Week 50 – VERT

“Effects of Risedronate Treatment on Vertebral and Nonvertebral Fractures in Women With Postmenopausal Osteoporosis”

by the Vertebral Efficacy with Risedronate Therapy (VERT) Study Group

JAMA. 1999 Oct 13;282(14):1344-52. [free full text]

Bisphosphonates are a highly effective and relatively safe class of medications for the prevention of fractures in patients with osteoporosis. The VERT trial published in 1999 was a landmark trial that demonstrated this protective effect with the daily oral bisphosphonate risedronate.

The trial enrolled post-menopausal women with either 2 or more vertebral fractures per radiography or 1 vertebral fracture with decreased lumbar spine bone mineral density. Patients were randomized to the treatment arm (risedronate 2.5mg PO daily or risedronate 5mg PO daily) to the daily PO placebo control arm. Measured outcomes included: 1) the prevalence of new vertebral fracture at 3 years follow-up, per annual imaging, 2) the prevalence of new non-vertebral fracture at 3 years follow-up, per annual imaging, and 3) change in bone mineral density, per DEXA q6 months.

2458 patients were randomized. During the course of the study, “data from other trials indicated that the 2.5mg risedronate dose was less effective than the 5mg dose,” and thus the authors discontinued further data collection on the 2.5mg treatment arm at 1 year into the study. All treatment groups had similar baseline characteristics. 55% of the placebo group and 60% of the 5mg risedronate group completed 3 years of treatment. The prevalence of new vertebral fracture within 3 years was 11.3% in the risedronate group and 16.3% in the placebo group (RR 0.59, 95% CI 0.43-0.82, p = 0.003; NNT = 20). The prevalence of new non-vertebral fractures at 3 years was 5.2% in the treatment arm and 8.4% in the placebo arm (RR 0.6, 95% CI 0.39-0.94, p = 0.02; NNT = 31). Regarding bone mineral density (BMD), see Figure 4 for a visual depiction of the changes in BMD by treatment group at the various 6-month timepoints. Notably, change from baseline BMD of the lumbar spine and femoral neck was significantly higher (and positive) in the risedronate 5mg group at all follow-up timepoints relative to the placebo group and at all timepoints except 6 months for the femoral trochanter measurements. Regarding adverse events, there was no difference in the incidence of upper GI adverse events among the two groups. GI complaints “were the most common adverse events associated with study discontinuance,” and GI events lead to 42% of placebo withdrawals but only 36% of the 5mg risedronate withdrawals.

Oral risedronate reduces the risk of vertebral and non-vertebral fractures in patients with osteoporosis while increasing bone mineral density. Overall, this was a large, well-designed RCT that demonstrated a concrete treatment benefit. As a result, oral bisphosphonate therapy has become the standard of care both for treatment and prevention of osteoporosis. This study, as well as others, demonstrated that such therapies are well-tolerated with relatively few side effects. A notable strength of this study is that it did not exclude patients with GI comorbidities.  One weakness is the modification of the trial protocol to eliminate the risedronate 2.5mg treatment arm after 1 year of study. Although this arm demonstrated a reduction in vertebral fracture at 1 year relative to placebo (p = 0.02), its elimination raises suspicion that the pre-specified analyses were not yielding the anticipated results during the interim analysis and thus the less-impressive treatment arm was discarded.

Further Reading/References:
1. Weekly alendronate vs. weekly risedronate [https://www.ncbi.nlm.nih.gov/pubmed/15619680]
2. Comparative effectiveness of pharmacologic treatments to prevent fractures: an updated systematic review (2014) [https://www.ncbi.nlm.nih.gov/pubmed/25199883]

Summary by Duncan F. Moore, MD

Image Credit: Nick Smith, CC BY-SA 3.0, via Wikimedia Commons

Week 48 – SYMPLICITY HTN-3

“A Controlled Trial of Renal Denervation for Resistant Hypertension”

N Engl J Med. 2014 Apr 10;370(15):1393-401 [free full text]

Approximately 10% of patients with hypertension have resistant hypertension (SBP > 140 despite adherence to three maximally tolerated doses of antihypertensives, including a diuretic). Evidence suggests that the sympathetic nervous system plays a large role in such cases, so catheter-based radiofrequency ablation of the renal arteries (renal denervation therapy) was developed as a potential treatment for resistant HTN. The 2010 SYMPLICITY HTN-2 trial was a small (n=106), non-blinded, randomized trial of renal denervation vs. continued care with oral antihypertensives that demonstrated a remarkable 30-mmHg greater decrease in SBP with renal denervation. Thus the 2014 SYMPLICITY HTN-3 trial was designed to evaluate the efficacy of renal denervation in a single-blinded trial with a sham-procedure control group.

The trial enrolled adults with resistant HTN with SBP ≥ 160 despite adherence to 3+ maximized antihypertensive drug classes, including a diuretic. (Pertinent exclusion criteria included secondary hypertension, renal artery stenosis > 50%, prior renal artery intervention.) Patients were randomized to either renal denervation with the Symplicity (Medtronic) radioablation catheter or to renal angiography only (sham procedure). The primary outcome was the mean change in office systolic BP from baseline at 6 months. (The examiner was blinded to intervention.) The secondary outcome was the change in mean 24-hour ambulatory SBP at 6 months. The primary safety endpoint was a composite of death, ESRD, embolic event with end-organ damage, renal artery or other vascular complication, hypertensive crisis within 30 days, or new renal artery stenosis of > 70%.

