Author: Ryan Commins

Week 33 – 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 –> 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. ALLHAT @ 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
6. Concepts in Hypertension, Volume 2 Issue 6

Summary by Ryan Commins MD

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

Week 29 – CHADS2

“Validation of Clinical Classification Schemes for Predicting Stroke”

JAMA. 2001 June 13;285(22):2864-70. [free full text]
—

Atrial fibrillation is the most common cardiac arrhythmia and affects 1-2% of the overall population with increasing prevalence as people age. Atrial fibrillation also carries substantial morbidity and mortality due to the risk of stroke and thromboembolism although the risk of embolic phenomena varies widely across various subpopulations. In 2001, the only oral anticoagulation options available were warfarin and aspirin, which had relative risk reductions of 62% and 22%, respectively, consistent across these subpopulations. Clinicians felt that high risk patients should be anticoagulated, but the two common classification schemes, AFI and SPAF, were flawed. Patients were often classified as low risk in one scheme and high risk in the other. The schemes were derived retrospectively and were clinically ambiguous. Therefore, in 2001, a group of investigators combined the two existing schemes to create the CHADS2 scheme and applied it to a new data set.

Population (NRAF cohort): Hospitalized Medicare patients ages 65-95 with non-valvular AF not prescribed warfarin at hospital discharge.

Intervention: Determination of CHADS2 score (1 point for recent CHF, hypertension, age ≥ 75, and DM; 2 points for a history of stroke or TIA)

Comparison: AFI and SPAF risk schemes

Measured Outcome: Hospitalization rates for ischemic stroke (per ICD-9 codes from Medicare claims), stratified by CHADS2 / AFI / SPAF scores.

Calculated Outcome: performance of the various schemes, based on c statistic (a measure of predictive accuracy in a binary logistic regression model)

Results:
1733 patients were identified in the NRAF cohort. When compared to the AFI and SPAF trials, these patients tended be older (81 in NRAF vs. 69 in AFI vs. 69 in SPAF), have a higher burden of CHF (56% vs. 22% vs. 21%), are more likely to be female (58% vs. 34% vs. 28%), and have a history of DM (23% vs. 15% vs. 15%) or prior stroke/TIA (25% vs. 17% vs. 8%). The stroke rate was lowest in the group with a CHADS2 = 0 (1.9 per 100 patient years, adjusting for the assumption that aspirin was not taken). The stroke rate increased by a factor of approximately 1.5 for each 1-point increase in the CHADS2 score.

CHADS2 score            NRAF Adjusted Stroke Rate per 100 Patient-Years
0                                      1.9
1                                       2.8
2                                      4.0
3                                      5.9
4                                      8.5
5                                      12.5
6                                      18.2

The CHADS2 scheme had a c statistic of 0.82 compared to 0.68 for the AFI scheme and 0.74 for the SPAF scheme.

Implication/Discussion
The CHADS2 scheme provides clinicians with a scoring system to help guide decision making for anticoagulation in patients with non-valvular AF.

The authors note that the application of the CHADS2 score could be useful in several clinical scenarios. First, it easily identifies patients at low risk of stroke (CHADS2 = 0) for whom anticoagulation with warfarin would probably not provide significant benefit. The authors argue that these patients should merely be offered aspirin. Second, the CHADS2 score could facilitate medication selection based on a patient-specific risk of stroke. Third, the CHADS2 score could help clinicians make decisions regarding anticoagulation in the perioperative setting by evaluating the risk of stroke against the hemorrhagic risk of the procedure. Although the CHADS2 is no longer the preferred risk-stratification scheme, the same concepts are still applicable to the more commonly used CHA2DS2-VASc.

This study had several strengths. First, the cohort was from seven states that represented all geographic regions of the United States. Second, CHADS2 was pre-specified based on previous studies and validated using the NRAF data set. Third, the NRAF data set was obtained from actual patient chart review as opposed to purely from an administrative database. Finally, the NRAF patients were older and sicker than those of the AFI and SPAF cohorts, and thus the CHADS2 appears to be generalizable to the very large demographic of frail, elderly Medicare patients.

