hypertension is present. In this regard, a multivariate analysis of controlled and uncontrolled trials by Maki et al has shown that each 10 mm Hg reduction in blood pressure decreases proteinuria by 14% (regression coefficient -0.14; 95% confidence interval -0.22 to -0.06)13. However, there seems to be a clear difference in the antiproteinuric capacity of the different classes of antihypertensive drugs, with ACEIs and non-dihydropyridine (ndh) CCBs having the greatest capacity of reducing urinary protein excretion. This difference very clearly emerges from the results of a meta-analysis by Weidmann, Schneider and Bohlen concerning the antiproteinuric capacity of different antihypertensives in diabetic nephropathy14. Despite similar degrees of blood pressure reduction, proteinuria tends to decrease more with ACEIs (an average of 45%) than with conventional therapy (an average of 23%) or CCBs other than nifedipine (an average of 35%). Furthermore, ACEIs reduced proteinuria by 28% without any change in blood pressure and variations of 1.5% thereafter were observed for each percent change in blood pressure, whereas proteinuria began to decrease only after a mean blood pressure reduction of 5% in the patients receiving conventional therapy. Moreover, according to this meta-analysis14, after a decrease in mean blood pressure of approximately 20 mm Hg, the antiproteinuric effect of all of the drugs becomes the same.
Figure 1 depicts a clear relationship between systolic blood pressure achieved during follow-up and proteinuria levels in the patients enrolled in the angiotensin-converting-enzyme inhibition in progressive renal insufficiency (AIPRI) study15, a large randomized controlled study that was aimed at testing the effect of benazepril on the progression of chronic nephropathies (mainly non-diabetic). As expected, proteinuria is directly related to systolic blood pressure. Interestingly enough, patients treated with ACEIs seem to have lower proteinuria levels than those treated with placebo even at lower systolic blood pressure values, suggesting an additional effect of ACE inhibition in comparison with conventional antihypertensive agents that is not due to blood pressure reduction.
Figure 1.
Relationship between systolic blood pressure achieved during follow-up and proteinuria levels in the Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency (AIPRI) study14. Proteinuria is directly related to systolic blood pressure, but patients treated with ACEIs have lower proteinuria levels than those treated with placebo even at lower systolic blood pressure values. Symbols are: (
, dotted line) benazepril group; (
, solid line) placebo group.
ACE INHIBITORS
Various experimental data have clearly demonstrated that the activation of the renin-angiotensin system can promote intraglomerular and systemic hypertension, and thus contribute to hemodynamically-mediated renal injury. Furthermore, angiotensin II, which is the principal mediator of the major effects of this system, can induce mesangial and tubular cells to proliferate by means of a direct or indirect mechanism, and possibly leads to matrix production and tubulointerstitial fibrosis.
According to the results of large trials, ACEIs reduce the rate of loss of renal function in diabetic16 and non-diabetic chronic renal diseases15,17; this effect is greatest in patients with substantial proteinuria at baseline. The renoprotective action of ACEIs also has recently been confirmed by a meta-analysis of patient-level data18, including 11 randomized trials and a total of 1860 patients with non-diabetic chronic renal diseases. A 30% reduction in the relative risk of developing the combined end-point of doubling of the baseline serum creatinine concentration or ESRD was observed in those treated with ACEIs in comparison with those treated with standard antihypertensive treatment. Patients with greater proteinuria at baseline benefited more from ACEI therapy. However, as also underlined by this meta-analysis, in the majority of the studies the systolic and diastolic blood pressure values achieved with ACEIs were lower than those obtained during standard hypertensive therapy. Thus, none of these studies have completely answered the question as to how much the renoprotective effect of ACEIs is independent of blood pressure reduction. However, it emerges very clearly that in any case it is necessary to add these agents to standard antihypertensive treatment in order to obtain an adequate blood pressure control.
A second limitation of these studies is that they were designed before the awareness of the need for strict blood pressure control in order to slow down CKD progression, and so none of them were aimed at reaching the currently accepted target blood pressure of 125/75 mm Hg. For this reason, it is still unclear whether they are really superior to other antihypertensive agents when low blood pressure values are achieved.
