Month: January 2018

Week 30 – Omeprazole for Bleeding Peptic Ulcers

“Effect of Intravenous Omeprazole on Recurrent Bleeding After Endoscopic Treatment of Bleeding Peptic Ulcers”

N Engl J Med. 2000 Aug 3;343(5):310-6. [free full text]
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Intravenous proton-pump inhibitor (PPI) therapy is a cornerstone of modern therapy for bleeding peptic ulcers. However, prior to this 2000 study by Lau et al., the role of PPIs in the prevention of recurrent bleeding after endoscopic treatment was unclear. At the time, re-bleeding rates after endoscopic treatment were noted to be approximately 15-20%. Although other studies had approached this question, no high-quality, large, blinded RCT had examined adjuvant PPI use immediately following endoscopic treatment.

Population: patients with bleeding gastroduodenal ulcer visualized on endoscopy in whom hemostasis was achieved following epinephrine injection and thermocoagulation (consecutive patients, single center in Hong Kong)

Intervention: omeprazole 80mg IV bolus followed by 8mg/hr infusion x72 hrs, followed by omeprazole 20mg PO x8 wks

Comparison: placebo bolus + drip x72 hrs, followed by omeprazole 20mg PO x8 wks

Outcome:
Primary – Recurrent bleeding within 30 days

Secondary

  1. Recurrent bleeding within 72 hrs
  2. Mean number of units of blood transfused within 30 days
  3. Duration of hospitalization
  4. All-cause mortality at 30 days


Results:
120 patients were randomized to each arm. The two groups had similar baseline characteristics, including ulcer-specific characteristics. The trial was terminated early due to the finding on interim analysis of a significantly lower recurrent bleeding rate in the omeprazole arm.

Bleeding re-occurred within 30 days in 8 (6.7%) omeprazole patients versus 27 (22.5%) placebo patients (HR 3.9, 95% CI 1.7-9.0; NNT 6.3). A Cox proportional-hazards model, when adjusted for size and location of ulcers, presence/absence of coexisting illness, and history of ulcer disease, revealed a similar hazard ratio (HR 3.9, 95% CI 1.7-9.1).

Recurrent bleeding was most common during the first 72 hrs (4.2% of the omeprazole group versus 20% of the placebo group, RR 4.80, 95% CI 1.89-12.2, p<0.001). For a nice visualization of the early separation of re-bleeding rates, see the Kaplan-Meier curve in Figure 1.

The mean number of units of blood transfused within 30 days was 2.7 ± 2.5 in the omeprazole group versus 3.5 ± 3.8 in the placebo group (p = 0.04). The number of units transfused after the initial endoscopic treatment was 1.7 ± 1.9 in the omeprazole group versus 2.4 ± 3.2 in the placebo group (p = 0.03).

Regarding duration of hospitalization, 46.7% of omeprazole patients were admitted for < 5 days versus 31.7% of placebo patients (p = 0.02). Median stay was 4 days in the omeprazole group versus 5 days in the placebo group (p = 0.006).

4.2% of the omeprazole patients died within 30 days, whereas 10% of the placebo patients died (p = 0.13).

Implication/Discussion:
Treatment with intravenous omeprazole immediately following endoscopic intervention for bleeding peptic ulcer significantly reduced the rate of recurrent bleeding. This effect was most prominent within the first 3 days of therapy. This intervention also reduced blood transfusion requirements and shortened hospital stays.

The presumed mechanism of action is increased gastric pH facilitating platelet aggregation.

In 2018, the benefit of this intervention seems so obvious based on its description alone, that one would imagine that such a trial would not be funded or published in such a high-profile journal. However, the annals of medicine are littered with now-discarded interventions that made sense from a theoretical or mechanistic perspective but were demonstrated to be ineffective or even harmful (e.g. pharmacologic suppression of ventricular arrhythmias post-MI or renal denervation for refractory HTN).

Today, bleeding peptic ulcers are treated with an IV PPI twice daily. Per UpToDate, meta-analyses have not shown a benefit of continuous PPI infusion over this IV BID dosing. However, per 2012 guidelines in the American Journal of Gastroenterology, patients with active bleeding or non-bleeding visible vessels should receive both endoscopic intervention and IV PPI bolus followed by infusion.


Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. UpToDate, “Overview of the Treatment of Bleeding Peptic Ulcers”
4. Laine L, Jensen DM. “Management of patients with ulcer bleeding.” Am J Gastroenterol. 2012.