535 patients were randomized. On average, patients were receiving five antihypertensive medications. There was no significant difference in reduction of SBP between the two groups at 6 months. ∆SBP was -14.13 ± 23.93 mmHg in the denervation group vs. -11.74 ± 25.94 mmHg in the sham-procedure group for a between-group difference of -2.39 mmHg (95% CI -6.89 to 2.12, p = 0.26 with a superiority margin of 5 mmHg). The change in 24-hour ambulatory SBP at 6 months was -6.75 ± 15.11 mmHg in the denervation group vs. -4.79 ± 17.25 mmHg in the sham-procedure group for a between-group difference of -1.96 mmHg (95% CI -4.97 to 1.06, p = 0.98 with a superiority margin of 2 mmHg). There was no significant difference in the prevalence of the composite safety endpoint at 6 months with 4.0% of the denervation group and 5.8% of the sham-procedure group reaching the endpoint (percentage-point difference of -1.9, 95% CI -6.0 to 2.2).

In patients with resistant hypertension, renal denervation therapy provided no reduction in SBP at 6-month follow-up relative to a sham procedure.

This trial was an astounding failure for Medtronic and its Symplicity renal denervation radioablation catheter. The magnitude of the difference in results between the non-blinded, no-sham-procedure SYMPLICITY HTN-2 trial and this patient-blinded, sham-procedure-controlled trial is likely a product of 1) a marked placebo effect of procedural intervention, 2) Hawthorne effect in the non-blinded trial, and 3) regression toward the mean (patients were enrolled based on unusually high BP readings that over the course of the trial declined to reflect a lower true baseline).

Currently, there is no role for renal denervation therapy in the treatment of HTN (resistant or otherwise). However, despite the results of SYMPLICITY HTN-3, other companies and research groups are assessing the role of different radioablation catheters in patients with low-risk essential HTN and with resistant HTN. (For example, see https://www.ncbi.nlm.nih.gov/pubmed/29224639.)

Further Reading/References:
1. NephJC, SYMPLICITY HTN-3
2. UpToDate, “Treatment of resistant hypertension,” heading “Renal nerve denervation”

Summary by Duncan F. Moore, MD

Week 45 – COURAGE

“Optimal Medical Therapy with or without PCI for Stable Coronary Disease”

by the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) Trial Research Group

N Engl J Med. 2007 Apr 12;356(15):1503-16 [free full text]

The optimal medical management of stable coronary artery disease has been well-described. However, prior to the 2007 COURAGE trial, the role of percutaneous coronary intervention (PCI) in the initial management of stable coronary artery disease was unclear. It was known that PCI improved angina symptoms and short-term exercise performance in stable disease, but its mortality benefit and reduction of future myocardial infarction and ACS were unknown.

The trial recruited patients with stable coronary artery disease. (See paper for inclusion/exclusion criteria. Disease had to be sufficiently and objectively severe, but not too severe, and symptoms could not be sustained at the highest CCS grade.) Patients were randomized to either optimal medical management (including antiplatelet, anti-anginal, ACEi/ARB, and cholesterol-lowering therapy) and PCI or to optimal medical management alone. The primary outcome was a composite of all-cause mortality and non-fatal MI.

2287 patients were randomized. Both groups had similar baseline characteristics with the exception of a higher prevalence of proximal LAD disease in the medical-therapy group. Median duration of follow-up was 4.6 years in both groups. Death or non-fatal MI occurred in 18.4% of the PCI group and in 17.8% of the medical-therapy group (p = 0.62). Death, non-fatal MI, or stroke occurred in 20.0% of the PCI group and 19.5% of the medical-therapy group (p = 0.62). Hospitalization for ACS occurred in 12.4% of the PCI group and 11.8% of the medical-therapy group (p = 0.56). Revascularization during follow-up was performed in 21.1% of the PCI group but in 32.6% of the medical-therapy group (HR 0.60, 95% CI 0.51–0.71, p < 0.001). Finally, 66% of PCI patients were free of angina at 1-year follow-up compared with 58% of medical-therapy patients (p < 0.001). Rates were 72% and 67% at 3 years (p = 0.02) and 72% and 74% at five years (not significant).

Thus, in the initial management of stable coronary artery disease, PCI in addition to optimal medical management provided no mortality benefit over optimal medical management alone. However, initial management with PCI did provide a time-limited improvement in angina symptoms.

As the authors of COURAGE nicely summarize on page 1512, the atherosclerotic plaques of ACS and stable CAD are different. Vulnerable, ACS-prone plaques have thin caps and spread outward along the wall of the coronary artery, as opposed to stable CAD plaques, which have thick fibrous caps and are associated with inward-directed remodeling that narrows the artery lumen (and cause reliable angina symptoms and luminal narrowing on coronary angiography).

Notable limitations of this study:

      • Generalizability was limited due to the population, which was largely male, white, and 42% came from VA hospitals.
      • Drug-eluting stents were not clinically available until the last 6 months of the study, so most stents placed were bare metal.

Later meta-analyses were weakly suggestive of an association of PCI with improved all-cause mortality. It is thought that there may be a subset of patients with stable CAD who achieve a mortality benefit from PCI.

The 2017 ORBITA trial made headlines and caused sustained controversy when it demonstrated in a randomized trial that, in the context of optimal medical therapy, PCI did not increase exercise time more than did a sham PCI. Take note of the relatively savage author’s reply to commentary regarding the trial. See blog discussion here. The ORBITA-2 trial is currently underway.

The ongoing ISCHEMIA trial is both eagerly awaited and involved in a degree of controversy after a recent change in endpoints.

It is important to note that all of the above discussions assume that the patient does not have specific coronary artery anatomy (e.g. left main disease, multi-vessel disease with decreased LVEF) in which initial CABG would provide a mortality benefit. Finally, PCI should be considered in patients whose physical activity is limited by angina symptoms despite optimal medical therapy.