CALCIUM CHANNEL BLOCKERS
Calcium channel blockers are effective vasodilators and blood pressure lowering agents, and have been extensively used in patients with CKD. CCBs also have various properties that might afford renal protection. Some of the main mechanisms postulated as mediating the renal protective effects of CCBs include their ability to delay renal growth19 and attenuate the mitogenic effect of a number of cytokines and growth factors that use changes in intracellular free Ca++ for signal transduction20. Furthermore, CCBs appear to reduce cell membrane damage secondary to oxygen free radical formation and the activation of phospholipases, as well as the angiotensin II-mediated increase in the mesangial trafficking of macromolecules20.
However, despite these theoretical and experimental attributes, the clinical evidence for the renoprotective efficacy of CCBs has been less consistent. A number of meta- and post-hoc analyses of clinical trials designed to detect the effects of ACEIs on CKD progression have revealed that some CCBs can reduce proteinuria13,14,21. This effect seems to be at least partially independent of blood pressure reduction, but it is not uniform for every type of CCB. Indeed, while ndh-CCBs seem to consistently reduce or blunt the rise in proteinuria, dihydropyridine (dh) CCBs, regardless of their duration of action, tend to have neutral effects on proteinuria. This observation is supported by most literature.
In the already-mentioned multivariate analysis of controlled and uncontrolled trials involving patients with diabetic and non-diabetic renal diseases by Maki et al13, ndh-CCBs together with ACEIs were capable of inducing a reduction in proteinuria, whereas dh-CCBs had no apparent effect on proteinuria. Another meta-analysis confirmed that the type of CCB is an important determinant of proteinuric response: nifedipine induced only a slight decrease in proteinuria (-8.0%) despite a marked fall in blood pressure (-14.3%), whereas other CCBs had a significantly greater antiproteinuric effect (-20.7%) with a less evident antihypertensive effect (-10.4%)21.
Caution is needed in evaluating these meta-analyses, because they mainly considered small and not always prospective studies, with a relatively short period of follow-up. Furthermore, sodium intake, which has been shown to be a critical determinant of albuminuria reduction associated with CCBs, has rarely been considered in these studies.
The Modification of Diet in Renal Disease (MDRD) study was not designed to assess the efficacy of CCBs; however, it is perhaps one of the largest trial that has used these agents. One group of patients was treated with the ndh-CCB diltiazem, in order to obtain blood pressure control and, after four years of follow-up, no increase in renal mortality was found in comparison with ACEIs22.
Bakris et al found that verapamil, another ndh-CCB, had similar effects to those of lisinopril in reducing the rate of CKD progression and proteinuria in 52 patients with type 2 diabetes23. Similarly, in a small, long-term, prospective randomized trial involving African Americans with type 2 diabetes and nephropathy, verapamil was found to reduce the decline in renal function and proteinuria to a greater extent than a 
-blocker, despite comparable blood pressure reduction24. On the other hand, in the same subset of patients, isradipine (a dh-CCB) increased proteinuria by about 50% from baseline25. Another small prospective study26 of 28 patients with type 2 diabetes found that, although less effective than enalapril in reducing microalbuminuria, nitrendipine (another dh-CCB) was associated with a greater increase in GFR after six months of follow-up; however, it needs to be remembered that the beneficial effect of ACEIs is often preceded by a transient decrease in GFR.
Interestingly enough, the results of a post-hoc analysis of the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) Trial showed that in older patients with isolated systolic hypertension, antihypertensive treatment starting with nitrendipine decreased by 64% the incidence of mild renal dysfunction (defined as serum creatinine 
176.8 mmol/L; P = 0.04) and that of proteinuria by 33% (P = 0.03)27. Active treatment reduced the risk of proteinuria more in diabetic than in non-diabetic patients. Although these beneficial effects can be explained on the basis of blood pressure reduction achieved with active therapy, it is at least clear that therapy with CCBs is better than no therapy.
To clarify the issue whether the differential antiproteinuric effects of CCBs may be explained by their effect on glomerular membrane permeability, Smith et al studied 21 patients with type 2 diabetes and nephropathy, who were randomized to receive either diltiazem CD or nifedipine (GITS)28. After 21 months of follow-up, despite similar blood pressure control, only the diltiazem group had a significant reduction in proteinuria (-57 
18 vs. 4 10% in the nifedipine group; P < 0.001) with improvement in glomerular size-selectivity and change in IgG clearance. On the other hand, no detectable effect of nifedipine retard in comparison with either enalapril or placebo was observed on renal morphology over three years in 54 type 1 diabetic patients with albuminuria and blood pressure below 150/90 mm Hg, indicating that, in this small cohort, disease evolution appeared unaffected by treatment with either enalapril or nifedipine29. However, it is worth noting that advanced glomerular structural abnormalities were already present at baseline, possibly affecting the rate of further structural damage and reducing the magnitude of treatment effectiveness.