As CHADS2 became widely used clinically in the early 2000s, its application to other cohorts generated a large intermediate-risk group (CHADS2 = 1), which was sometimes > 60% of the cohort (though in the NRAF cohort, CHADS2 = 1 accounted for 27% of the cohort). In clinical practice, this intermediate-risk group was to be offered either warfarin or aspirin. Clearly, a clinical-risk predictor that does not provide clear guidance in over 50% of patients needs to be improved. As a result, the CHA2DS2-VASc scoring system was developed from the Birmingham 2009 scheme. When compared head-to-head in registry data, CHA2DS2-VASc more effectively discriminated stroke risk among patients with a baseline CHADS2 score of 0 to 1. Because of this, CHA2DS2-VASc is the recommended risk stratification scheme in the most recent AHA/ACC/HRS guidelines. In modern practice, anticoagulation is unnecessary when CHA2DS2-VASc score = 0, should be considered (vs. antiplatelet or no treatment) when score = 1, and is recommended when score ≥ 2.

Further Reading:
1. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation
2. CHA2DS2-VASc in Chest (2010)
3. CHADS2 @ 2 Minute Medicine

Summary by Ryan Commins, MD

Image Credit: Alisa Machalek, NIGMS/NIH – National Institute of General Medical Sciences, Public Domain, via Wikimedia Commons

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

Week 15 – CHADS2

“Validation of Clinical Classification Schemes for Predicting Stroke”

JAMA. 2001 June 13;285(22):2864-70. [free full text]
—

Atrial fibrillation is the most common cardiac arrhythmia and affects 1-2% of the overall population with increasing prevalence as people age. Atrial fibrillation also carries substantial morbidity and mortality due to the risk of stroke and thromboembolism although the risk of embolic phenomenon varies widely across various subpopulations. In 2001, the only oral anticoagulation options available were warfarin and aspirin, which had relative risk reductions of 62% and 22%, respectively, consistent across these subpopulations. Clinicians felt that high risk patients should be anticoagulated, but the two common classification schemes, AFI and SPAF, were flawed. Patients were often classified as low risk in one scheme and high risk in the other. The schemes were derived retrospectively and were clinically ambiguous. Therefore, in 2001, a group of investigators combined the two existing schemes to create the CHADS2 scheme and applied it to a new data set.

Population (NRAF cohort): Hospitalized Medicare patients ages 65-95 with non-valvular AF not prescribed warfarin at hospital discharge.

Intervention: Determination of CHADS2 score (1 point for recent CHF, hypertension, age ≥ 75, and DM; 2 points for a history of stroke or TIA)

Comparison: AFI and SPAF risk schemes

Measured Outcome: Hospitalization rates for ischemic stroke (per ICD-9 codes from Medicare claims), stratified by CHADS2 / AFI / SPAF scores.

Calculated Outcome: performance of the various schemes, based on c statistic (a measure of predictive accuracy in a binary logistic regression model)

Results:
1733 patients were identified in the NRAF cohort. When compared to the AFI and SPAF trials, these patients tended be older (81 in NRAF vs. 69 in AFI vs. 69 in SPAF), have a higher burden of CHF (56% vs. 22% vs. 21%), are more likely to be female (58% vs. 34% vs. 28%), and have a history of DM (23% vs. 15% vs. 15%) or prior stroke/TIA (25% vs. 17% vs. 8%). The stroke rate was lowest in the group with a CHADS2 = 0 (1.9 per 100 patient years, adjusting for the assumption that aspirin was not taken). The stroke rate increased by a factor of approximately 1.5 for each 1-point increase in the CHADS2 score.

CHADS2 score           NRAF Adjusted Stroke Rate per 100 Patient-Years
0                                      1.9
1                                      2.8
2                                      4.0
3                                      5.9
4                                      8.5
5                                      12.5
6                                      18.2

The CHADS2 scheme had a c statistic of 0.82 compared to 0.68 for the AFI scheme and 0.74 for the SPAF scheme.

