The Best Time to Take Your Blood Pressure Pills

Majority of blood pressure medicines are one daily and people take their blood pressure medicines often in the morning. There have been some data based on our understanding of the diurnal variations or circadian rhythms that taking medications at bedtime may work better. For example, peak activity of the renin–angiotensin–aldosterone system (RAAS) occurs during sleep. Further, data from some uncontrolled studies have suggested that taking blood pressure medications at evening (or bedtime) may be beneficial. However, a randomized controlled clinical trial (the gold standard for scientific evidence) has been lacking. That is until now!

A recent study published in the European Heart Journal, by Hermida et al, addressed this very same question. Investigators enrolled 19 084 hypertensive patients (10 614 men and 8470 women) and assigned patients to take the entire dose of their blood pressure pills at bedtime or in the morning. Of all the patients, 1752 experienced either a death due to heart attack, heart attack without death, had stent placed in their heart blood vessels, developed new heart failure, or a stroke. Patients who were taking their medications had 45% lower risk of all outcomes combined, 56% lower risk of heart attach death, 34% lower risk of heart attack, 40% lower risk of stents in their heart blood vessels, 42% lower risk of heart failure, and 49% lower risk of stroke.

Note, these are large differences – these patients were taking their blood pressure pills but just taking pills at a different time made a huge difference. The difference is larger than many other pills that are often prescribed by physicians. If you, or your loved one, takes blood pressure pills, consider talking to your doctor if you should take your pills at bed-time.

Fragility Index for Randomized Controlled Trials

An interesting question – how ‘fragile’ are the results of a randomized controlled trial (RCT)?

RCTs are gold-standard for determining the efficacy of a treatment. RCTs randomly assigned patients to an intervention arm or to a placebo (or standard of care or active treatment) arm. Because patients are randomly assigned, we expect that all patient characteristics (genetic, environmental etc.) would be balanced in the two groups. RCTs are often published with significant results – small RCTs without significant results are generally either not published or published in low-tier journals and don’t get prominence

Even when we randomly assign patients to a treatment arm or control arm, there is always a possibility that the two arm may be imbalanced by chance on measured or unmeasured variables. Further, it is also possible that just by chance one group may have statistically significant result than the other group without any true benefit (or harm) of the treatment. While we generally use a p-value of less than 0.05 (which says that there is a 1 in 20 probability that the results are observed due to chance only – not the right definition but its simple!), there remains a small chance that results will be not significant.

In comes ‘Fragility Index’, a measure of determining the robustness of results. Fragility index is the minimum number of patients who must be moved from the nonevent group to the event group to turn a significant result nonsignificant. The fragility index is an easy to calculate index that provides an intuitive way to understand the precision of trial results. Knowing the fragility index and comparing it to the number of patients lost to follow-up can help to understand the uncertainty in evidence even when a study has positive results.

Khan et al, examined cardiovascular clinical trials published between 2007-17 in major Cardiology journals. All trials were large with >500 patient enrollment. Among the 123 RCTs the median fragility index was 13.In almost 1/3rd of trials, the number of patients lost to follow-up was more than the fragility index.

In another study Gaudino et al examined the clinical trials used to support evidence in cardiology guidelines and determined the fragility index. They found that more than a quarter of RCTs supporting current guidelines on myocardial revascularization have a fragility index 3 or lower. Further over 40% of trials had a fragility index which was lower than the number of patients lost to follow-up.

Anti-platelet Drugs after Coronary Intervention

The type and duration of anti-platelet therapy after cardiac catheterization and stent placement (also called percutaneous coronary intervention or PCI) is an ongoing debate.

There are two main groups of drugs. One is aspirin which is under use for over 100 years and we know a lot about it. The other group is P2Y12 blockers. P2Y12 is a receptor on the surface of platelets and these drugs block this receptor. The most well-known drug in this group is clopidogrel or Plavix.

A Japanese study examined the role of aspirin + clopidogrel for one month followed by 12-months of clopidogrel versus aspirin + clopidogrel for 12 months showed that the earlier strategy was superior. In contrast, a Korean study, also published in JAMA, found that there is no statistically significant difference between the two.

