There is a general sense that most outcomes trials in patients receiving dialysis failed to yield statistically significant benefits, in contrast to many cardiovascular (CV) trials in the general population. It is unknown whether methodologic reasons caused this discrepancy. We performed a systematic MEDLINE search for randomized trials with mortality end points of the 42 compounds most commonly used for CV indications. In total, 115 trials were selected for review. We further reviewed 9 mortality end point trials in patients receiving dialysis. The CV trials in populations not receiving dialysis enrolled from 66 to 33,357 participants with an average of 4,910; 59% of the trials showed statistically significant results. The average hazard ratio (HR) was 0.77, ranging from 0.10 to 1.65; 10 drugs had ≥5 published trials each. In the population receiving dialysis, most drugs were studied in single trials; the average number of patients was 1,500 with a range of 127 to 3,883. The average HR was 0.77 and ranged from 0.06 to 1.30. Only 22% of the trials showed statistically significant results. The limitations listed in the general population and dialysis studies were similar. In conclusion, no apparent methodologic issues were detected (other than sample size) that could justify the lower frequency of randomized trials with statistically significant results in patients receiving dialysis. The most obvious difference was the paucity of trials with each drug in the dialysis cohorts; this lowers the chances of at least 1 trial being successful.
The previous reports in cardiovascular (CV) medicine are replete with results from randomized clinical trials (RCTs) that have assessed the effects of various pharmacologic interventions on hard clinical end points including death. In contrast, the nephrology reports contain relatively few RCTs that have examined clinical outcomes in patients with end-stage renal disease (ESRD) on dialysis. The disparity is particularly noteworthy because patients undergoing dialysis are recognized widely to have very high morbidity and mortality rates primarily from CV causes. Most RCTs completed to date in the dialysis population have had mortality as an end point, whereas other CV end points have been evaluated less often. Nearly all studies in patients with ESRD have been substantially smaller than those done in the general population, and the observed effect size has been relatively smaller. Few of the RCTs reported thus far in subjects with ESRD have demonstrated differences between treatment groups that were statistically significant. Whether such findings are attributable to the nature of the underlying disease processes that affect this very high-risk population, to certain aspects of research design and/or statistical analysis, to the duration of the interventions being evaluated, and/or to the length of follow-up or a combination of these factors, is uncertain. We reviewed and evaluated findings from a large number of CV mortality RCTs conducted in the general population and in subjects with ESRD. We sought to determine whether there were common patterns that could help explain the failure to document statistically meaningful differences between treatment groups in RCTs that enrolled subjects with ESRD and RCTs that enrolled patients from the general population.
Methods
We initially examined the list of the most frequently prescribed medications in the United States as reported in terms of total number of prescriptions by IMS from the National Prescription Audit of 2013. We selected all CV medications from that list. We further expanded the list to include the most frequently used CV medications based on the Web site of the American Heart Association. This expanded list was reviewed by an academic physician (PR) with expertise in clinical trials to include drugs used for the most frequently encountered CV conditions. The final list of drugs thus contained 42 CV treatments addressing outcomes in the general population ( Appendix A ). For comparison, two nephrologists (KK-Z, WGG) identified 9 drugs that are most frequently used in ESRD that have been tested in randomized trials ( Appendix B ). This approach was possible because of the limited number of ESRD-specific drugs and trials. For the treatments identified in the previously mentioned process, we searched medical databases for outcomes trials with mortality as a primary or co-primary end point. Specifically, we completed a MEDLINE search using the name of each compound together with the publication type “randomized controlled trial” and the MeSH term “cardiovascular diseases/mortality.” We also searched product inserts and clinicaltrials.gov to capture trials that might have been missed in the MEDLINE search.
The PubMed/MEDLINE search on the 42 selected drugs for the general population resulted in 1,083 references based on our search design. On screening the abstracts, we selected 349 articles and abstracted 224 articles reporting on 198 trials. There were more articles than trials because some articles reported different analyses from the same trial. Because our analyses focused on long-term indications, we excluded 83 trials conducted in the perioperative period and as short-term treatment (i.e., <30 days follow-up), bringing the total number of trials in the general population to 115. Our search for outcomes studies in ESRD resulted in 9 trials. Overall, we summarized data from 124 trials published before May 2014: 115 long-term CV trials in the general population and 9 trials in patients with ESRD ( Supplementary Tables 1 and 2 ). We compiled tables containing information about the number, duration, the size of the trials, the rate of primary events, effect size, and precision. A p value <0.05 was considered statistically significant. The limitations of each study as described in the original reports were also noted.