Further Reading:
1. COURAGE @ Wiki Journal Club
2. COURAGE @ 2 Minute Medicine
3. Canadian Cardiovascular Society grading of angina pectoris
4. ORBITA-2 @ ClinicalTrials.gov
5. ISCHEMIA @ ClinicalTrials.gov
6. Discussion re: ISCHEMIA trial changes @ CardioBrief

Summary by Duncan F. Moore, MD

Image Credit: National Institutes of Health, US Public Domain, via Wikimedia Commons

Week 44 – National Lung Screening Trial (NLST)

“Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening”

by the National Lung Cancer Screening Trial (NLST) Research Team

N Engl J Med. 2011 Aug 4;365(5):395-409 [free full text]

Despite a reduction in smoking rates in the United States, lung cancer remains the number one cause of cancer death in the United States as well as worldwide. Earlier studies of plain chest radiography for lung cancer screening demonstrated no benefit, and in 2002 the National Lung Screening Trial (NLST) was undertaken to determine whether then recent advances in CT technology could lead to an effective lung cancer screening method.

The study enrolled adults age 55-74 with 30+ pack-years of smoking (if former smokers, they must have quit within the past 15 years). Patients were randomized to either the intervention of three annual screenings for lung cancer with low-dose CT or to the comparator/control group to receive three annual screenings for lung cancer with PA chest radiograph. The primary outcome was mortality from lung cancer. Notable secondary outcomes were all-cause mortality and the incidence of lung cancer.

53,454 patients were randomized, and both groups had similar baseline characteristics. The low-dose CT group sustained 247 deaths from lung cancer per 100,000 person-years, whereas the radiography group sustained 309 deaths per 100,000 person-years. A relative reduction in rate of death by 20.0% was seen in the CT group (95% CI 6.8 – 26.7%, p = 0.004). The number needed to screen with CT to prevent one lung cancer death was 320. There were 1877 deaths from any cause in the CT group and 2000 deaths in the radiography group, so CT screening demonstrated a risk reduction of death from any cause of 6.7% (95% CI 1.2% – 13.6%, p = 0.02). Incidence of lung cancer in the CT group was 645 per 100,000 person-years and 941 per 100,000 person-years in the radiography group (RR 1.13, 95% CI 1.03 – 1.23).

Lung cancer screening with low-dose CT scan in high-risk patients provides a significant mortality benefit. This trial was stopped early because the mortality benefit was so high. The benefit was driven by the reduction in deaths attributed to lung cancer, and when deaths from lung cancer were excluded from the overall mortality analysis, there was no significant difference among the two arms. Largely on the basis of this study, the 2013 USPSTF guidelines for lung cancer screening recommend annual low-dose CT scan in patients who meet NLST inclusion criteria. However, it must be noted that, even in the “ideal” circumstances of this trial performed at experienced centers, 96% of abnormal CT screening results in this trial were actually false positives. Of all positive results, 11% led to invasive studies.

Per UpToDate, since NSLT, there have been several European low-dose CT screening trials published. However, all but one (NELSON) appear to be underpowered to demonstrate a possible mortality reduction. Meta-analysis of all such RCTs could allow for further refinement in risk stratification, frequency of screening, and management of positive screening findings.

No randomized trial has ever demonstrated a mortality benefit of plain chest radiography for lung cancer screening. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial tested this modality vs. “community care,” and because the PLCO trial was ongoing at the time of creation of the NSLT, the NSLT authors trial decided to compare their intervention (CT) to plain chest radiography in case the results of plain chest radiography in PLCO were positive. Ultimately, they were not.

Further Reading:
1. USPSTF Guidelines for Lung Cancer Screening (2013)
2. NLST @ ClinicalTrials.gov
3. NLST @ Wiki Journal Club
4. NLST @ 2 Minute Medicine
5. UpToDate, “Screening for lung cancer”

Summary by Duncan F. Moore, MD

Image Credit: Yale Rosen, CC BY-SA 2.0, via Wikimedia Commons

Week 42 – BeSt

“Clinical and Radiographic Outcomes of Four Different Treatment Strategies in Patients with Early Rheumatoid Arthritis (the BeSt Study).”

Arthritis & Rheumatism. 2005 Nov;52(11):3381-3390. [free full text]

Rheumatoid arthritis (RA) is among the most prevalent of the rheumatic diseases with a lifetime prevalence of 3.6% in women and 1.7% in men [1]. It is a chronic, systemic, inflammatory autoimmune disease of variable clinical course that can severely impact physical functional status and even mortality. Over the past 30 years, as the armamentarium of therapies for RA has exploded, there has been increased debate about the ideal initial therapy. The BeSt (Dutch: Behandel-Strategieën “treatment strategies”) trial was designed to compare, according to the authors, four of “the most frequently used and discussed strategies.” Regimens incorporating traditional disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, and newer therapies, such as TNF-alpha inhibitors, were compared directly.

The trial enrolled 508 DMARD-naïve patients with early rheumatoid arthritis. Pertinent exclusion criteria included history of cancer and pre-existing laboratory abnormalities or comorbidities (e.g. elevated creatinine or ALT, alcohol abuse, pregnancy or desire to conceive, etc.) that would preclude the use of various DMARDs. Patients were randomized to one of four treatment groups. Within each regimen, the Disease Activity Score in 44 joints (DAS-44) was assessed q3 months, and, if > 2.4, the medication regimen was uptitrated to the next step within the treatment group.

Four Treatment Groups

  1. Sequential monotherapy: methotrexate (MTX) 15mg/week, uptitrated PRN to 25-30mg/week. If insufficient control, the following sequence was pursued: sulfasalazine (SSZ) monotherapy, leflunomide monotherapy, MTX + infliximab, gold with methylprednisolone, MTX + cyclosporin A (CSA) + prednisone
  2. Step-up combination therapy: MTX 15mg/week, uptitrated PRN to 25-30mg/week. If insufficient control, SSZ was added, followed by hydroxychloroquine (HCQ), followed by prednisone. If patients failed to respond to those four drugs, they were switched to MTX + infliximab, then MTX + CSA + prednisone, and finally to leflunomide.
  3. Initial combination therapy with tapered high-dose prednisone: MTX 7.5 mg/week + SSZ 2000 mg/day + prednisone 60mg/day (tapered in 7 weeks to 7.5 mg/day). If insufficient control, MTX was uptitrated to 25-30 mg/week. Next, combination would be switched to MTX + CSA + prednisone, then MTX + infliximab, then leflunomide monotherapy, gold with methylprednisolone, and finally azathioprine with prednisone.
  4. Initial combination therapy with infliximab: MTX 25-30 mg/week + infliximab 3 mg/kg at weeks 0, 2, 6, and q8 weeks thereafter. There was a protocol for infliximab-dose uptitration starting at 3 months. If insufficient control on MTX and infliximab 10 mg/kg, patients were switched to SSZ, then leflunomide, then MTX + CSA + prednisone, then gold + methylprednisolone, and finally AZA with prednisone.