Implication/Discussion
The CHADS2 scheme provides clinicians with a scoring system to help guide decision making for anticoagulation in patients with non-valvular AF.

The authors note that the application of the CHADS2 score could be useful in several clinical scenarios. First, it easily identifies patients at low risk of stroke (CHADS2 = 0) for whom anticoagulation with warfarin would probably not provide significant benefit. The authors argue that these patients should merely be offered aspirin. Second, the CHADS2 score could facilitate medication selection based on a patient-specific risk of stroke. Third, the CHADS2 score could help clinicians make decisions regarding anticoagulation in the perioperative setting by evaluating the risk of stroke against the hemorrhagic risk of the procedure. Although the CHADS2 is no longer the preferred risk-stratification scheme, the same concepts are still applicable to the more commonly used CHA2DS2-VASc.

This study had several strengths. First, the cohort was from seven states that represented all geographic regions of the United States. Second, CHADS2 was pre-specified based on previous studies and validated using the NRAF data set. Third, the NRAF data set was obtained from actual patient chart review as opposed to purely from an administrative database. Finally, the NRAF patients were older and sicker than those of the AFI and SPAF cohorts, and thus the CHADS2 appears to be generalizable to the very large demographic of frail, elderly Medicare patients.

As CHADS2 became widely used clinically in the early 2000s, its application to other cohorts generated a large intermediate-risk group (CHADS2 = 1), which was sometimes > 60% of the cohort (though in the NRAF cohort, CHADS2 = 1 accounted for 27% of the cohort). In clinical practice, this intermediate-risk group was to be offered either warfarin or aspirin. Clearly, a clinical-risk predictor that does not provide clear guidance in over 50% of patients needs to be improved. As a result, the CHA2DS2-VASc scoring system was developed from the Birmingham 2009 scheme. When compared head-to-head in registry data, CHA2DS2-VASc more effectively discriminated stroke risk among patients with a baseline CHADS2 score of 0 to 1. Because of this, CHA2DS2-VASc is the recommended risk stratification scheme in the AHA/ACC/HRS 2014 Practice Guideline for Atrial Fibrillation. In modern practice, anticoagulation is unnecessary when CHA2DS2-VASc score = 0, should be considered (vs. antiplatelet or no treatment) when score = 1, and is recommended when score ≥ 2.

Further Reading:
1. AHA/ACC/HRS 2014 Practice Guideline for Atrial Fibrillation
2. CHA2DS2-VASc (2010)
3. 2 Minute Medicine

Summary by Ryan Commins, MD

Image Credit: Alisa Machalek, NIGMS/NIH – National Insititue of General Medical Sciences, Public Domain

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]
—

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 20 – CHADS2

“Validation of Clinical Classification Schemes for Predicting Stroke”

JAMA. 2001 June 13;285(22):2864-70. [free full text]
—

Atrial fibrillation is the most common cardiac arrhythmia and affects 1-2% of the overall population, with increasing prevalence as people age. Atrial fibrillation also carries substantial morbidity and mortality due to the risk of stroke and thromboembolism, although the risk of embolic phenomenon varies widely across various subpopulations. In 2001, the only oral anticoagulation options available were warfarin and aspirin, which had relative risk reductions of 62% and 22%, respectively, consistent across these subpopulations. Clinicians felt that high risk patients should be anticoagulated, but the two common classification schemes, AFI and SPAF, were flawed. Patients were often classified as low risk in one scheme and high risk in the other. The schemes were derived retrospectively and were clinically ambiguous. Therefore, in 2001 a group of investigators combined the two existing schemes to create the CHADS2 scheme and applied it to a new data set.

Population (NRAF cohort): Hospitalized Medicare patients ages 65-95 with non-valvular AF not prescribed warfarin at hospital discharge. Patient records were manually abstracted by five quality improvement organizations in seven US states (California, Connecticut, Louisiana, Maine, Missouri, New Hampshire, and Vermont).