Conversely, in 241 patients with non-diabetic renal disease and randomized to receive either long-acting nifedipine or fosinopril, renal survival over three years of follow-up was significantly worse in the CCBs than in the ACEIs group30. This went together with a 57% mean decrease in proteinuria in the fosinopril group and a 7% mean increase in the group receiving nifedipine. During follow-up, however, the patients receiving ACEIs showed systolic blood pressure values 4 to 6 mm Hg lower than those receiving the CCBs, possibly contributing to the different outcome in the arm receiving the ACEIs. By logistic regression analysis, the positive effect of fosinopril remained when the data were adjusted for blood pressure levels. As Marin et al correctly pointed out, no clear difference between the two treatments was observed during the first year of follow-up, probably because fosinopril, like every ACEI, induces an initial functional fall in GFR30. Thus, this finding stresses the importance of an adequate follow-up period in studies aimed at testing the renoprotective effect of antihypertensive drugs.
The different renal outcomes and proteinuric effects of dh-CCBs and ndh-CCBs may be related to the fact that they do not inhibit the same calcium channel. The cell distribution of a given calcium channel may vary depending on the type of the inhibited channel31. Indeed, it has been reported that the dh L-type CCBs have an adverse impact on glomerulosclerosis in the remnant kidney model despite significant blood pressure reduction32. Conversely, mibefradil, a CCB with significant antiproliferative activity and a tenfold greater selectivity for T- compared with L-type channels, provides renoprotection in several animal models33,34. However, the same agent failed to significantly reduce glomerular sclerosis despite significant reduction in blood pressure in the rat remnant kidney model35. The reasons for the differences between studies are not readily apparent. However, it is possible that the models differ in their susceptibility to hypertensive renal damage and such differences manifest themselves either as differences in the blood pressure threshold at which renal damage develop, and/or differences in the relationship between systemic blood pressure load and renal microvascular injury.
Indeed, another possible explanation of the different action of CCBs is to be sought in renal autoregulation. All CCBs cause vasodilation of the afferent arteriole, thus allowing the linear transmission of systemic hypertension into the glomerular capillaries and leading to hyperfiltration. However, ndh-CCBs and some dh-CCBs also vasodilate the efferent arteriole and only partially affect renal autoregulation36,37. Interestingly, even if amlodipine, a dh-CCB, has not been shown to vasodilate the efferent arteriole, it was more effective than enalapril in reducing proteinuria and glomerulosclerosis in advanced stages of renal injury in a rat hyperfiltration model36, thus suggesting that its renoprotective action does not involve a reduction in glomerular capillary pressure. However, the same agent was found to be ineffective in other animal models33,35.
The results of clinical studies about the effects of amlodipine on proteinuria and renal function are conflicting as well. The Irbesartan Diabetic Nephropathy Trial (IDNT) investigated the effects of irbesartan (300 mg daily), amlodipine (10 mg/daily), or placebo in 1715 hypertensive patients with nephropathy due to type 2 diabetes for a mean follow up of 2.6 years38. Treatment with irbesartan was associated with a relative risk of the primary composite end-point (the doubling of baseline serum creatinine, ESRD, or death for any cause) that was 20% lower than that in the placebo group (P = 0.02). Patients in the amlodipine group had a similar relative risk of reaching the primary composite end-point than those of the control group. It is worth noting that even if these data indicate that amlodipine has no additional renoprotective effect compared with conventional antihypertensive treatment, they also indicate that this agent can be safely used in CKD patients to achieve blood pressure control because it does not cause a worsening in renal function.