Once clinical response was adequate for at least 6 months, there was a protocol for tapering the drug regimen.

The primary endpoints were: 1) functional ability per the Dutch version of the Health Assessment Questionnaire (D-HAQ), collected by a blinded research nurse q3 months and 2) radiographic joint damage per the modified Sharp/Van der Heijde score (SHS). Pertinent secondary outcomes included DAS-44 score and laboratory evidence of treatment toxicity.

At randomization, enrolled RA patients had a median duration of symptoms of 23 weeks and median duration since diagnosis of RA of 2 weeks. Mean DAS-44 was 4.4 ± 0.9. 72% of patients had erosive disease. Mean D-HAQ score at 3 months was 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 (p < 0.001 for groups 1 and 2 vs. groups 3 and 4; paired tests otherwise insignificant). Mean D-HAQ at 1 year was 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 (p = 0.010 for group 1 vs. group 3, p = 0.003 for group 1 vs. group 4; paired tests otherwise insignificant). At 1 year, patients in group 3 or 4 had less radiographic progression in joint damage per SHS than patients in group 1 or 2. Median increases in SHS were 2.0, 2.5., 1.0, and 0.5 in groups 1-4, respectively (p = 0.003 for group 1 vs. group 3, p < 0.001 for group 1 versus group 4, p = 0.007 for group 2 vs. group 3, p < 0.001 for group 2 vs. group 4). Regarding DAS-44 score: low disease activity (DAS-44 ≤ 2.4) at 1 year was reached in 53%, 64%, 71%, 74% of groups 1-4, respectively (p = 0.004 for group 1 vs. group 3, p = 0.001 for group 1 vs. group 4, p not significant for other comparisons). There were no group differences in prevalence of adverse effects.

Overall, among patients with early RA, initial combination therapy that included either prednisone (group 3) or infliximab (group 4) resulted in better functional and radiographic improvement than did initial therapy with sequential monotherapy (group 1) or step-up combination therapy (group 2). In the discussion, the authors note that given the treatment group differences in radiographic progression of disease, “starting therapy with a single DMARD would be a missed opportunity in a considerable number of patients.” Contemporary commentary by Weisman notes that “the authors describe both an argument and a counterargument arising from their observations: aggressive treatment with combinations of expensive drugs would ‘overtreat’ a large proportion of patients, yet early suppression of disease activity may have an important influence on subsequent long‐term disability and damage.”

Fourteen years later, it is a bit difficult to place the specific results of this trial in our current practice. Its trial design is absolutely byzantine and compares the 1-year experience of a variety of complex protocols that theoretically have substantial eventual potential overlap. Furthermore, it is difficult to assess if the relatively small group differences in symptom (D-HAQ) and radiographic (SHS) scales were truly clinically significant even if they were statistically significant. The American College of Rheumatology 2015 Guideline for the Treatment of Rheumatoid Arthritis synthesized the immense body of literature that came before and after the BeSt study and ultimately gave a variety of conditional statements about the “best practice” treatment of symptomatic early RA. (See Table 2 on page 8.) The recommendations emphasized DMARD monotherapy as the initial strategy but in the specific setting of a treat-to-target strategy. They also recommended escalation to combination DMARDs or biologics in patients with moderate or high disease activity despite DMARD monotherapy.

References / Additional Reading:
1. “The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases.” Arthritis Rheum. 2011 Mar;63(3):633-9. [https://www.ncbi.nlm.nih.gov/pubmed/21360492]
2. BeSt @ Wiki Journal Club
3. “Progress toward the cure of rheumatoid arthritis? The BeSt study.” Arthritis Rheum. 2005 Nov;52(11):3326-32.
4. “Review: treat to target in rheumatoid arthritis: fact, fiction, or hypothesis?” Arthritis Rheumatol. 2014 Apr;66(4):775-82. [https://www.ncbi.nlm.nih.gov/pubmed/24757129]
5. “2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis” Arthritis Rheumatol. 2016 Jan;68(1):1-26
6. RheumDAS calculator

Summary by Duncan F. Moore, MD

Image Credit: Braegel, CC BY 3.0, via Wikimedia Commons

Week 37 – LOTT

“A Randomized Trial of Long-Term Oxygen for COPD with Moderate Desaturation”

by the Long-Term Oxygen Treatment Trial (LOTT) Research Group

N Engl J Med. 2016 Oct 27;375(17):1617-1627. [free full text]

The long-term treatment of severe resting hypoxemia (SpO2 < 89%) in COPD with supplemental oxygen has been a cornerstone of modern outpatient COPD management since its mortality benefit was demonstrated circa 1980. Subsequently, the utility of supplemental oxygen in COPD patients with moderate resting daytime hypoxemia (SpO2 89-93%) was investigated in trials in the 1990s; however, such trials were underpowered to assess mortality benefit. Ultimately, the LOTT trial was funded by the NIH and Centers for Medicare and Medicaid Services (CMS) primarily to determine if there was a mortality benefit to supplemental oxygen in COPD patients with moderate hypoxemia as well to analyze as numerous other secondary outcomes, such as hospitalization rates and exercise performance.

The LOTT trial was originally planned to enroll 3500 patients. However, after 7 months the trial had randomized only 34 patients, and mortality had been lower than anticipated. Thus in late 2009 the trial was redesigned to include broader inclusion criteria (now patients with exercise-induced hypoxemia could qualify) and the primary endpoint was broadened from mortality to a composite of time to first hospitalization or death.