Summary by Duncan F. Moore, MD

Week 29 – 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]
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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 –> (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

Week 28 – SOLVD

“Effect of Enalapril on Survival in Patients with Reduced Left Ventricular Ejection Fractions and Congestive Heart Failure”

by the Studies of Left Ventricular Dysfunction (SOLVD) Investigators

N Engl J Med. 1991 Aug 1;325(5):293-302. [free full text]
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Heart failure with reduced ejection fraction (HFrEF) is a very common and highly morbid condition. We now know that blockade of the renin-angiotensin-aldosterone system (RAAS) with an ACEi or ARB is a cornerstone of modern HFrEF treatment. The 1991 SOLVD trial played an integral part in demonstrating the benefit of and broadening the indication for RAAS blockade in HFrEF.

Population: patients with HFrEF and LVEF ≤ 35%, already on treatment, not on an ACEi, and Cr ≤ 2.0

Intervention: treatment with enalapril BID, starting at 2.5mg, uptitrated as tolerated to 20mg BID

Comparison: treatment with placebo BID, starting at 2.5mg, uptitrated as tolerated to 20mg BID

(There was a single-blind run-in period with enalapril in all patients, followed by a single-blind placebo run-in period. Finally, the patient was randomized to his/her actual study drug in a double-blind fashion.)

Outcome:

Primary

  1. All-cause mortality
  2. Death or hospitalization for CHF

Secondary

  1. Hospitalization for CHF
  2. All-cause hospitalization
  3. Cardiovascular mortality
  4. Heat failure mortality

 

Results:
2569 patients were enrolled. Baseline characteristics were similar among the two groups. Follow-up duration ranged from 22 to 55 months.

510 (39.7%) placebo patients died during follow-up compared to 452 (35.2%) enalapril patients (relative risk reduction of 16% per log-rank test, 95% CI 5-26% RRR, p = 0.0036). See Figure 1 for the relevant Kaplan-Meier curves.

736 (57.3%) placebo patients died or were hospitalized for CHF during follow-up compared to 613 (47.7%) enalapril patients (relative risk reduction 26%, 95% CI 18-34, p < 0.0001).

There were 971 hospitalizations for heart failure in the placebo group but only 683 in the enalapril group. (Many patients who ultimately died of CHF were hospitalized multiple times prior to death.) 950 placebo patients were hospitalized for any reason versus 893 enalapril patients (p = 0.006).

There were 461 cardiovascular deaths in the placebo group but only 399 in the enalapril group (relative risk reduction 18%, 95% CI 6-28%). There were 251 deaths due to heart failure in the placebo group, but only 209 in the enalapril group (relative risk reduction 22%, 95% CI 6-35%).

Regarding subgroup analysis, the authors point to Figure 4 and note that “the effects of enalapril were consistent among most…subgroups.”

320 placebo patients discontinued the study drug versus only 182 patients in the enalapril group. 82% of placebo patients and 87% of enalapril patients reported side effects. Enalapril patients were significantly more likely to report dizziness, fainting, and cough. There was no difference the prevalence of angioedema.


Implication/Discussion:
Treatment of HFrEF with enalapril significantly reduced mortality and hospitalizations for heart failure. The authors note that for every 1000 study patients treated with enalapril, approximately 50 premature deaths and 350 heart failure hospitalizations are averted. The mortality benefit of enalapril appears to be immediate and increases for approximately 24 months.

Per the authors, “reductions in deaths and rates of hospitalization from worsening heart failure may be related to improvements in ejection fraction and exercise capacity, to a decrease in signs and symptoms of congestion, and also to the known mechanism of action of the agent – i.e., a decrease in preload and afterload when the conversion of angiotensin I to angiotensin II is blocked.”

Strengths of this study include its double-blind, randomized design, large sample size, and long follow-up. The fact that the run-in period allowed for the exclusion prior to randomization of patients who did not immediately tolerate enalapril is a major limitation of this study.

Prior to SOLVD, studies of ACEi in HFrEF had focused on patients with severe symptoms. The 1987 CONSENSUS trial was limited to patients with NYHA class IV symptoms. SOLVD broadened the indication of ACEi treatment to a wider group of symptoms and correlating EFs.

Per the current 2013 ACCF/AHA guidelines for the management of heart failure, ACEi/ARB therapy is a Class I recommendation in all patients with HFrEF in order to reduce morbidity and mortality.