Conversely, the results of an interim analysis of the African American Study of Kidney Disease and Hypertension (AASK) study, a randomized, double-blind trial of 1094 African Americans with hypertensive renal disease, are not of univocal interpretation39. In this study, patients were randomly assigned to receive amlodipine (5 to 10 mg/day; N = 217), ramipril (2.5 to 10 mg/day; N = 436) or metoprolol (50 to 200 mg/day; N = 441) in a 3 
2 factorial design, with other antihypertensive agents added to achieve one of two blood pressure goals. The data and safety monitoring board decided to prematurely terminate the amlodipine arm after the detection of worse outcomes in patients receiving amlodipine than those in the other two arms. However, the effects of amlodipine on renal function differed according to baseline proteinuria. In patients with an urinary protein to creatinine ratio openface>0.22 (corresponding approximately to a proteinuria openface>300 mg/day), the ramipril group had a 48% reduced risk of the clinical end-points (reduction in GFR of more than 50%, ESRD, or death) and a significantly slower mean decline in GFR in comparison with the amlodipine group. In patients without significant baseline proteinuria, protein excretion acutely increased during the first six months of therapy with amlodipine and to a lower extent during the following months. It is worth noting that proteinuria also increased slightly in patients of this subgroup who were treated with ramipril. However, in patients treated with amlodipine, GFR increased and, despite a gradual GFR decline, which occurred after the sixth month of treatment, at three years it remained above baseline values and slightly higher than in the ramipril group. A similar trend in GFR was observed also in the subgroup of patients with mean baseline GFR 40 mL/min. The rate of GFR decline during the chronic phase was slightly steeper in the amlodipine than in the ramipril group; thus, it remains unknown whether a longer follow-up could have changed the results of this analysis. Indeed, a secondary analysis of the Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency (AIPRI) study suggested that slowly progressive patients (as was the case of this subgroup without proteinuria) probably need a longer time before recognizing the beneficial effect of ACEIs on the rate of decline in GFR40. In this study, the rate of progression was initially faster in the benazepril group, but subsequently it became slower than in the placebo group; the time at which the serum creatinine profiles in the benazepril and placebo groups crossed was earlier in relation to the extent of the two-phase effect of the drug and rapidity of the progression of the underlying renal disease40.
When the entire cohort of the AASK study was considered, no significant difference in mean GFR decline from baseline to three years was observed between the two treatment groups39.
One possible explanation of these conflicting results could be that, since the majority of CCBs allows the linear transmission of systemic hypertension into the glomerular capillaries, the maximal renoprotective benefits of CCBs may require strict blood pressure control, and the reports of their lack of efficacy may be partially due to inadequate control. An artifact also may be introduced when short-acting CCBs are used, because these may intermittently leave renal vessels unprotected against high systemic blood pressure, particularly when preglomerular vessels are still vasodilated as a result of the drugs' preferential action on the afferent arteriole.
COMBINATION TREATMENT WITH ACE-INHIBITORS AND CALCIUM CHANNEL BLOCKERS
Given that ACEIs can decrease intraglomerular pressure whereas the majority of CCBs cannot, and that both drug classes may have important cellular activity through the inhibition of cytokine secretion and action, it has been suggested that their combination could provide greater benefit than that obtained with each of them alone. Furthermore, CCBs seem to have the capability of reducing angiotensin II-induced vasoconstriction of the efferent glomerular arterioles, of reducing angiotensin II-induced glomerular contraction and of interfering with renal vasoconstriction and natriuresis induced by angiotensin II. It appears then that CCBs act like a non-specific postreceptor antagonist of angiotensin II. The combination of ACEIs with CCBs could then, from one side reduce the generation of angiotensin II (ACEI-mediated effect), from the other side interfere with the action of angiotensin II (CCB-mediated effect). Experimental animal studies have shown that the adverse effect of nitrendipine monotherapy on glomerular structure and function may be prevented by the combination of nitrendipine and enalapril when blood pressure is normalized41. In subtotally nephrectomized rats, the combination of ramipril and nifedipine has been found to provide protection against the development of glomerulosclerosis, mesangial proliferation and podocyte enlargement42. However, the more intense blood pressure reduction obtained with the combination of the two drugs partially limit the conclusions that can be drawn from this study.
Brown et al studied the effect of the combination of lisinopril and the benzothiazepine CCB TA-3090 on beagle dogs with alloxan-induced diabetes mellitus43. Although similar blood pressure values were obtained with the single agents alone and the combination, the association of the two drugs had a greater antiproteinuric effect than either of the single agents. Treatment with lisinopril and TA-3090 (alone or in combination) also reduced the extent of glomerular hypertrophy. In stroke-prone rat, the combination of non-hypotensive doses of verapamil and the ACEI trandolapril attenuates the increase in proteinuria and progression to glomerulosclerosis, regardless of the reduction in blood pressure44.