The revised LOTT trial enrolled COPD patients with moderate resting hypoxemia (SpO2 89-93%) or moderate exercise-induced desaturation during the 6-minute walk test (SpO2 ≥ 80% for ≥ 5 minutes and < 90% for ≥ 10 seconds). Patients were randomized to either supplemental oxygen (24-hour oxygen if resting SpO2 89-93%, otherwise oxygen only during sleep and exercise if the desaturation occurred only during exercise) or to usual care without supplemental oxygen. Supplemental oxygen flow rate was 2 liters per minute and could be uptitrated by protocol among patients with exercise-induced hypoxemia. The primary outcome was time to composite of first hospitalization or death. Secondary outcomes included hospitalization rates, lung function, performance on 6-minute walk test, and quality of life.

368 patients were randomized to the supplemental-oxygen group and 370 to the no-supplemental-oxygen group. Of the supplemental-oxygen group, 220 patients were prescribed 24-hour oxygen support, and 148 were prescribed oxygen for use during exercise and sleep only. Median duration of follow-up was 18.4 months. Regarding the primary outcome, there was no group difference in time to death or first hospitalization (p = 0.52 by log-rank test). See Figure 1A. Furthermore, there were no treatment-group differences in the primary outcome among patients of the following pre-specified subgroups: type of oxygen prescription, “desaturation profile,” race, sex, smoking status, SpO2 nadir during 6-minute walk, FEV1, BODE  index, SF-36 physical-component score, BMI, or history of anemia. Patients with a COPD exacerbation in the 1-2 months prior to enrollment, age 71+ at enrollment, and those with lower Quality of Well-Being Scale score at enrollment all demonstrated benefit from supplemental O2, but none of these subgroup treatment effects were sustained when the analyses were adjusted for multiple comparisons. Regarding secondary outcomes, there were no treatment-group differences in rates of all-cause hospitalizations, COPD-related hospitalizations, or non-COPD-related hospitalizations, and there were no differences in change from baseline measures of quality of life, anxiety, depression, lung function, and distance achieved in 6-minute walk.

The LOTT trial presents compelling evidence that there is no significant benefit, mortality or otherwise, of oxygen supplementation in patients with COPD and either moderate hypoxemia at rest (SpO2 > 88%) or exercise-induced hypoxemia. Although this trial’s substantial redesign in its early course is noted, the trial still is our best evidence to date about the benefit (or lack thereof) of oxygen in this patient group. As acknowledged by the authors, the trial may have had significant selection bias in referral. (Many physicians did not refer specific patients for enrollment because “they were too ill or [were believed to have benefited] from oxygen.”) Another notable limitation of this study is that nocturnal oxygen saturation was not evaluated. The authors do note that “some patients with COPD and severe nocturnal desaturation might benefit from nocturnal oxygen supplementation.”

For further contemporary contextualization of the study, please see the excellent post at PulmCCM from 11/2016. Included in that post is a link to an overview and Q&A from the NIH regarding the LOTT study.

References / Additional Reading:
1. PulmCCM, “Long-term oxygen brought no benefits for moderate hypoxemia in COPD”
2. LOTT @ 2 Minute Medicine
3. LOTT @ ClinicalTrials.gov
4. McDonald, J.H. 2014. Handbook of Biological Statistics (3rd ed.). Sparky House Publishing, Baltimore, Maryland.
5. Centers for Medicare and Medicaid Services, “Certificate of Medical Necessity CMS-484– Oxygen”
6. Ann Am Thorac Soc. 2018 Dec;15(12):1369-1381. “Optimizing Home Oxygen Therapy. An Official American Thoracic Society Workshop Report.”

Summary by Duncan F. Moore, MD

Image Credit: Patrick McAleer, CC BY-SA 2.0 UK, via Wikimedia Commons

Week 34 – PLCO

“Mortality Results from a Randomized Prostate-Cancer Screening Trial”

by the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial project team

N Engl J Med. 2009 Mar 26;360(13):1310-9. [free full text]

The use of prostate-specific-antigen (PSA) testing to screen for prostate cancer has been a contentious subject for decades. Prior to the 2009 PLCO trial, there were no high-quality prospective studies of the potential benefit of PSA testing.

The trial enrolled men ages 55-74 (excluded if hx prostate, lung, or colorectal cancer, current cancer treatment, or > 1 PSA test in the past 3 years). Patients were randomized to annual PSA testing for 6 years with annual digital rectal exam (DRE) for 4 years or to usual care. The primary outcome was the prostate-cancer-attributable death rate, and the secondary outcome was the incidence of prostate cancer.

38,343 patients were randomized to the screening group, and 38,350 were randomized to the usual-care group. Baseline characteristics were similar in both groups. Median follow-up duration was 11.5 years. Patients in the screening group were 85% compliant with PSA testing and 86% compliant with DRE. In the usual-care group, 40% of patients received a PSA test within the first year, and 52% received a PSA test by the sixth year. Cumulative DRE rates in the usual-care group were between 40-50%. By seven years, there was no significant difference in rates of death attributable to prostate cancer. There were 50 deaths in the screening group and only 44 in the usual-care group (rate ratio 1.13, 95% CI 0.75 – 1.70). At ten years, there were 92 and 82 deaths in the respective groups (rate ratio 1.11, 95% CI 0.83–1.50). By seven years, there was a higher rate of prostate cancer detection in the screening group. 2820 patients were diagnosed in the screening group, but only 2322 were diagnosed in the usual-care group (rate ratio 1.22, 95% CI 1.16–1.29). By ten years, there were 3452 and 2974 diagnoses in the respective groups (rate ratio 1.17, 95% CI 1.11–1.22). Treatment-related complications (e.g. infection, incontinence, impotence) were not reported in this study.