Results
The 115 RCTs in the general population encompassed the use of 30 therapies (i.e., no mortality trials were found for the remaining 12 therapies from the search list). Among the 30 therapies for which we found mortality trials, 10 drugs were evaluated in 5 or more outcomes trials. The number of study participants ranged from 66 to 33,357 with an average of 4,910. A statistically significant result was observed in 59%, with an average hazard ratio (HR) of 0.77, ranging from 0.10 to 1.65. Table 1 provides the duration and size of the largest trials we reviewed for each compound in the general population.
| Trial Name (ref number) | Arms | Primary endpoint | N subjects | Event rate per 1000 year | HR or RR | p-value |
|---|---|---|---|---|---|---|
| ALLHAT | amlodipine vs chlorthalidone | fatal CHD or MI | 33357 | 13.2 | 0.98 | 0.65 |
| Physicians’ Health Study | aspirin vs placebo | MI | 22071 | 3.4 | 0.56 | <0.00001 |
| Dutch TIA Trial | atenolol vs placebo | death from vascular causes, stroke, or MI | 1473 | 52.2 | 1 | n.s. |
| ASCOT-LLA | atorvastatin vs placebo | MI or fatal CHD | 10305 | 7.7 | 0.64 | 0.0005 |
| CIBIS-II | bisoprolol vs placebo | mortality | 2647 | 111.6 | 0.66 | <0.0001 |
| CAPPP | captopril vs conventional Hx treatment | MI, stroke, or cardiovascular death | 10985 | 10.9 | 1.05 | 0.52 |
| COMET | carvedilol vs metoprolol | mortality | 3029 | 76.0 | 0.83 | 0.002 |
| SHEP | chlorthalidone vs placebo | stroke | 4736 | 12.3 | 0.64 | 0.0003 |
| CAPRIE | clopidogrel vs aspirin | ischaemic stroke, MI, or vascular death | 19185 | 53.4 | 0.913 | 0.043 |
| DIG | digoxin vs placebo | mortality | 7788 | 35.8 | 0.66 | 0.001 |
| NORDIL | diltiazem vs diuretics + beta-blockers | stroke, MI, or CV death | 10881 | 16.4 | 1 | 0.97 |
| CONSENSUS II | enalapril vs placebo | mortality | 6090 | 247.2 | 1.1 | 0.26 |
| EPHESUS | eplerenone vs placebo | mortality | 6632 | 116.7 | 0.85 | 0.008 |
| Helsinki Heart Study | gemfibrozil vs placebo | MI or cardiac death | 4081 | 6.9 | 0.66 | <0.02 |
| VA Cooperative Study | hydralazine + isosorbide dinitrate vs placebo | mortality | 642 | 191.7 | 0.879545 | 0.093 |
| EWPHE | hydrochlorothiazide + triamterene vs placebo | mortality | 840 | 72.6 | 0.91 | 0.41 |
| ACTIVE I | irbesartan + placebo | stroke, MI, or vascular death | 9016 | 52.1 | 0.99 | 0.85 |
| ALLHAT | lisinopril vs chlorthalidone | fatal CHD, MI | 33357 | 13.2 | 0.99 | 0.81 |
| MERIT-HF | metoprolol vs placebo | mortality | 3991 | 91.0 | 0.66 | 0.0062 |
| Coronary Drug Project | niacin vs placebo | mortality | 3908 | 30.1 | 0.89 | 0.0004 |
| TRITON-TIMI 38 | prasugrel vs clopidogrel | CV death, MI, or stroke | 13608 | 86.6 | 0.81 | <0.001 |
| PPP Project | pravastatin vs placebo | stroke | 19768 | 5.8 | 0.8 | 0.01 |
| QUIET | quinapril vs placebo | cardiac death or arrest, MI, o.a. | 1750 | 176.1 | 1.04 | 0.6 |
| HOPE | ramipril vs placebo | MI, stroke, or CV death | 9297 | 31.8 | 0.78 | <0.001 |
| JUPITER | Rosuvastatin vs placebo | MI, stroke, revasc., angina, or CV death | 17802 | 10.7 | 0.56 | < 0.00001 |
| MRC/BHF HPS | simvastatin vs placebo | mortality | 20536 | 27.6 | 0.87 | 0.0003 |
| RAES | spironolactone vs placebo | mortality | 1663 | 201.4 | 0.7 | <0.001 |
| PLATO | ticagrelor vs clopidogrel | vascular death, MI, or stroke | 18624 | 100.8 | 0.84 | <0.001 |
| NAVIGATOR | valsartan vs placebo | development of diabetes | 9306 | 22.6 | 0.96 | 0.22 |
| TPT | warfarin vs placebo | coronary death, MI | 5499 | 14.0 | 0.79 | 0.02 |
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