Several early studies suggested that combination treatment with ACEIs and CCBs may be effective also in humans by reducing more effectively albuminuria than the respective monotherapies. However, the results are difficult to interpret because blood pressure was not lowered to the same extent in the three interventions. Consequently, the effect of blood pressure as a confounding factor cannot be ruled out. In any case, in 52 patients with type 2 diabetes and mild renal failure, Bakris et al found that the combination of lisinopril and verapamil exerted an additive antiproteinuric effect and delayed the reduction in GFR in comparison with the two drugs alone, despite no greater reduction in systemic blood pressure23.
The same authors published the results of a randomized open-label study involving 44 patients with type 2 diabetes and evidence of nephropathy who were treated with trandolapril, verapamil or a combination of both drugs45. At similar levels of blood pressure, the reduction in proteinuria from baseline was significantly greater in the patients receiving the combination treatment (-62% 10%) than in those receiving trandolapril alone (-33 8%) or verapamil alone (-27 8%). No significant differences in GFR were noted after one year of follow-up.
The Nephros Study recently suggested that combination treatment also may be a favorable option in patients with non-diabetic renal disease46. One hundred and sixty-five patients were randomly assigned to receive ramipril, felodipine or the combination of both for a mean of nearly two years. After correction for the acute drug effect, the group receiving ramipril plus felodipine had a lower loss of GFR in comparison with the felodipine group, but no significant difference was observed between the ramipril and the combination-therapy group. Furthermore, despite a significant rise in albuminuria after two years in the felodipine group, no significant change was found in the other groups. Another small-size prospective study of 60 patients with CKD found that combination treatment with spirapril and isradipine for 21 months was able to slow down more effectively the rate of GFR decline than the two agents alone (mean decline of GFR of -0.32, -0.58 and -0.14 mL/min month 1.73 m2 in the spirapril, isradipine and combination group, respectively)47. However, this difference was not statistically significant, probably because of large variation in GFR and a too small sample size. Furthermore, a trend toward a better blood pressure control in the combination group was observed, further complicating the interpretations of the results.
Even if these findings do not support that combination treatment is better than ACEI alone, they suggest at least that it is equal. This is very important from the practical point of view, since in patients with CKD the addition of a CCB to an ACEI is often required to achieve adequate blood pressure control. From this point of view, it also should be considered that ACEIs and CCBs do not interfere with each other's antihypertensive action and mutually reduce the frequency of their side effects to some extent.
Altogether these findings provide preliminary evidence that combination therapy may have additive (or even synergistic) effects on proteinuria reduction in patients with diabetic non-diabetic nephropathies, but deserve further confirmation in larger studies.
CONCLUSIONS
Angiotensin converting enzyme inhibitors are certainly effective in reducing proteinuria and preventing the progression of renal damage in type 1 diabetic nephropathy and in non-diabetic nephropathies, while it is still to be proved if they are superior to ATIIRAs in the setting of type 2 diabetic nephropathy. Even if it is still unclear whether this is also true at the currently recommended target blood pressure of 125/75 mm Hg, ACEIs, probably together with ATIIRAs, should be considered as first line treatment for patients with CKD.
The renoprotective effect of ndh-CCBs and of some new long-acting dh-CCBs seems to be of lower extent than that observed by blocking the renin-angiotensin system. This is particularly true in the presence of clinically significant proteinuria. However, these agents are well tolerated in everyday clinical practice and provide valid reduction in blood pressure values. Thus, they probably should be considered as second-line antihypertensive treatment in patients with CKD.
The possibility that combination treatments with ACEIs and CCBs may have additive or even synergistic renoprotective effects other than blood pressure control is extremely fascinating, but at present the available data are insufficient to confirm this hypothesis.
In any case, we have to lower blood pressure to levels recommended by current guidelines, and perhaps further, and CCBs are indispensable tools to achieve these stricter targets. This probably reduces the relevance of the debate about the importance of exactly quantify the magnitude of the effect of combination therapy with ACEIs and CCBs.
Finally, we need not forget that CCBs, together with ACEis and ATIIRAs, are useful agents to prevent cardiovascular disease and mortality, as recently underlined by a meta-analysis of very large clinical trials11.
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