In summary, yearly PSA screening increased the prostate cancer diagnosis rate but did not impact prostate-cancer mortality when compared to the standard of care. However, there were relatively high rates of PSA testing in the usual-care group (40-50%). The authors cite this finding as a probable major contributor to the lack of mortality difference. Other factors that may have biased to a null result were prior PSA testing and advances in treatments for prostate cancer during the trial. Regarding the former, 44% of men in both groups had already had one or more PSA tests prior to study enrollment. Prior PSA testing likely contributed to selection bias.

PSA screening recommendations prior to this 2009 study:

      • American Urological Association and American Cancer Society – recommended annual PSA and DRE, starting at age 50 if normal risk and earlier in high-risk men
      • National Comprehensive Cancer Network: “a risk-based screening algorithm, including family history, race, and age”
      • 2008 USPSTF Guidelines: insufficient evidence to determine balance between risks/benefits of PSA testing in men younger than 75; recommended against screening in age 75+ (Grade I Recommendation)

The authors of this study conclude that their results “support the validity of the recent [2008] recommendations of the USPSTF, especially against screening all men over the age of 75.”

However, the conclusions of the European Randomized Study of Screening for Prostate Cancer (ERSPC), which was published concurrently with PLCO in NEJM, differed. In ERSPC, PSA was screened every 4 years. The authors found an increased rate of detection of prostate cancer, but, more importantly, they found that screening decreased prostate cancer mortality (adjusted rate ratio 0.80, 95% CI 0.65–0.98, p = 0.04; NNT 1410 men receiving 1.7 screening visits over 9 years). Like PLCO, this study did not report treatment harms that may have been associated with overly zealous diagnosis.

The USPSTF reexamined its PSA guidelines in 2012. Given the lack of mortality benefit in PLCO, the pitiful mortality benefit in ERSPC, and the assumed harm from over-diagnosis and excessive intervention in patients who would ultimately not succumb to prostate cancer, the USPSTF concluded that PSA-based screening for prostate cancer should not be offered (Grade D Recommendation).

In the following years, the pendulum has swung back partially toward screening. In May 2018, the USPSTF released new recommendations that encourage men ages 55-69 to have an informed discussion with their physician about potential benefits and harms of PSA-based screening (Grade C Recommendation). The USPSTF continues to recommend against screening in patients over 70 years old (Grade D).

Screening for prostate cancer remains a complex and controversial topic. Guidelines from the American Cancer Society, American Urological Association, and USPSTF vary, but ultimately all recommend shared decision-making. UpToDate has a nice summary of talking points culled from several sources.

Further Reading/References:
#. PLCO @ 2 Minute Medicine
#. ERSPC @ Wiki Journal Club
#. UpToDate, Screening for Prostate Cancer

Summary by Duncan F. Moore, MD

Image Credit: Otis Brawley, Public Domain, NIH National Cancer Institute Visuals Online

Week 33 – Varenicline vs. Bupropion and Placebo for Smoking Cessation

“Varenicline, an α2β2 Nicotinic Acetylcholine Receptor Partial Agonist, vs Sustained-Release Bupropion and Placebo for Smoking Cessation”

JAMA. 2006 Jul 5;296(1):56-63. [free full text]

Assisting our patients in smoking cessation is a fundamental aspect of outpatient internal medicine. At the time of this trial, the only approved pharmacotherapies for smoking cessation were nicotine replacement therapy and bupropion. As the α2β2 nicotinic acetylcholine receptor (nAChR) was thought to be crucial to the reinforcing effects of nicotine, it was hypothesized that a partial agonist for this receptor could yield sufficient effect to satiate cravings and minimize withdrawal symptoms but also limit the reinforcing effects of exogenous nicotine. Thus Pfizer designed this large phase 3 trial to test the efficacy of its new α2β2 nAChR partial agonist varenicline (Chantix) against the only other non-nicotine pharmacotherapy at the time (bupropion) as well as placebo.

The trial enrolled adult smokers (10+ cigarettes per day) with fewer than three months of smoking abstinence in the past year (notable exclusion criteria included numerous psychiatric and substance use comorbidities). Patients were randomized to 12 weeks of treatment with either varenicline uptitrated by day 8 to 1mg BID, bupropion SR uptitrated by day 4 to 150mg BID, or placebo BID. Patients were also given a smoking cessation self-help booklet at the index visit and encouraged to set a quit date of day 8. Patients were followed at weekly clinic visits for the first 12 weeks (treatment duration) and then a mixture of clinic and phone visits for weeks 13-52. Non-smoking status during follow-up was determined by patient self-report combined with exhaled carbon monoxide < 10ppm. The primary endpoint was the 4-week continuous abstinence rate for study weeks 9-12 (as confirmed by exhaled CO level). Secondary endpoints included the continuous abstinence rate for weeks 9-24 and for weeks 9-52.

1025 patients were randomized. Compliance was similar among the three groups and the median duration of treatment was 84 days. Loss to follow-up was similar among the three groups. CO-confirmed continuous abstinence during weeks 9-12 was 44.0% among the varenicline group vs. 17.7% among the placebo group (OR 3.85, 95% CI 2.70–5.50, p < 0.001) vs. 29.5% among the bupropion group (OR vs. varenicline group 1.93, 95% CI 1.40–2.68, p < 0.001). (OR for bupropion vs. placebo was 2.00, 95% CI 1.38–2.89, p < 0.001.)  Continuous abstinence for weeks 9-24 was 29.5% among the varenicline group vs. 10.5% among the placebo group (p < 0.001) vs. 20.7% among the bupropion group (p = 0.007). Continuous abstinence rates weeks 9-52 were 21.9% among the varenicline group vs. 8.4% among placebo group (p < 0.001) vs. 16.1% among the bupropion group (p = 0.057). Subgroup analysis of the primary outcome by sex did not yield significant differences in drug efficacy by sex.