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. Effects of enalapril on mortality in severe congestive heart failure – Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). 1987
4. 2013 ACCF/AHA guideline for the management of heart failure: executive summary

Summary by Duncan F. Moore, MD

Week 27 – UPLIFT

“A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease”

by the Understanding Potential Impacts on Function with Tiotropium (UPLIFT) investigators

N Engl J Med. 2008 October 9; 359(15):1543-1554 [free full text]
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The 2008 UPLIFT trial was a four-year, randomized, double-blind, prospective study investigating whether or not tiotropium could reduce the rate of decline of FEV1 (a common metric for COPD progression).  A previous retrospective study had shown a reduced rate of FEV1 decline at one year with daily tiotropium. However, this finding had not been shown in any prospective study. As of 2008, smoking cessation was the only intervention demonstrated prospectively to decrease the rate of decline in FEV1.

Population:  Patients were selected from 490 investigational centers in 37 countries

Inclusion: COPD, age ≥ 40, ≥ 10 pack-year smoking history, post-bronchodilator FEV1 ≤70% of predicted value, and FEV1/FVC ≤70%

Exclusion: history of asthma, COPD exacerbation or respiratory infection within the past 4 weeks, history of pulmonary resection, or use of supplemental O2 for more than 12 hours per day

Intervention: daily tiotropium 18mcg + usual respiratory medications

Control: daily placebo + usual respiratory medications

(Of note, in both arms, the usual respiratory medications could not include an anticholinergic.)

Outcomes:

Co-primary:

  • Rate of decline in mean FEV1 before bronchodilation
  • Rate of decline in mean FEV1 after bronchodilation

Secondary:

  • Rate of decline in FVC
  • Quality of life as measured by St. George’s Respiratory Questionnaire (SGRQ, ranges 0-100 with lower scores indicating improved quality)
  • Rate of COPD exacerbations
  • All-cause mortality

Results:
2987 patients were assigned to receive tiotropium, and 3006 were assigned to receive placebo. Baseline characteristics were similar between the two groups. 44.6% of placebo and 36.2% of tiotropium patients did not complete at least 45 months of treatment.

The primary outcomes of decline in mean FEV1 either before or after bronchodilation were not significantly different between the two groups. Before bronchodilation, the difference in mean decline was 0 ml/year (p=0.95). After bronchodilation, the mean decline with tiotropium was 2 ml/year less than with placebo (p=0.21)

Regarding secondary outcomes:
There was no significant difference in rate of decline of FVC. The SGRQ was significantly lower (better) at all time points in the tiotropium group and, on average, was 2.7 points lower than in the placebo group (95% CI 2.0-3.3, p<0.001). The number of COPD exacerbations per year in the tiotropium group was 0.73 vs. 0.85 in the placebo group (RR 0.86, 95% CI 0.81-0.91; p<0.001), and the median time to first exacerbation was longer in the tiotropium group (16.7 months vs. 12.5 months, 95% CI 11.5-13.8,). All-cause mortality was not significantly different among the two groups (14.9% vs. 16.5%, HR 0.89; 95% CI 0.79-1.02; p=0.09). Respiratory failure developed in 88 patients in the tiotropium group vs. 120 in the placebo group (RR 0.67, 95% CI 0.51 to 0.89).

Discussion:
The UPLIFT study demonstrated no significant change in rate of decline in FEV1 with tiotropium therapy compared to placebo. However, tiotropium therapy improved quality of life and reduced the frequency of COPD exacerbations and respiratory failure. Overall, this study is an excellent example how a well-designed prospective study can overturn the results of prior retrospective analyses.

The authors offered three potential reasons for the lack of difference in rate of FEV1 decline among the groups. First, tiotropium may not actually alter the decline of lung function in COPD. Second, since both groups were permitted any respiratory medications other than another anticholinergic, there may have been a “ceiling effect” reached by the alternative medications, and thus no additional benefit offered by tiotropium therapy. Third, the authors noted the placebo group dropouts tended to be have more severe COPD, and so the remaining “healthy survivor” patients may have biased the group differences toward a null result.

Limitations of this study include a high dropout rate in both groups as well as a large male predominance (~75%) that limits generalizability. Finally, the limited clinical benefits of daily tiotropium use are not likely to be cost-effective. In 2010, researchers applied the treatment effects demonstrated in UPLIFT to an observational dataset of 56,321 tiotropium users in Belgium and estimated an average cost of 1.2 million euros per quality-adjusted life year (QALY) gained.

Further Reading/References:
1. Wiki Journal Club
2. 2 Minute Medicine
3. Neyt et al., “Tiotropium’s cost-effectiveness for the treatment of COPD: a cost-utility analysis under real-world conditions” (2010)

Summary by Gordon Pelegrin, MD