The results may appear different and the reason my be that the two studies were somewhat different. Below are some of the differences:

1. Korean study allowed the use of other P2Y12 inhibitors/blockers such as prasugrel or ticagrelor while Japanese study allowed on clopidogrel.

2. Korean study had lower adherence to drug therapy in the P2Y12 group as compared to combined group (79% vs. 95%).

3. P2Y12 inhibitors were given for 3-months in the first group in Korean study while Japanese study had for 1-month only.

Despite these somewhat difference results, the overall message is the same. Patients may have similar outcomes when given clopidogrel (or other P2Y12 inhibitors) alone after an initial period of combined therapy with aspirin. This may be a particularly good news for those patients who are at higher risk of bleeding.

Anti-platelet Therapy after Cardiac Stent Placement

The type and duration of anti-platelet therapy after cardiac catheterization and stent placement (also called percutaneous coronary intervention or PCI) is an ongoing debate. Aspirin is under use for over 100 years and we know a lot about it. Plus, it is a cheaper drug. Clopidogrel, better known by its market name Plavix, is now in marker for many years and its generic versions are available. Almost all studies have examined the use of additional anti-platelet drugs after PCI on top of aspirin use. What if we examine the use of anti-platelet drugs on top of clopidogrel use?

A study published in JAMA examined this question in a multi-center, open-label, randomized clinical trial conducted in Japan. They enrolled 3045 patients to either 1 month of aspirin + clopidogrel therapy followed by clopidogrel therapy alone versus 12 months of aspirin + clopidogrel therapy. The outcome they were looking at was a combined outcome of cardiovascular death, myocardial infarction, stroke (ischemic or hemorrhagic), stent thrombosis, or bleeding.

I am certain that authors were hoping for finding that the two treatments were similar. To their surprise, not only 1-month of aspirin + clopidogrel followed by clopidogrel alone was similar in efficacy but was superior to the 12-months of aspirin + clopidogrel (2.35% vs. 3.70%; P<0.001). In other words, a shorter duration of combined therapy followed by clopidogrel therapy is as effective, if not better, than 12-months of combined therapy. These findings are important especially for patients who are at high risk of bleeding.

Aspirin and Body Weight

Low dose aspirin has been shown to reduce cardiovascular events but the observed effect may vary by weight. In fact, in one of our studies, we have shown that not only obese individuals had greater baseline platelet reactivity, they also had greater residual platelet reactivity after low-dose aspirin therapy. Comparing obese and nonobese individuals after aspirin therapy, results for aggregometry to collagen were 6.7 vs 6.1 ohms, P=.008; aggregometry to adenosine diphosphate were 13.1 vs 11.8 ohms,P<.0001; aggregometry to arachidonic acid (AA) were 4.9% vs 8.3% nonzero aggregation, P=.002; urinary excretion of 11-dehydro-thromboxane B2 (Tx-M) were 4.9% vs 8.3% nonzero aggregation, P=.002; and aspirin resistance were 26.% vs 20.5%, P=.002; respectively.

Now an individual-patient meta-analysis of primary prevention randomized controlled trials with low-dose aspirin have shown that clinical outcomes are also different in patients with weight>70Kg than in patients with weight<70Kg. On the other hand, when a higher dose of aspirin was examined, individuals with weight>70Kg obtained clinical benefits. Clinical benefits were not limited to cardiovascular outcomes but also included colorectal outcomes.

An obvious implication of such studies is that individuals with weight>70Kg should take perhaps more than one baby aspirin to receive benefit from aspirin.

Diabetes and Risk of Cancer

Patients with diabetes mellitus are at increased risk of cardiovascular complications such as heart attack, stroke, peripheral arterial disease etc. Commonly, the cause of death in diabetes is due to cardiovascular events.

Does diabetes increases risk of cancer in addition of increased risk of cardiovascular diseases? This important question was explored in this interesting study of over half-million Chinese. Investigators enrolled patients with and without diabetes and without any prior diagnosis in the study between 2004-2008 and then followed them until the end of 2013 for development of any cancer. During the follow-up period, they found more than 17,000 cases of cancer. Diabetes was associated with an increased risk of all-cause cancer and site-specific cancer.