This study demonstrated that varenicline was superior to both placebo and bupropion in facilitating smoking cessation at up to 24 weeks. At greater than 24 weeks, varenicline remained superior to placebo but was similarly efficacious as bupropion. This was a well-designed and executed large, double-blind, placebo- and active-treatment-controlled multicenter US trial. The trial was completed in April 2005 and a new drug application for varenicline (Chantix) was submitted to the FDA in November 2005. Of note, an “identically designed” (per this study’s authors), manufacturer-sponsored phase 3 trial was performed in parallel and reported very similar results in the in the same July 2006 issue of JAMA (PMID: 16820547) as the above study by Gonzales et al. These robust, positive-outcome pre-approval trials of varenicline helped the drug rapidly obtain approval in May 2006.

Per expert opinion at UpToDate, varenicline remains a preferred first-line pharmacotherapy for smoking cessation. Bupropion is a suitable, though generally less efficacious, alternative, particularly when the patient has comorbid depression. Per UpToDate, the recent (2016) EAGLES trial demonstrated that “in contrast to earlier concerns, varenicline and bupropion have no higher risk of associated adverse psychiatric effects than [nicotine replacement therapy] in smokers with comorbid psychiatric disorders.”

Further Reading/References:
1. This trial @ ClinicalTrials.gov
2. Sister trial: “Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial.” JAMA. 2006 Jul 5;296(1):56-63.
3. Chantix FDA Approval Letter 5/10/2006
4. Rigotti NA. Pharmacotherapy for smoking cessation in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. [https://www.uptodate.com/contents/pharmacotherapy-for-smoking-cessation-in-adults] (Accessed on February 16, 2019).
5. “Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomised, placebo-controlled clinical trial.” Lancet. 2016 Jun 18;387(10037):2507-20.
6. 2 Minute Medicine: “Varenicline and bupropion more effective than varenicline alone for tobacco abstinence”
7. 2 Minute Medicine: “Varenicline safe for smoking cessation in patients with stable major depressive disorder”

Summary by Duncan F. Moore, MD

Image Credit: Сергей Фатеев, CC BY-SA 3.0, via Wikimedia Commons

Week 30 – Bicarbonate and Progression of CKD

“Bicarbonate Supplementation Slows Progression of CKD and Improves Nutritional Status”

J Am Soc Nephrol. 2009 Sep;20(9):2075-84. [free full text]

Metabolic acidosis is a common complication of advanced CKD. Some animal models of CKD have suggested that worsening metabolic acidosis is associated with worsening proteinuria, tubulointerstitial fibrosis, and acceleration of decline of renal function. Short-term human studies have demonstrated that bicarbonate administration reduces protein catabolism and that metabolic acidosis is an independent risk factor for acceleration of decline of renal function. However, until this 2009 study by de Brito-Ashurst et al., there were no long-term studies demonstrating the beneficial effects of oral bicarbonate administration on CKD progression and nutritional status.

The study enrolled CKD patients with CrCl 15-30ml/min and plasma bicarbonate 16-20 mEq/L and randomized them to treatment with either sodium bicarbonate 600mg PO TID (with protocolized uptitration to achieve plasma HCO3  ≥ 23 mEq/L) for 2 years, or to routine care. The primary outcomes were: 1) the decline in CrCl at 2 years, 2) “rapid progression of renal failure” (defined as decline of CrCl > 3 ml/min per year), and 3) development of ESRD requiring dialysis. Secondary outcomes included 1) change in dietary protein intake, 2) change in normalized protein nitrogen appearance (nPNA), 3) change in serum albumin, and 4) change in mid-arm muscle circumference.

134 patients were randomized, and baseline characteristics were similar among the two groups. Serum bicarbonate levels increased significantly in the treatment arm. (See Figure 2.) At two years, CrCl decline was 1.88 ml/min in the treatment group vs. 5.93 ml/min in the control group (p < 0.01). Rapid progression of renal failure was noted in 9% of intervention group vs. 45% of the control group (RR 0.15, 95% CI 0.06–0.40, p < 0.0001, NNT = 2.8), and ESRD developed in 6.5% of the intervention group vs. 33% of the control group (RR 0.13, 95% CI 0.04–0.40, p < 0.001; NNT = 3.8). Regarding nutritional status, dietary protein intake increased in the treatment group relative to the control group (p < 0.007). Normalized protein nitrogen appearance decreased in the treatment group and increased in the control group (p < 0.002). Serum albumin increased in the treatment group but was unchanged in the control group, and mean mid-arm muscle circumference increased by 1.5 cm in the intervention group vs. no change in the control group (p < 0.03).

In conclusion, oral bicarbonate supplementation in CKD patients with metabolic acidosis reduces the rate of CrCl decline and progression to ESRD and improves nutritional status. Primarily on the basis of this study, the KDIGO 2012 guidelines for the management of CKD recommend oral bicarbonate supplementation to maintain serum bicarbonate within the normal range (23-29 mEq/L). This is a remarkably cheap and effective intervention. Importantly, the rates of adverse events, particularly worsening hypertension and increasing edema, were unchanged among the two groups. Of note, sodium bicarbonate induces much less volume expansion than a comparable sodium load of sodium chloride.

In their discussion, the authors suggest that their results support the hypothesis of Nath et al. (1985) that “compensatory changes [in the setting of metabolic acidosis] such as increased ammonia production and the resultant complement cascade activation in remnant tubules in the declining renal mass [are] injurious to the tubulointerstitium.” The hypercatabolic state of advanced CKD appears to be mitigated by bicarbonate supplementation. The authors note that “an optimum nutritional status has positive implications on the clinical outcomes of dialysis patients, whereas [protein-energy wasting] is associated with increased morbidity and mortality.”

Limitations to this trial include its open-label, no-placebo design. Also, the applicable population is limited by study exclusion criteria of morbid obesity, overt CHF, and uncontrolled HTN.