Intervention: Determination of CHADS2 score (1 point for recent CHF, hypertension, age ≥ 75, and DM; 2 points for a history of stroke or TIA)

Comparison: AFI and SPAF risk schemes

Measured Outcome: Hospitalization rates for ischemic stroke (per ICD-9 codes from Medicare claims), stratified by CHADS2 / AFI / SPAF scores.

Calculated Outcome: performance of the various schemes, based on c statistic (a measure of predictive accuracy in a binary logistic regression model)

Results:
1733 patients were identified in the NRAF cohort. When compared to the AFI and SPAF trials, these patients tended be older (81 in NRAF vs. 69 in AFI vs. 69 in SPAF), have a higher burden of CHF (56% vs. 22% vs. 21%), more likely to be female (58% vs. 34% vs. 28%), had a history of DM (23% vs. 15% vs. 15%) and prior stroke or TIA (25% vs. 17% vs. 8%). The stroke rate was lowest in the group with a CHADS2 = 0 (1.9 per 100 patient years, adjusting for the assumption that aspirin was not taken). The stroke rate increased by a factor of approximately 1.5 for each 1-point increase in the CHADS2 score.

CHADS2 score            NRAF Adjusted Stroke Rate per 100 Patient-Years
0                                      1.9
1                                      2.8
2                                      4.0
3                                      5.9
4                                      8.5
5                                      12.5
6                                      18.2

The CHADS2 scheme had a c statistic of 0.82 compared to 0.68 for the AFI scheme and 0.74 for the SPAF scheme.

Implication/Discussion
The CHADS2 scheme provides clinicians with a scoring system to help guide decision making for anticoagulation in patients with non-valvular AF.

The authors note that the application of the CHADS2 score could be useful in several clinical scenarios. First, it easily identifies patients at low risk of stroke (CHADS2 = 0) for whom anticoagulation with warfarin would probably not provide significant benefit. The authors argue that these patients should merely be offered aspirin. Second, the CHADS2 score could facilitate medication selection based on a patient-specific risk of stroke. Third, the CHADS2 score could help clinicians make decisions regarding anticoagulation in the perioperative setting by evaluating the risk of stroke against the hemorrhagic risk of the procedure. Although the CHADS2 is no longer the preferred risk-stratification scheme, the same concepts are still applicable to the more commonly used CHA2DS2-VASc.

This study had several strengths. First, the cohort was from seven states that represented all geographic regions of the United States. Second, CHADS2 was pre-specified based on previous studies and validated using the NRAF data set. Third, the NRAF data set was obtained from actual patient chart review as opposed to purely from an administrative database. Finally, the NRAF patients were older and sicker than those of the AFI and SPAF cohorts, thus the CHADS2 appears to be generalizable to the very large demographic of frail, elderly Medicare patients.

As CHADS2 became widely used clinically in the early 2000s, its application to other cohorts generated a large intermediate-risk group (CHADS2 = 1), which was sometimes > 60% of the cohort (though in the NRAF cohort, CHADS2 = 1 accounted for 27% of the cohort). In clinical practice, this intermediate-risk group was to be offered either warfarin or aspirin. Clearly, a clinical-risk predictor that does not provide clear guidance in over 50% of patients needs to be improved. As a result, the CHA2DS2-VASc scoring system was developed from the Birmingham 2009 scheme. When compared head-to-head in registry data, CHA2DS2-VASc more effectively discriminated stroke risk among patients with a baseline CHADS2 score of 0 to 1. Because of this, CHA2DS2-VASc is the recommended risk stratification scheme in the AHA/ACC/HRS 2014 Practice Guideline for Atrial Fibrillation. In modern practice, anticoagulation is unnecessary when CHA2DS2-VASc score = 0, should be considered (vs. antiplatelet or no treatment) when score = 1, and is recommended when score ≥ 2.

Further Reading:
1. AHA/ACC/HRS 2014 Practice Guideline for Atrial Fibrillation
2. CHA2DS2-VASc (2010)
3. 2 Minute Medicine

Summary by Ryan Commins, MD