Diabetes increased the risk of overall cancer by 13%, of liver cancer by 51%, of the pancreatic cancer by 76% and of the breast cancer by 21%. Investigators further reported that higher random blood glucose levels were associated with increased risk of cancer. Perhaps, it is the elevated blood glucose levels in diabetics that is responsible for cancer.

Geographic Latitude, Blood Pressure, and Serum Cholesterol

This is a provocative study pointing out the association of geographic latitude with serum cholesterol levels. Obviously such studies, at country level, are fraught with biases including ecological fallacy. However, the underlying etiology of the observed differences need to be explored further.

Updated Guidelines - Diabetics and Cardiovascular Disease

American Heart Association and American Diabetes Association has recently published an update to the guidelines for the prevention of cardiovascular disease in adults with type 2 diabetes mellitus. There are certain interesting aspects to it.

1. Use of Hemoglobin A_1C for the diagnosis of diabetes mellitus
 Pre-diabetes = A_1C between 5.7% and 6.4%
Diabetes Mellitus = A_1C >/= 6.5%

2. Lifestyle Management of Diabetes
Physical Activity
Nutrition
Weight Reduction (through physical activity, nutrition, weight-loss drugs, and/or bariatric surgery)

3. Cardiovascular risk reduction
Control of blood glucose (A_1C <7%)
Control of blood pressure (< 140/90)
Control of Cholesterol (statins)
Aspirin for moderate 10-year CVD risk (5-10%)

4. Screening for cardiovascular diseases in asymptomatic patients
Paucity of data suggesting any specific benefits of invasive interventions over medical therapy alone makes any CAD screening in the asymptomatic patient with diabetes mellitus highly controversial.

Life Expectancy After Myocardial Infarction

This study examines sex and race differences in long-term survival after AMI using life expectancy and YPLL to account for differences in population-based life expectancy. Investigators used the Cooperative Cardiovascular Project, a prospective cohort study of Medicare beneficiaries hospitalized for AMI between 1994 and 1995 (N = 146,743).

Investigators found that the life expectancy estimates after myocardial infarction were similar for men and women of the same race but lower for black patients than white patients.

Below is a figure from the manuscript summarizing the findings

Greater Collagen-Induced Platelet Aggregation Following Cyclooxygenase 1 Inhibition Predicts Incident Acute Coronary Syndromes

Platelets have several pathways that initiate aggregation such as thrombin-, collagen-, thromboxane-, and ADP-mediated pathways. Individuals vary widely in their ability to have platelet aggregation through each of these pathways. Furthermore, this variability is not correlated. In other words, an individual may have low aggregation though one pathway but may have high aggregation through another pathway. This phenomenon may be more important when we try to measure platelet aggregation the laboratory to assess whether there is increased risk of in vivo platelet aggregation (and hence cardiovascular events).

Collagen is one of the first agonists that initiates platelet aggregation at the site of vessel wall injury. Therefore, examining an association of collagen-mediated platelet aggregation with subsequent cardiovascular events makes sense. Moreover, if we can decrease variability in platelet aggregation by blocking one or another pathway, we may be better able to assess activation through collagen pathway.

Aspirin is commonly used for prevention of cardiovascular disease and works by inhibiting thromboxane-pathway an dis very effective in completely inhibiting activity through this pathway. Thus aspirin can be used to inhibit variability through one pathway and effect of collagen can be studied with fewer interactions. We followed the same logic in this paper where we examined platelet aggregation after 2-week aspirin therapy in healthy individuals. Most of these individuals did not use aspirin after the 2-week study period. During follow-up increased collagen-mediated platelet aggregation was significantly associated with acute coronary syndrome.

“After COX1 pathway inhibition, collagen-induced aggregation was significantly greater in participants with ACS compared with those without (29.0 vs. 23.6 ohms, p < 0.001). In Cox proportional hazards models, this association remained significant after adjusting for traditional cardiovascular risk factors (HR = 1.10, 95%CI = 1.06-1.15; p < 0.001).”