Further Reading:
1. Nath et al. “Pathophysiology of chronic tubulo-interstitial disease in rats: Interactions of dietary acid load, ammonia, and complement component-C3” (1985)
2. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (see page 89)
3. UpToDate, “Pathogenesis, consequences, and treatment of metabolic acidosis in chronic kidney disease”

Week 25 – ALLHAT

“Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs. Diuretic”

The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

JAMA. 2002 Dec 18;288(23):2981-97. [free full text]

Hypertension is a ubiquitous disease, and the cardiovascular and mortality benefits of BP control have been well described. However, as the number of available antihypertensive classes proliferated in the past several decades, a head-to-head comparison of different antihypertensive regimens was necessary to determine the optimal first-step therapy. The 2002 ALLHAT trial was a landmark trial in this effort.

Population:
33,357 patients aged 55 years or older with hypertension and at least one other coronary heart disease (CHD) risk factor (previous MI or stroke, LVH by ECG or echo, T2DM, current cigarette smoking, HDL < 35 mg/dL, or documentation of other atherosclerotic cardiovascular disease (CVD)). Notable exclusion criteria: history of hospitalization for CHF, history of treated symptomatic CHF, or known LVEF < 35%.

Intervention:
Prior antihypertensives were discontinued upon initiation of the study drug. Patients were randomized to one of three study drugs in a double-blind fashion. Study drugs and additional drugs were added in a step-wise fashion to achieve a goal BP < 140/90 mmHg.

Step 1: titrate assigned study drug

  • chlorthalidone: 12.5 –> 5 (sham titration) –> 25 mg/day
  • amlodipine: 2.5 –> 5 –>  10 mg/day
  • lisinopril: 10 –> 20 –> 40 mg/day

Step 2: add open-label agents at treating physician’s discretion (atenolol, clonidine, or reserpine)

  • atenolol: 25 to 100 mg/day
  • reserpine: 0.05 to 0.2 mg/day
  • clonidine: 0.1 to 0.3 mg BID

Step 3: add hydralazine 25 to 100 mg BID

Comparison:
Pairwise comparisons with respect to outcomes of chlorthalidone vs. either amlodipine or lisinopril. A doxazosin arm existed initially, but it was terminated early due to an excess of CV events, primarily driven by CHF.

Outcomes:
Primary –  combined fatal CAD or nonfatal MI

Secondary

  • all-cause mortality
  • fatal and nonfatal stroke
  • combined CHD (primary outcome, PCI, or hospitalized angina)
  • combined CVD (CHD, stroke, non-hospitalized treated angina, CHF [fatal, hospitalized, or treated non-hospitalized], and PAD)

Results:
Over a mean follow-up period of 4.9 years, there was no difference between the groups in either the primary outcome or all-cause mortality.

When compared with chlorthalidone at 5 years, the amlodipine and lisinopril groups had significantly higher systolic blood pressures (by 0.8 mmHg and 2 mmHg, respectively). The amlodipine group had a lower diastolic blood pressure when compared to the chlorthalidone group (0.8 mmHg).

When comparing amlodipine to chlorthalidone for the pre-specified secondary outcomes, amlodipine was associated with an increased risk of heart failure (RR 1.38; 95% CI 1.25-1.52).

When comparing lisinopril to chlorthalidone for the pre-specified secondary outcomes, lisinopril was associated with an increased risk of stroke (RR 1.15; 95% CI 1.02-1.30), combined CVD (RR 1.10; 95% CI 1.05-1.16), and heart failure (RR 1.20; 95% CI 1.09-1.34). The increased risk of stroke was mostly driven by 3 subgroups: women (RR 1.22; 95% CI 1.01-1.46), blacks (RR 1.40; 95% CI 1.17-1.68), and non-diabetics (RR 1.23; 95% CI 1.05-1.44). The increased risk of CVD was statistically significant in all subgroups except in patients aged less than 65. The increased risk of heart failure was statistically significant in all subgroups.

Discussion:
In patients with hypertension and one risk factor for CAD, chlorthalidone, lisinopril, and amlodipine performed similarly in reducing the risks of fatal CAD and nonfatal MI.

The study has several strengths: a large and diverse study population, a randomized, double-blind structure, and the rigorous evaluation of three of the most commonly prescribed “newer” classes of antihypertensives. Unfortunately, neither an ARB nor an aldosterone antagonist was included in the study. Additionally, the step-up therapies were not reflective of contemporary practice. (Instead, patients would likely be prescribed one or more of the primary study drugs.)

The ALLHAT study is one of the hallmark studies of hypertension and has played an important role in hypertension guidelines since it was published. Following the publication of ALLHAT, thiazide diuretics became widely used as first line drugs in the treatment of hypertension. The low cost of thiazides and their limited side-effect profile are particularly attractive class features. While ALLHAT looked specifically at chlorthalidone, in practice the positive findings were attributed to HCTZ, which has been more often prescribed. The authors of ALLHAT argued that the superiority of thiazides was likely a class effect, but according to the analysis at Wiki Journal Club, “there is little direct evidence that HCTZ specifically reduces the incidence of CVD among hypertensive individuals.” Furthermore, a 2006 study noted that that HCTZ has worse 24-hour BP control than chlorthalidone due to a shorter half-life. The ALLHAT authors note that “since a large proportion of participants required more than 1 drug to control their BP, it is reasonable to infer that a diuretic be included in all multi-drug regimens, if possible.” The 2017 ACC/AHA High Blood Pressure Guidelines state that, of the four thiazide diuretics on the market, chlorthalidone is preferred because of a prolonged half-life and trial-proven reduction of CVD (via the ALLHAT study).

Further Reading / References:
1. 2017 ACC Hypertension Guidelines
2. Wiki Journal Club
3. 2 Minute Medicine
4. Ernst et al, “Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure.” (2006)
5. Gillis Pharmaceuticals [https://www.youtube.com/watch?v=HOxuAtehumc]
6. Concepts in Hypertension, Volume 2 Issue 6

Summary by Ryan Commins MD

Image Credit: Kimivanil, CC BY-SA 4.0, via Wikimedia Commons